Synthesis and antimicrobial activity of some novel 2-thienyl substituted heterocycles

Article abstract of DOI:10.1515/hc-2013-0197

A series of 2-thienyl substituted derivatives of thiazoles, oxazoles and spiro(indole-azole) were synthesized. The structures of the synthesized compounds were confirmed by IR, NMR and mass spectral data.

Full text of DOI:10.1515/hc-2013-0197

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2014; 20(1): 25–31
DOI 10.1515/hc-2013-0197ꢀ
Mohamed Salah K. Youssef and Ahmed Abdou O. Abeed*
Synthesis and antimicrobial activity of some novel
2-thienyl substituted heterocycles
Abstract: A series of 2-thienyl substituted derivatives of obtained by heating of 2 with acetic anhydride in pyri-
thiazoles, oxazoles and spiro(indole-azole) were synthe- dine. The structure of 4 was confirmed by IR, NMR and
sized. The structures of the synthesized compounds were mass spectral analyses.
confirmed by IR, NMR and mass spectral data.
The reaction of thiosemicarbazone 2 with ethyl chlo-
roacetate, chloroacetamide or chloroacetone afforded
Keywords: 2-acetylthiophene; antimicrobial activity; MIC; the thiazolidinones 5 and 6. It is of interest to mention
spiro; thiazolidines.
that the products of reacting 2 with ethyl chloroacetate
or chloroacetamide were identical. The IR spectrum of 5
contains bands at ν 3120 cm-1 due to NH function and the
*Corresponding author: Ahmed Abdou O. Abeed, Faculty of Science,
Chemistry Department, Assiut University, Assiut 71516, Egypt,
e-mail: ahmed_abeed76@yahoo.com
Mohamed Salah K. Youssef: Faculty of Science, Chemistry
Department, Assiut University, Assiut 71516, Egypt
1
Cꢀ= ꢀO band of the thiazolidine ring at ν 1720 cm-1. The H
NMR spectrum shows methylene protons signals of the
thiazolidine function and NH signals at 3.82 and 11.93
ppm, respectively. The 13C NMR spectrum of 5 is also
consistent with the given structure. Compound 5 con-
tains active methylene group. As such, it was condensed
with aromatic aldehydes and D-glucose in the presence
of piperidine to yield the arylidenes 7a–d. Subjecting
the prepared aldehydo-hexose chalcone 7d to acetyla-
tion using a mixture of acetic anhydride and pyridine
Introduction
Thiophene derivatives are important compounds [1–8]
with considerable biological activity, such as antimicro-
bial [9, 10], anti-inflammatory and analgesic activities
[11–14]. Spiroindoles possessing a stereogenic center at C-3
[15, 16] and thiazolidine derivatives have also wide appli-
cations in synthetic and medicinal chemistry [17–21]. In
view of the above mentioned findings and as continuation
of our efforts in the synthesis of new biologically active
heterocycles [22, 23]. We report herein the synthesis of
thiazolidines and spiroindoles linked to thiophene and
evaluation of their antimicrobial activities.
1
gave the crystalline product 8. The H NMR spectrum of
8 contains signals for five OAc groups in the range of δ
2.30–2.60 ppm. These acetyl groups show a characteris-
tic absorption band around ν 1670 cm-1 in the IR spectrum
(Scheme 1).
Condensation of 1 with malononitrile in the presence
of morpholine led to the formation of dicyanoethylidene
derivative 9. The IR spectrum of 9 shows a strong band
at ν 2200 cm-1 for two cyano groups. Treatment of 9 with
phenylhydrazine in boiling ethanol furnished one isolable
product for which structures 10, 11 and 12 seemed possi-
ble (Scheme 2). The IR spectrum of the isolated product
shows a lack of the CN absorption band and the presence
of absorption band at 3385 cm-1 for an NH group. Fur-
Results and discussion
1
thermore, the H NMR spectrum contains a broad singlet
Chemistry
signal at 7.90 ppm (D2O exchangeable) for the NH proton.
These findings provide firm support for the structure 12
The reaction of 2-acetylthiophene (1) with thiosemicar- and exclude the pyrazoline derivative 10. The structure of
bazide afforded 1-(thiophen-2-yl)ethanone thiosemicar- 12 was supported by its independent synthesis as shown
bazone (2) according to a previously described method in Scheme 2.
[24]. Treatment of the thiosemicarbazone 2 with freshly
The chalcone 14 was prepared according to a pre-
distilled acetic anhydride gave ethylidene thiosemicar- viously described method [25]. Hydrazinolysis of 14 in
bazide derivative 3. Compound 3 was cyclized by heating ethanol yielded spiro[indole-pyrazole]-2(1H)-one 15.
to give 5-acetamidothiazolidine 4. Compound 4 was also Otherwise, the hydrazinolysis in acetic acid gave the
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ꢁꢁꢁꢂ
26ꢀ
ꢀM.S.K. Youssef and A.A.O. Abeed: 2-Thienyl substituted heterocycles
Me
S
O
1
Me
N
Ac2O
ClCH2CONH2
S
CSNHAc
or
EtOH NH2NNHCSNH2
N
O
Me
N
3
ClCH2COOEt
Ac
HN
S
Me
N
EtOH, AcONa
Fusion
176°C, 10 min.
S
S
5
NNHCSNH2
2
RCHO
EtOH, piperidine
Ac2O
Me
S
ClCH2COMe
EtOH, AcONa
pyridine
S
HN
Ac
O
N
Me
N
N
4
HN
Ac
S
R
N
Me
Me
S
HN
7a-d
S
N
N
S
Ac2O
for 7d
6
7a: R = Ph
7b: R = 4-Cl(C6H4)
7c
Me
Ac
N
O
AcO
AcO
OAc
AcO
OAc
S
: R = 4-NO2(C6H4)
7d: R = (CHOH)4CH2OH
N
N
S
8
Scheme 1ꢀ
acetyl derivative 16. The presence of acetyl group in the
product 16 was established using IR and 1H NMR spectra.
The reaction of 14 with hydroxylamine in ethanol
containing AcONa produced spiro[indole-oxazole]-
Antimicrobial evaluation
Antibacterial evaluation
2(1H)-one 17. Finally, phenyl-substituted spiro[indole- All compounds were screened for their antibacterial activi-
pyrazole]-2(1H)-one 18 was obtained by condensation of ties against Gram-positive bacteria (Staphylococcus aureus
chalcone 14 with phenylhydrazine. Analytical and spec- AUMC B-54, Micrococcus luteus AUMC B-112, Bacillus cereus
1
tral data (IR, H NMR, 13C NMR and EI-MS) confirmed AUMC B-52, Escherichia coli AUMC B-53, Pseudomonas
the structures of the synthesized compounds 17 and 18 aeruginosa AUMC B-73, Serratia marcescens AUMC B-55).
(Scheme 3).
Chloramphenicol was used as the reference (Table 1). The
minimum inhibitory concentrations (MICs) were recorded.
All compounds exhibit significant antibacterial activities.
Thiazolidinones 7b–d and phenyl substituted spiro[indole-
pyrazole]-2-one 18 are remarkably active against the tested
antibacterial species at the MIC range of 5–41 μg/mL. Sub-
stitution of hydrogen atom at para position of the aromatic
ring in compounds 7a–c by a chlorine atom, or nitro group
results in increasing of the antibacterial activity.
Ph
HN
N
N
S
NH2
10
Me
NC
Me
CH2(CN)2
EtOH, morpholine
PhNHNH2
1
CN
S
9
Antifungal evaluation
NHNHPh
CN
PhNHNH2
EtOH
The compounds were also screened for their antifungal
activities against six antifungal species, Candida albicans
AUMC 1299, Geotrichum candidum AUMC 226, Fusarium
oxysporum AUMC 5119, Aspergillus flavus AUMC 1276,
Trichophyton rubrum AUMC 1804 and Scopulariopsis
NNHPh
S
- CH2(CN)2
S
Me
Me
CN
12
11
Scheme 2ꢀ
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M.S.K. Youssef and A.A.O. Abeed: 2-Thienyl substituted heterocyclesꢀ
ꢀ27
1
O
EtOH, TEA
O
N
H
O
OH
S
13
O
N
H
Ph
N
O
N
N
O
NH
S
NH2NH2
EtOH
PhNHNH2
EtOH
S
HCl, AcOH
N
N
18
15
H
H
O
S
NH
14
N
O
Ac
N
O
O
N
S
NH2NH2
AcOH
NH2OH
S
HCl
N
H
AcONa, EtOH
N
O
17
16
H
Scheme 3ꢀ
Table 1ꢁThe antibacterial activity of the synthesized compounds, MIC (μg/mL).
No. ꢂ
S. aureus
(Gram+)
ꢂ M. luteus
(Gram+)
ꢂ B. cereus
(Gram+)
ꢂ
E. coli
(Gram-)
ꢂ P. aeruginosa
ꢂ S. marcescens
(Gram-)
(Gram-)
2
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
130
125
65
78
72
49
21.5
10
5
10
74
15
50
70
48
30
42
34
10
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
100
90
60
78
68
60
41
30
20
11
–
38
49
60
50
41
28
20
10
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
50
20
15
17
20
15
10
10
5
10
37
52
30
60
50
40
49
28
10
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
64
38.5
30
35
34
25
20
15
10
–
29
48
55
100
80
64
35
30
10
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
100
80
55
72
72
59
30
20
10
90
19
125
80
120
79
51
46
40
10
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
70
34.5
25
30
28
15
11
10
5
20
40
10
22
50
42
30
27
17
4.5
3
4
5
6
7a
7b
7c
7d
8
9
12
13
14
15
16
17
18
Ref.aꢃ
aChloramphenicol was used as antibacterial standard. –, no activity.
brevicaulis AUMC 361. As shown in Table 2, most of the
tested compounds are active. The spiro compounds
Conclusion
15–18 show strong antifungal activities in comparison to A novel series of thiazolidines and spiro(indole-azole)
chalcone 14.
derivatives was synthesized. The antimicrobial activity of
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ꢁꢁꢁꢂ
28ꢀ ꢀM.S.K. Youssef and A.A.O. Abeed: 2-Thienyl substituted heterocycles
Table 2ꢁThe antifungal activity of the synthesized compounds, MIC (μg/mL).
No. ꢂ
C. albicansꢂ
G. candidumꢂ
T. rubrumꢂ
F. oxysporumꢂ
A. flavusꢂ
S. brevicaulis
2
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
110ꢃ
20ꢃ
15ꢃ
20ꢃ
21ꢃ
12ꢃ
10ꢃ
8ꢃ
120ꢃ
80ꢃ
62ꢃ
65ꢃ
56ꢃ
46ꢃ
41ꢃ
25ꢃ
15ꢃ
40ꢃ
–ꢃ
35ꢃ
55ꢃ
72ꢃ
62ꢃ
50ꢃ
42ꢃ
40ꢃ
20ꢃ
100ꢃ
34ꢃ
20ꢃ
32ꢃ
30ꢃ
20ꢃ
15ꢃ
10ꢃ
10ꢃ
26ꢃ
–ꢃ
30ꢃ
64ꢃ
95ꢃ
73ꢃ
61ꢃ
49ꢃ
45ꢃ
10ꢃ
90ꢃ
100ꢃ
80ꢃ
96ꢃ
78ꢃ
58ꢃ
47ꢃ
25ꢃ
15ꢃ
26ꢃ
–ꢃ
23ꢃ
44ꢃ
68ꢃ
30ꢃ
20ꢃ
15ꢃ
12ꢃ
10ꢃ
80ꢃ
57ꢃ
30ꢃ
48ꢃ
44ꢃ
34ꢃ
32ꢃ
20ꢃ
10ꢃ
55ꢃ
–ꢃ
13ꢃ
70ꢃ
96ꢃ
68ꢃ
50ꢃ
38ꢃ
30ꢃ
10ꢃ
69
66
52
63
62
36
24
20
10
48
–
32
100
120
90
70
52
41
20
3
4
5
6
7a
7b
7c
7d
8
5ꢃ
100ꢃ
–ꢃ
9
12
13
14
15
16
17
18
24ꢃ
50ꢃ
64ꢃ
48ꢃ
40ꢃ
31ꢃ
30ꢃ
10ꢃ
Ref.aꢃ
aClotrimazole was used as antifungal standard. –, no activity.
these compounds was evaluated. Compounds 7a–d and N-(3-Acetyl-5-methyl-5-(thiophen-2-yl)-1,3,4-
15–18 display remarkable antimicrobial potency.
thiadiazolidin-2-ylidene)acetamide (4)
Method AꢀA mixture of thiosemicarbazone 2 (0.99 g, 0.005 mol)
and acetic anhydride (3 mL) in pyridine (25 mL) was heated under
Experimental
reflux for 3 h, then cooled and poured onto ice water. The solid
formed was filtered, dried and crystallized from ethanol to afford red
powder; yield 70%; mp 183–184°C; 1H NMR: δ 2.02 (s, 3H, acetyl), 2.13
Chemistry
(s, 3H, acetyl), 2.31 (s, 3H, CH3), 7.04–7.46 (m, 3H, thiophene-H), 11.70
(s, 1H, NH, D2O exchangeable); 13C NMR: δ 22.5, 23.9, 27.6, 76.0, 120.9,
129.1, 134.7, 140.7, 148.7, 168.0, 169.5; IR: ν 3350 (NH), 2920 (CH-aliph.),
1720 and 1700 cm-1 (Cꢀ= ꢀO); MS: m/z 283.28 ([M]+, 91). Anal. Calcd for
C11H13N3O2S2 (283.37): C, 46.62; H, 4.62; N, 14.83; S, 22.63. Found: C,
46.58; H, 4.59; N, 14.85; S, 22.57.
Melting points were determined with an APP Digital ST 15 melting
point apparatus. Infrared spectra were recorded in KBr pellets using
1
a Pye-Unicam SP3–100 spectrophotometer. The H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were determined using a JNM-LA
Series 400 spectrometer and DMSO-d6. Mass spectra were measured
using a JOEL JMS 600 spectrometer. Elemental analyses were carried
out on a Vario EL C, H, N, S Analyzer.
Method BꢀThe thiosemicarbazide 3 was heated in an oil bath at
176°C for 10 min. The solid was triturated with petroleum ether (bp
60–80°C), filtered, dried and crystallized from ethanol. The product
was identical to that produced by method A.
1-[1-(2-Thienyl)ethylidene]-2,4-
diacetylthiosemicarbazide (3)
2-[(1-(2-Thienyl)ethylidene)hydrazono]
A solution of thiosemicarbazone 2 (0.99 g, 0.005 mol) in acetic anhy-
dride (20 mL) was heated under reflux for 2 h. Afer cooling, excess
acetic anhydride was decomposed in an ice water mixture. The solid
formed was filtered, dried and crystallized from ethanol to afford yel-
low powder; yield 65%; mp 173–175°C; 1H NMR: δ 2.02 (s, 3H, CH3), 2.31
(s, 3H, COCH3), 2.49 (s, 3H, NCOCH3), 7.04–7.46 (m, 3H, thiophene-H),
11.70 (s, 1H, NH, D2O exchangeable); 13C NMR: δ 14.7, 22.2, 23.9, 122.3,
129.1, 134.7, 140.7, 155.9, 163.9, 171.0, 183.1; IR: ν 3200 (NH), 2920 (CH-
aliph.), 1650 and 1670 for 2 (Cꢀ= ꢀO), 1590 (Cꢀ= ꢀN) cm-1; MS: m/z 283.23
([M]+, 87%). Anal. Calcd for C11H13N3O2S2 (283.37): C, 46.62; H, 4.62; N,
14.83; S, 22.63. Found: C, 46.65; H, 4.58; N, 14.80; S, 22.58.
thiazolidin-4-one (5)
Method AꢀThiosemicarbazone 2 (0.99 g, 0.005 mol) and ethyl
chloroacetate (0.62 mL, 0.005 mol) were dissolved in hot abso-
lute ethanol (20 mL) containing anhydrous sodium acetate (1 g).
The reaction mixture was heated under reflux for 5 h, then cooled
and poured onto crushed ice. The solid product was filtered, dried
and crystallized from ethanol to afford pale yellow crystals; yield
1
74%; mp 278–279°C; H NMR: δ 2.30 (s, 3H, CH3), 3.82 (s, 2H, CH2
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M.S.K. Youssef and A.A.O. Abeed: 2-Thienyl substituted heterocyclesꢀ
ꢀ29
thiazolidine), 7.00–7.57 (m, 3H, thiophene-H), 11.93 (s, 1H, NH, D2O Calcd for C16H12ClN3OS2 (361.87): C, 53.11; H, 3.34; Cl, 9.80; N, 11.61; S,
exchangeable); 13C NMR: δ 14.9, 32.9, 123.8, 129.1, 134.7, 141.7, 156.3, 17.72. Found: C, 53.09; H, 3.31; Cl, 9.77; N, 11.63; S, 17.74.
163.6, 174.0; IR: ν 3120 (NH), 2825 (CH-aliph.), 1720 cm-1 (Cꢀ= ꢀO thi-
azolidine); MS: m/z 239.24 ([M]+, 82%). Anal. Calcd for C9H9N3OS2 5-p-Nitrobenzylidene-2-[(1-(2-thienyl)ethylidene)hydrazono]
(239.32): C, 45.17; H, 3.79; N, 17.56; S, 26.80. Found: C, 45.16; H, 3.81; thiazolidin-4-oneꢀ(7c) Yellow crystals; yield 65%; mp 211–213°C;
N, 17.53; S, 26.78.
1H NMR: δ 2.15 (s, 3H, CH3), 6.90–8.00 (m, 7H, aromatic-H + thio-
phene-H), 8.20 (s, 1H, ꢀ= ꢀCH), 13.40 (s, 1H, NH, D2O exchangeable); IR:
Method BꢀA mixture of thiosemicarbazone 2 (0.99 g, 0.005 mol) ν 3150 (NH), 3020 (CH arom.), 2930 (CH aliph.), 1695 (Cꢀ= ꢀO thiazo-
and chloroacetamide (0.46 g, 0.005 mmol) in ethanol (20 mL) con- lidine), 1570 cm-1 (NO2); MS: m/z 372.39 ([M]+, 67%). Anal. Calcd for
taining anhydrous sodium acetate (1 g) was heated under reflux for C16H12N4O3S2 (372.42): C, 51.60; H, 3.25; N, 15.04; S, 17.22. Found: C,
5 h, then cooled and poured onto crushed ice. The solid product 51.58; H, 3.21; N, 15.01; S, 17.25.
was filtered, dried and crystallized from ethanol to afford pale yel-
low crystals. The product was identical to compound 5 obtained by 5-Glucosylidene-2-[(1-(thien-2-yl)ethylidene)hydrazono]thia-
1
method A.
zolidin-4-oneꢀ(7d) White crystals; yield 61%; mp 201–203°C; H
NMR: δ 2.22 (s, 3H, CH3), 2.90–3.02 (m, 2H, alditolyl 2H), 3.10–3.30 (m,
2H, alditolyl 2H), 4.10–4.30 (m, 2H, alditolyl 2H), 4.60 (s, 2H, 2 OH,
D2O exchangeable), 4.90–5.30 (2 m, 1H each, 2 OH, D2O exchange-
able), 5.70 (d, 1H, 1 OH, D2O exchangeable), 6.10 (s, 1H each, CHꢀ= ꢀC),
6.49–7.98 (m, 3H, thiophene-H), 11.10 (s, 1H, NH, D2O exchangea-
ble); IR: ν 3150 (NH), 2950 (CH-aliph.), 1680 cm-1 (Cꢀ= ꢀO thiazolidine);
MS: m/z 401.83 ([M]+, 70%). Anal. Calcd for C15H19N3O6S2 (401.46): C,
44.88; H, 4.77; N, 10.47; S, 15.97. Found: C, 44.86; H, 4.74; N, 10.46;
S, 15.94.
4-Methyl-2-[(1-(2-thienyl)ethylidene)
hydrazono]-2,3-dihydrothiazole (6)
To a solution of thiosemicarbazone 2 (0.99 g, 0.005 mol) in abso-
lute ethanol (20 mL) was added the equivalent amount of chloro-
acetone (0.46 mL, 0.005 mol) and anhydrous sodium acetate (1 g).
The mixture was heated under reflux for 5 h, cooled and poured
onto ice water. The solid product was collected by filtration, dried
and crystallized from ethanol to afford yellow powder; yield 65%; mp
201–203°C; 1H NMR: δ 1.80 (s 3H, CH3), 2.30 (s, 3H, CH3 thiazolidine),
6.20 (s, 1H, CH-thiazolidine), 6.40 (s, 1H, CH thiazolidine), 6.90–7.40
(m, 3H, thiophene-H), 9.30 (s, 1H, NH, D2O exchangeable); 13C NMR:
δ 14.9, 24.2, 98.4, 120.9, 129.1, 134.7, 140.9, 150.1, 155.3, 162.1; IR: ν 3250
(NH), 2978 cm-1 (CH-aliph.); MS: m/z 237.28 ([M]+, 69). Anal. Calcd for
C10H11N3S2 (237.34): C, 50.60; H, 4.67; N, 17.70; S, 27.02. Found: C, 50.62;
H, 4.69; N, 17.68; S, 27.06.
2,3,4,5,6-Penta-O-acetyl-aldehydo-D-glu-
cose-3-acetyl-2-[(1-(2-thienyl)ethylidene)
hydrazono]thiazolidin-4-one (8)
A solution of 7d (2.0 g, 0.005 mol) in pyridine (15 mL) was treated
with acetic anhydride (20 mL) and the mixture was stirred at ambi-
ent temperature for 24 h, then was poured onto ice water and
extracted with CHCl3 (3 ꢀ× ꢀ 20 mL). The organic layer was washed
with 10% NaHSO4 solution (2 ꢀ× ꢀ 20 mL), dried (Na2SO4), cooled
and poured onto crushed ice. The precipitate was collected, dried
and crystallized from ethanol to give white powder; yield 61%; mp
156–158°C; 1H NMR: δ 2.10 (s, 3H, CH3), 2.30–2.60 (m, 15H, 5 COCH3),
3.20 (s, 3H, NCOCH3), 4.30–5.50 (5 m, 6H, alditolyl H), 6.00–6.20
(m, 1H, Cꢀ= ꢀCH), 6.90–7.45 (m, 3H, thiophene-H);13C NMR: δ 14.8, 19.0,
20.1, 21.2, 21.9, 22.5, 23.5, 60.6, 62.1, 63.9, 65.5, 68.7, 118.6, 123.7, 124.5,
135.6, 142.7, 145.1, 163.1, 165.0, 170.0, 175.0, 175.7, 175.2, 176.1, 176.9,
178.1; IR: ν 2920 (CH-aliph.), 1680 (Cꢀ= ꢀO thiazolidine), 1670 (Cꢀ= ꢀO)
alditolyl, 1590 cm-1 (Cꢀ= ꢀN); MS: m/z 653.60 ([M]+, 91%). Anal. Calcd
for C27H31N3O12S2 (653.68): C, 49.61; H, 4.78; N, 6.43; S, 9.81. Found: C,
49.58; H, 4.82; N, 6.45; S, 9.78.
General procedure for the synthesis of 7a–d
A mixture of 5 (1.20 g, 0.005 mol), aromatic aldehyde (0.005 mol) and
piperidine (0.005 mol) in dioxane (20 mL) was heated under reflux
for 3 h, then cooled and poured onto ice water. The solid product
7a–d was collected by filtration, washed with water and crystallized
from ethanol.
5-Benzylidene-2-[(1-(2-thienyl)ethylidene)hydrazono]thiazo-
lidin-4-oneꢀ(7a) A brown powder; yield 69%; mp 232–234°C; H
1
NMR: δ 2.20 (s, 3H, CH3), 6.90–7.75 (m, 8H, aromatic-H + thiophene-
H), 8.25 (s, 1H, ꢀ= ꢀCH), 11.20 (s, 1H, NH, D2O exchangeable); 13C NMR:
δ 15.8, 115.8, 123.7, 129.2, 129.8, 131.2, 133.1, 134.8, 135.8, 137.2, 138.1,
140.3, 142.7, 163.3, 164.6, 173.0; IR: ν 3120 (NH), 3015 (CH arom.), 2920
(CH aliph.), 1690 cm-1 (Cꢀ= ꢀO thiazolidine); MS: m/z 327.40 ([M]+, 67%).
Anal. Calcd for C16H13N3OS2 (327.42): C, 58.69; H, 4.00; N, 12.83; S, 19.59.
Found: C, 58.65; H, 4.03; N, 12.80; S, 19.63.
2-[1-(2-Thienyl)ethylidene]malononitrile (9)
To solution of 1 (0.63 mL, 0.005 mol) in absolute ethanol (20 mL) was
added malononitrile (0.33 g, 0.005 mol) and a catalytic amount of
morpholine. The mixture was heated under reflux for 3 h and then
cooled. The solid product was collected, dried and crystallized from
1
5-p-Chlorobenzylidene-2-[(1-(2-thienyl)ethylidene)hydrazono] ethanol to give pale yellow crystals; yield 74%; mp 197–199°C; H
thiazolidin-4-oneꢀ(7b) A red powder; yield 67%; mp 223–225°C; 1H NMR: δ 2.40 (s, 3H, CH3), 6.90–7.45 (m, 3H, thiophene-H); 13C NMR:
NMR: δ 2.15 (s, 3H, CH3), 6.90–7.80 (m, 7H, aromatic-H + thiophene- δ 30.2, 90.7, 118.1, 118.9, 122.7, 124.8, 135.7, 142.9, 161.5; IR: ν 2940 (CH-
H), 8.20 (s, 1H, ꢀ= ꢀCH), 11.10 (s, 1H, NH, D2O exchangeable); IR: ν 320 aliph.), 2200 cm-1 (CN); MS: m/z 174.20 ([M]+, 64%). Anal. Calcd for
(NH), 3015 (CH arom.), 2960 and 2855 (CH aliph.), 1690 cm-1 (Cꢀ= ꢀO C9H6N2S (174.22): C, 62.05; H, 3.47; N, 16.08; S, 18.40. Found: C, 62.08;
thiazolidine); MS: m/z 361.81 ([M]+, 67%), 363.64 ([M+2]+, 23%). Anal. H, 3.49; N, 16.11; S, 18.46.
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30ꢀ ꢀM.S.K. Youssef and A.A.O. Abeed: 2-Thienyl substituted heterocycles
N-[1-(2-Thienyl)ethylidene]-
N′-phenylhydrazine (12)
2′-Acetyl-5′-(2-thienyl)-2′,4′-
dihydrospiro[indole-3,3′-pyrazole]-
2(1H)-one (16)
Method AꢀPhenylhydrazine (0.57 g, 0.005 mol) was added to a solu-
tion of 1 (0.63 mL, 0.005 mol) in ethanol (25 mL) and the mixture was
heated under reflux for 1 h. Upon cooling, the precipitate was col-
lected by filtration, dried and crystallized from ethanol to give white
powder; yield 70%; mp 177–178°C; 1H NMR: δ 2.40 (s, 3H, CH3), 6.85–
7.90 (m, 9H, Ar-H + thiophene-H + NH, D2O exchangeable);13C NMR: δ
15.2, 120.4, 123.7, 126.2, 126.9, 135.8, 141.8, 147.3, 150.1, 160.5; IR: ν 3385
(NH), 3040, 3010 (CH-arom.), 2920 cm-1 (CH-aliph.); MS: m/z 216.22
([M]+, 61%). Anal. Calcd for C12H12N2S (216.30): C, 66.63; H, 5.59; N,
12.95; S, 14.82. Found: C, 66.61; H, 5.57; N, 12.92; S, 14.85.
A mixture of chalcone derivative 14 (0.26 g, 0.001 mol) and hydra-
zine hydrate (5 mL) in acetic acid (20 mL) was heated under reflux
for 5 h. On cooling, the solid formed was filtered and crystallized
1
from dioxane; yield 69%; mp 201–203°C; H NMR: δ 2.30 (s, 2H,
CH2), 2.60 (s, 3H, COCH3), 6.90–8.10 (m, 7H, Ar-H + thiophene-H),
10.50 (s, 1H, NH, D2O exchangeable); IR: ν 3210 (NH), 3010 and 3000
(CH-arom.), 2920 (CH-aliph.), 1690 (Cꢀ= ꢀO indole), 1660 cm-1 (Cꢀ= ꢀO);
MS: m/z 311.32 ([M]+, 71%). Anal. Calcd for C16H13N3O2S (311.36): C,
61.72; H, 4.21; N, 13.50; S, 10.30. Found: C, 61.70; H, 4.18; N, 13.55;
S, 10.24.
Method BꢀA mixture of 9 (0.87 g, 0.005 mol) and phenyl hydrazine
(0.54 g, 0.005 mol) in ethanol (20 mL) was heated for 3 h. Upon cool-
ing, the precipitate was filtered, dried and crystallized from ethanol
to give white powder. The product was identical to that obtained by
method A.
5′-(2-Thienyl)-1′,4′-dihydrospiro[indole-3,3′-
oxazole]-2(1H)-one (17)
A solution of 14 (0.26 g, 0.001 mol) and hydroxylamine hydrochloride
(0.07 g, 0.001 mol) in ethanol (20 mL) containing anhydrous sodium
acetate (0.4 g) was heated under reflux for 5 h, then cooled and
poured onto crushed ice. The solid product thus formed was collected
by filtration, dried and crystallized from ethanol to give white pow-
der; yield 69%; mp 193–195°C; 1H NMR: δ 1.90 (s, 2H, CH2), 6.90–8.00
(m, 7H, Ar-H + thiophene-H), 10.10 (s, 1H, NH, D2O exchangeable);
IR: ν 3310 (NH), 3010, 3000 (CH-arom.), 2960 (CH-aliph.), 1685 cm-1
(Cꢀ= ꢀO indole); MS: m/z 270.28 ([M]+, 64%). Anal. Calcd for C14H10N2O2S
(270.31): C, 62.21; H, 3.73; N, 10.36; S, 11.86. Found: C, 62.18; H, 3.75;
N, 10.39; S, 11.89.
3-Hydroxy-3-(2-oxo-2-(2-thienyl)ethyl)
indolin-2-one (13)
A mixture of 1 (0.63 g, 0.005 mol), isatin (0.73 g, 0.005 mol), 3–4 drops
of diethylamine and ethanol (25 mL) was heated under reflux on the
steam bath for 30 min. Afer standing for several days at room tem-
perature, the product was collected by filtration, dried and crystal-
lized from ethanol to afford white powder; mp 177–178°C [25].
5′-(2-Thienyl)-2′-phenyl-2′,4′-
dihydrospiro[indole-3,3′-pyrazole]-2(1H)-one
(18)
A mixture of chalcone 14 (0.26 g, 0.001 mol) and phenylhydrazine
(0.11 g, 0.001 mol) in ethanol (20 mL) was heated under reflux for 5 h
and then cooled. The precipitate was filtered and crystallized from
methanol to give white crystals; yield 60%; mp 183–185°C; 1H NMR: δ
2.30 (s, 2H, CH2), 6.70–8.15 (m, 12H, Ar-H + thiophene-H), 10.00 (s, 1H,
NH, D2O exchangeable); IR: ν 3300 (NH), 3010 and 3000 (CH-arom.),
2920 (CH-aliph.), 1690 cm-1 (Cꢀ= ꢀO indole); MS: m/z 345.46 ([M]+, 72%).
Anal. Calcd for C20H15N3OS (345.42): C, 69.54; H, 4.38; N, 12.17; S, 9.28.
Found: C, 69.52; H, 4.36; N, 12.19; S, 9.30.
3-(2-Oxo-2-(2-thienyl)ethylidene)indolin-
2-one (14)
A mixture of 13 (1.36 g, 0.005 mmol), concentrated hydrochloric acid
(0.25 mL) and glacial acetic acid (8 mL) was heated on the steam bath
for 15–30 min. Afer addition of ethanol and standing at room temper-
ature, the product was filtered, dried and crystallized from ethanol;
mp 176–177°C [25].
5′-4-(2-Thienyl)-2′,4′-dihydrospiro[indole-
3,3′-pyrazole]-2(1H)-one (15)
A mixture of chalcone 14 (0.26 g, 0.001 mol) and hydrazine hydrate
(5 mL) in ethanol (20 mL) was heated under reflux for 6 h. On cool-
ing, the solid formed was filtered and crystallized from ethanol to
afford pale yellow crystals; yield 71%; mp 197–199°C; 1H NMR: δ 2.20
(s, 2H, CH2), 6.95–7.90 (m, 7H, A-H + thiophene-H), 8.50 (s, 1H, pyra-
zole-NH, D2O exchangeable), 10.20 (s, 1H, NH, D2O exchangeable);
IR: ν 3250 and 3150 (NH), 2920 (CH-aliph.), 1690 cm-1 (Cꢀ= ꢀO indole);
MS: m/z 269.30 ([M]+, 71%). Anal. Calcd for C14H11N3OS (269.32): C,
62.43; H, 4.12; N, 15.60; S, 11.91. Found: C, 62.41; H, 4.10; N, 15.63;
S, 11.94.
Antimicrobial screening
The screened compounds were dissolved in DMSO to form a solu-
tion of 5% concentration. Filter paper discs (Whatman No. 3 and
5 mm diameter) were saturated with this solution. The discs were
placed on the surface of solidified Nutrient agar dishes seeded by
the tested bacteria or Czapek Dox agar dishes seeded by the tested
fungi. The diameter of inhibition zones (mm) were measured at the
end of the incubation period (24–48 h at 37°C for bacteria and for
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M.S.K. Youssef and A.A.O. Abeed: 2-Thienyl substituted heterocyclesꢀ
ꢀ31
4–7 days at 28°C for fungi) [26]. Discs saturated with DMSO were calculated as μg/mL. The antibacterial and antifungal activities
used as control. Chloramphenicol and clotrimazole were used as
reference drugs. The biologically active compounds were then
data are given in Tables 1 and 2.
diluted with DMSO to prepare a series of concentrations in order Received September 4, 2013; accepted November 16, 2013; previ-
to determine the MIC of each compound. The MIC values were ously published online January 23, 2014
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