Synthesis and chemical characterisation of new bis-thieno [2,3-b]thiophene derivatives

Article abstract of DOI:10.3390/molecules15053329

Using 3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide as synthon a series of new bis-heterocycles incorporating the thieno[2,3-b] thiophene nucleus was prepared and characterized.

Full text of DOI:10.3390/molecules15053329

,Molecules 2010, 15, 3329-3337; doi:10.3390/molecules15053329
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Chemical Characterisation of New Bis-Thieno
[2,3-b]thiophene Derivatives
Yahia Nasser Mabkhoot
Department of Chemistry, Science of College, King Saud University, PO Box 2455, Riyadh-11451,
Saudi Arabia; E-Mail: yahia@ksu.edu.sa
Received: 5 March 2010; in revised form: 29 April 2010 / Accepted: 6 May 2010 /
Published: 7 May 2010
Abstract: Using 3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide as
synthon a series of new bis-heterocycles incorporating the thieno[2,3-b]thiophene nucleus
was prepared and characterized.
Keywords: thieno[2,3-b]thiophene; 2,5-dicarbohydrazide; 5-Amino-3-cyano(1,2,3)tria-
zole-1-carbonyl
1. Introduction
Thienothiophene derivatives represent important building blocks in organic and medicinal
chemistry. They have been developed for different pharmaceutical purposes and have been tested as
potential antitumor, antiviral, antibiotic, and antiglaucoma drugs, or as inhibitors of platelet
aggregation [1–6]. On the other hand, hydrazone derivatives are reported to possess antimicrobial [7],
antitubercular [8], anticonvulsant [9] and anti-inflammatory [10] activities.
The utility of hydrazides as key intermediates in the synthesis of several series of heterocyclic
compounds and the broad spectrum of biological activities that have been reported for their cyclized
products [11–14] has aroused interest in exploring the utility of hydrazides as versatile precursors for
the synthesis of a variety of substituted heterocycles [15–19]. Several Schiff’s bases, hydrazones and
hydrazides of isoniazid have shown good activity against tubercular, fungal and bacterial infections
[20,21]. A number of hydrazide–hydrazone derivatives have been claimed to possess interesting
antibacterial, antifungal, anticonvulsant, antiinflammatory, antimalarial and antituberculosis- activities
[22]. Acid hydrazides can be considered as useful intermediates leading to the formation of several
heterocycles such as pyrazole and triazoles. Pyrazole derivatives are a very interesting class of

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heterocyclic compounds that have remarkable pharmacological activities as antibacterial, antifungal,
and hypoglycemic compounds, as tumor necrosis inhibitor, and in the treatment of thromboembolic
disorders [23–26]. In continuation of these findings, we report herein the synthesis of some novel bis-
heterocycles containing a thieno[2,3-b]thiophene moiety as a base unit which are of interest as
potential biologically active compounds or pharmaceuticals.
2. Results and Discussion
Diethyl 3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarboxylate (1) was prepared according to
literature methods [27]. Next, the reaction of compound 1 with hydrazine hydrate in refluxing ethanol
gave the bis-hydrazide 2 (Scheme 1). The IR spectrum of the latter revealed the appearance of three
absorption bands at 3,304, 3,220, and 3,159 cm–1 due to NH2 and NH functions and its mass spectrum
showed a peak corresponding to its molecular ion at m/z = 346 [M+].
Scheme 1. Reaction of 2,5-dicarbohydrazide 2 with aromatic aldehydes.
P h
P h
O
O
NH2-NH2
C2H5OH
O
O
S
S
C2H5O
OC2H5
S
S
H2NHN
NHNH2
1
2
C2H5OH
CHO
x
3
a
H
X
b
P-OH
O-OH
Ph
c
O
O
S
S
HC NHN
NHN
CH
X
X
3a-c
Subsequent treatment of compound 2 with appropriate aldehydes in refluxing ethanol yielded the
corresponding hydrazones 3a-c (Scheme 1). The structures of the latter products were established on
the basis of the appearance of an NH absorption band in the 3,229–3,140 cm-1 region and a carbonyl
1
function band in the 1665-1644 cm-1 region of their IR spectra, whereas their H-NMR spectra
revealed the presence of a signal due to the -CH=N- proton in the 8.12–8.56 ppm region and a D2O
exchangeable signal (NH) in the 9.98-10.75 ppm region.
The hydrazide derivative 2 also reacted with active methylene derivatives 4a-c to afford the
corresponding pyrazolo derivatives 5a-c (Scheme 2). The structures of compounds 5a-c were in
agreement with their spectral and analytical data. For example, the 1H-NMR spectrum of compound 5b
contained a new singlet at δ = 8.10 ppm, not present in the spectrum of the starting material, and
attributed to the CH of the pyrazolo ring, and the mass spectra of 5a-c contained molecular ion peaks
at m/z = 478, 478, and 474, respectively, in agreement with their calculated masses.

Molecules 2010, 15
Scheme 2. Reaction of 2,5-dicarbohydrazide 2 with active methelene derivatives 4a-c.
3331
Ph
O
O
S
S
H2NHN
NHNH2
2
X
CH2
C2H5OH
X
Y
Y
CN
CN
4a
4b
4a-c
COOC2H5
COCH3
COCH3
COCH3
NH2
4c
5a
Ph
NH2
OH
O
O
N
5b
CH3
CH3
S
S
N
N
N
5c
CH3
Y
Y
X
X
H
H
5a-c
Treatment of compound 2 with the sodium nitrite in acetic acid yielded the corresponding azide
derivative 6 (Scheme 3). Its IR spectrum and its 1H-NMR were free of NH and NH2 proton signals.
Scheme 3. Reaction of 3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbonyl diazide
(6) with active methylene derivatives.
Ph
Ph
O
O
O
O
NaNO2
AcOH
S
S
H2NHN
NHNH2
S
S
N3
N3
6
2
C2H5O-Na+
CH2(COOC2H5)2
CNCH2CN
SHCH2COOH
Ph
Ph
O
N
O
O
N
O
S
S
N
N
N
S
S
N
N
N
N
N
N
NH2
H2N
N
OH
COOC2H5
HO
C2H5OOC
CN
NC
7a
7c
Ph
O
O
N
S
S
N
N
N
N
N
OH
HO
SH
HS
7b

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The reaction of compound 6 with active methylene derivatives in sodium ethoxide afforded the
corresponding triazole derivatives 7a-c (Scheme 3). The structures of the latter were deduced from
13
their elemental analyses and spectral data. The C-NMR spectrum of 7c, as an example, revealed
fourteen carbon signals. Its 1H-NMR spectrum displayed singlets at δ 4.25 ppm attributable to the NH2
protons. Its IR spectrum revealed the appearance of an absorption band at 3,309 cm–1 due to the NH2
groups, in addition to the carbonyl absorption band at 1,685 cm–1. Its mass spectrum showed a peak
corresponding to its molecular ion at m/z = 500 [M+].
3. Experimental
3.1. General
All melting points were measured on a Gallenkamp melting point apparatus. IR spectra were
measured as KBr pellets on a Pye-Unicam SP 3-300 spectrophotometer. The NMR spectra were
1
recorded on a Varian Mercury VX-300 NMR spectrometer. H-NMR (300 MHz) and 13C-NMR
(75.46 MHz) were run in dimethylsulphoxide (DMSO-d6). Mass spectra were recorded on a Shimadzu
GCMS-QP 1000 EX mass spectrometer at 70 eV. Elemental analysis was carried out on an Elementar
Vario EL analyzer. Thieno[2,3-b]thiophene derivative 1 was prepared following a literature procedure [27].
3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide (2). A mixture of compound 1 (3.74 g,
10 mmol) and hydrazine hydrate (1.0g, 20 mmol) in absolute ethanol (100 mL) was refluxed for 2 h.
The separated white solid was filtered off and recrystallized from EtOH / DMF to give the title
compound 2. Yield: 87%; m.p. 204-206°C; IR (νmax): 3,304, 3,220, 3,159 (NH, NH2), 1639 (C=O)
cm-1; 1H-NMR: δ 1.85 (s, 3H, CH3), 4.39–4.50 (br. s, 4H, NH2, D2O exchangeable), 7.39–7.49 (m, 5H,
13
ArH), 8.26 (s, 1H, NH), 9.41(s, 1H, NH); C-NMR: δ 14.4, 128.8, 130.2, 132.9, 134.5, 136.3, 138.8,
146.0, 162.1, 162.8, 171.3; MS m/z (%): 347 (M+ + 1, 94), 348 (M+ + 2, 66.7), 346 (M+, 100), 206.9
(25.3); Anal. calcd. for C15H14N4O2S2 (346.43): C, 52.01; H, 4.07; N, 16.17; S, 18.51. Found: C, 51.97;
H, 4.11; N, 16.18; S, 18.47.
3.2. Reaction of 3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide (2) with aldehydes
A mixture of the hydrazide 2 (3.46 g, 10 mmol) and the appropriate aldehyde (20 mmol) in ethanol
(50 mL) was refluxed for 4 h. The formed solid product was collected by filtration, washed with
ethanol and dried. Recrystallization from the appropriate solvent afforded the corresponding hydrazone
derivatives 3a-c.
Dibenzylidene-3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide (3a). Yellowish solid;
1
77%; m.p. 295 °C (EtOH/DMF); IR νmax: 3,140 (NH), 1,657 (C=O) cm-1; H-NMR: δ 2.13 (s, 3H,
13
CH3), 7.43-7.68 (m, 15H, ArH), 6.77(s, 2H, -CH=N-), 10.75 (br. s, 2H, NH, D2O-exchangable); C-
NMR: δ 12.3, 123.7, 127.5, 128.7, 129.5, 131.6, 135.4, 136.7, 150.8, 159.3, 173.2; MS m/z (%) 523
(M++1, 88.6%), 522 (M+, 100%), 207.9 (8.1%), 116 (8.4%), 62.9 (71.4.5%); Anal. calcd. for
C29H22N4O2S2 (522.6): C, 66.64; H,4.24; N, 10.52; S, 12.27. Found: C, 66.70; H, 4.14; N, 10.70; S,
12.24.

Molecules 2010, 15
3333
Bis(2-hydroxybenzylidene)-3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide
(3b).
Yellowish solid; yield 80%; m.p. >300 °C (EtOH/ DMF); IR νmax: 3,304 (OH), 3,229 (NH), 1,644
(C=O) cm-1; 1H-NMR: δ 2.00 (s, 3H, CH3), 7.36-7.57 (m, 13H, ArH), 6. 85 (s, 2H, -CH=N ), 9.57 (br.
s, 2H, NH,), 9.98(s, 1H, OH,), 11.7 (s, 1H, OH,); 13C-NMR: δ 12.3, 123.6, 127.3, 128.8, 129.5, 131.6,
135.4, 136.7, 150.8, 159.3, 172.8; MS m/z (%) 555 (M++1, 88.6%), 554 (M+, 100%), 222 (9.4%), 161
(7.6%), 46.9 (44.7.5%); Anal. calcd. for C29H22N4O4S2 (554.6): C, 62.80; H,4.00; N, 10.10; S, 11.56.
Found: C, 62.70; H, 4.14; N, 10.11; S, 12.44.
Bis(4-hydroxybenzylidene)-3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide
(3c).
Yellowish solid; yield 85%; m.p. >300 °C (EtOH/ DMF); IR νmax: 3,306 (OH), 3,229 (NH), 1,665
(C=O) cm-1; 1H-NMR: δ 2.00 (s, 3H, CH3), 7.33-7.67 (m, 13H, ArH), 6.86 (s, 2H, -CH=N-), 8.57 (br.
s, 2H, NH), 9.99 (s, 1H, OH), 11.66 (s, 1H, OH); 13C-NMR: δ 12.3, 123.2, 126.3, 128.9, 131.5, 135.9,
136.7, 150.8, 159.3, 176.6; MS m/z (%) 555 (M++1, 88.6%), 554 (M+, 100%), 222 (9.4%), 161
(7.6%), 46.9 (44.7.5%); Anal. calcd. for C29H22N4O4S2 (554.6): C, 62.80; H,4.00; N, 10.10; S, 11.56.
Found: C, 62.70; H, 4.14; N, 10.11; S, 12.44.
3.3. Reaction of 3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbohydrazide (2) with active
methylene derivatives
A mixture of the hydrazide 2 (3.46 g, 10 mmol) and the appropriate malononitrile, ethyl
acetoacetate or acetyl acetone 4a-c (20 mmol) in ethanol (20 mL) was refluxed for 5 h. After cooling
the obtained solid was collected by filtration, dried and crystallized from EtOH/DMF.
[5-(3,5-Diamino-pyrazole-1-carbonyl)-3-methyl-4-phenylthieno[2,3-b]thiophene-2-yl]-(3,5-diamino-
pyrazol-1-yl)-methanone (5a). Yellowish solid; yield 60%; m.p. >300 °C; IR νmax: 3,310–2,840
1
(2NH2), 1,670 (C=O) cm-1; H-NMR: δ 2.00 (s, 3H, CH3), 4.33 and 4.50 (br. s, 4H, 4NH2, D2O
13
exchangeable), 7.40–7.43 (m, 5H, ArH), 6.67 (s, 2H, -2CH=C); C-NMR: δ 12.7, 89.7, 127.7, 128.3,
129.8, 135.1, 139.7, 142.2, 140.3, 144.1, 152.8, 174.0; MS m/z (%) 479 (M++1, 88.6%), 478 (M+,
100%), 207 (30.7%), 76 (15.8%); Anal. calcd. for C21H18N8O2S2 (478.5): C, 52.71; H, 3.79; N, 23.42;
S, 13.40. Found: C, 52.56; H, 3.65; N, 23.52; S, 13.28.
[5-(5-Hydroxy-3-methyl-pyrazole-1-carbonyl)-3-methyl-4-phenylthieno[2,3-b]thiophene-2-yl]-(5-
hydroxy-3-methyl-pyrazol-1-yl)-methanone (5b). Yellowish solid; yield 60%; m.p. 296 °C; IR νmax
:
3,310 (OH), 1,669 (C=O) cm-1; H-NMR: δ 2.00 (s, 3H, CH3), 2.43 (s, 6H, 2CH3), 7.42–7.43 (m, 5H,
ArH), 6.10 (s, 2H, -CH=C), 13.1 (s, 2H, OH); 13C-NMR: δ 12.7, 13.9, 91.7, 127.7, 128.3, 129.8, 135.1,
139.7, 142.2, 143.2, 144.1, 152.8, 174.0; MS m/z (%) 479 (M++1, 88.6%), 478 (M+, 100%), 207
(32.1%), 76 (11.8%); Anal. calcd. for C23H18N4O4S2 (478.5): C, 57.73; H, 3.79; N, 11.71; S, 13.40.
Found: C, 58.00; H, 3.64; N, 11.70; S, 13.49.
1
[5-(3,5-Dimethyl-pyrazole-1-carbonyl)-3-methyl-4-phenylthieno[2,3-b]thiophene-2-yl]-(3,5-dimethyl-
yrazol-1-yl)-methanone (5c). Colorless solid; yield 65%; m.p. >300 °C; IR νmax: 1,670 (C=O) cm-1; 1H-
NMR: δ 1.91 (s, 3H, CH3), 1.96 (s, 6H, CH3), 2.00 (s, 6H, 2CH3) 7.41–7.42 (m, 5H, ArH), 6.10 (s, 2H,

Molecules 2010, 15
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13
-CH=C); C-NMR: δ 12.7, 15.6, 92.0, 128.3, 129.8, 135.1, 139.7, 142.2, 140.2, 144.1, 146.8, 164,1
174.0; MS m/z (%) 475.6 (M++1, 88.6%), 474.6 (M+, 100%), 207 (14.1%), 76 (11.8%), 46.9 (9.9%);
Anal. calcd. for C25H22N4O2S2 (474.6): C, 63.27; H, 4.67; N, 11.81; S, 13.51. Found: C, 63.10; H,
4.68; N, 11.67; S, 13.49.
3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-dicarbonyl diazide (6). A mixture of compound 2
(3.74 g, 10 mmol) in acetic acid (30 mL) was treated with 10% sodium nitrite (2.76 g, 40 mmol) which
was added dropwise at -5 °C with stirring for 1 h. The solid product was filtered off and recrystallized
from ethanol. Colorless solid; yield 87%; m.p. 122°C; IR νmax: 1,678 (C=O) cm-1; 1H-NMR: δ 2.01 (s,
3H, CH3), 7.34–7.47 (m, 5H, ArH); 13C-NMR: δ 14.6, 128.4, 128.7, 129.0, 129.5, 129.7, 131.0, 131.3,
147.0, 164.1; MS m/z (%) 369 (M++1, 88.6%), 368 (M+, 100%); Anal. calcd. for C15H8N6O2S2
(369.39): C, 48.90; H, 2.19; N, 22.81; S, 17.41. Found: C, 49.03; H, 2.30; N, 22.86; S, 17.42.
3.4. General procedure for the synthesis of compounds 7a-c
A solution of Na (0.56 g, 20 mmol) in ethanol (20 mL) was added in one portion to an ice-cold
solution of compound 6 (3.68 g, 10 mmol) and an active methylene compound (ethyl acetoacetate,
thioglycolic acid or malononitrile) (20 mmol). The mixture was stirred overnight at room temperature,
the solvent evaporated in vacuo, and the concentrated ethanol solution then poured into cold water and
the corresponding products were collected by filtration and recrystallized from ethanol.
Ethyl-1-[(5-{4-[ethoxycarbonyl)-5-hydroxy(1,2,3)triazol-1-yl]}-4-methyl-3-phenyl-thieno[2,3-
b]thiophene-2-yl) carbonyl]-5-hydroxy(1,2,3)triazole-4-carboxylate (7a). Yellow solid; yield 70%;
1
m.p. 148 °C; IR νmax: 3,268 (OH), 1,713 (C=O), 1,686 (C=O) cm-1; H-NMR: δ 1.67 (t, 6H, 2CH3),
2.02 (q, 4H, 2CH3), 4.14 (s, 2H, CH2), 7.41-7.55 (m, 5H, ArH), 12.12 (s, 2H, 2OH); 13C-NMR: δ 10.2,
14.1, 15.5, 59.5, 61,4, 62.3, 128.2, 129.8, 135.1, 139.6, 142.2, 144.4, 147.3, 165.2, 167.7; MS m/z (%)
597 (M++1, 88.6%), 596 (M+, 100%), 373 (99.9%), 329 (62.3%); Anal. calcd. for C25H20N6O8S2
(596.6): C, 50.33; H, 3.38; N, 14.09; S, 10.75. Found: C, 50.38; H, 3.40; N, 14.00; S, 10.73.
[5-(5-Hydroxy-4-mercapto(1,2,3)triazole-1-carbonyl)-3-methyl-4-phenyl-thieno[2,3-b]thiophene-2-
yl]-(5-hydroxy-4-mercapto(1,2,3)triazol-1-yl)-methanone (7b). Yellow solid; yield 75%; m.p. 168 °C;
1
IR νmax; 3,268 (OH), 1,682 (C=O) cm-1; H-NMR: δ 2.00 (s, 3H, CH3), 7.38–7.50 (m, 5H, ArH),
8.51(s, 2H, 2OH), 9.25(s, 2H, 2SH); 13C-NMR: δ 10.2, 58.5, 127.6, 129.8, 132.6, 135.1, 139.6, 142.2,
144.4, 152.3, 163.2, 167.0; MS m/z (%) 516 (M++1, 88.6%), 515 (M+, 100%), 374 (99.9%), 227
(89.3%); Anal. calcd. for C19H12N6O4S4 (516.6): C, 44.17; H, 2.34; N, 16.27; S, 24.83. Found: C,
44.20; H, 2.40; N, 16.09; S, 24.77.
[5-(5-Amino-3-cyano(1,2,3)triazole-1-carbonyl)-3-methyl-4-phenyl-thieno[2,3-b]thiophene-2-yl]-(5-
amino-3-cyano(1,2,3)triazol-1-yl)-methanone (7c). Yellow solid; yield 65%; m.p. 155°C; IR νmax
:
3309 (NH2), 1568 (N=N), 1685 (C=O) cm-1; 1H-NMR: δ 2.04 (s, 3H, CH3), 4.05–427(br. s, 4H, 2NH2,
13
D2O exchangeable), 7.34–7.45 (m, 5H, ArH); C-NMR: δ 10.2, 58.5, 127.6, 129.8, 132.6, 135.1,
139.6, 140.4, 142.2, 144.4, 152.3, 163.2, 167.0; MS m/z (%) 501 (M++1, 88.6%), 500 (M+, 100%),

Molecules 2010, 15
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207 (22.7%), 76 (6.6%); Anal. calcd. for C21H12N10O2S2 (500): C, 50.39; H, 2.42; N, 27.98; S, 12.81.
Found: C, 50.36; H, 2.42; N, 27.77; S, 12.67.
4. Conclusions
Synthesis and identification of some bis-heterocycles 3a-c, 5a-c, 6 and 7a-c containing thieno[2,3-
b]thiophene as a base unit via the versatile, hitherto unreported 3-methyl-4-phenylthieno[2,3-
b]thiophene-2,5-dicarbohydrazide (2) was reported.
Acknowledgements
The author is grateful to King Saud University and the Deanship of Scientific Research. He also
offers his thanks to the Faculty of Science and Department of Chemistry for their support.
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Sample Availability: Samples of compounds 1-7a-c are available from the author.
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