A facile domino protocol for the regioselective synthesis and discovery of novel 2-amino-5-arylthieno-[2,3-b]thiophenes as antimycobacterial agents

Article abstract of DOI:10.1016/j.tetlet.2009.08.085

A series of novel 2-amino-5-arylthieno[2,3-b]thiophenes has been synthesized regioselectively from the reaction of 5-aryldihydro-3(2H)-thiophenones with ethyl cyanoacetate/malononitrile and sulfur powder in the presence of morpholine under thermal as well

Full text of DOI:10.1016/j.tetlet.2009.08.085

Tetrahedron Letters 50 (2009) 6191–6195
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile domino protocol for the regioselective synthesis and discovery
of novel 2-amino-5-arylthieno-[2,3-b]thiophenes as antimycobacterial agents
b
b
Kamaraj Balamurugan a, Subbu Perumal a, , Aaramadaka Sunil Kumar Reddy , Perumal Yogeeswari ,
*
Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science, Pilani, Hyderabad Campus,
Jawahar Nagar, Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2-amino-5-arylthieno[2,3-b]thiophenes has been synthesized regioselectively from the
reaction of 5-aryldihydro-3(2H)-thiophenones with ethyl cyanoacetate/malononitrile and sulfur powder
in the presence of morpholine under thermal as well as microwave irradiation conditions. This transfor-
mation presumably occurs via domino Gewald reaction–dehydrogenation sequence. The 2-amino-5-aryl-
thieno[2,3-b]thiophenes were evaluated for their in vitro activity against Mycobacterium tuberculosis
H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 12 compounds screened, ethyl
2-amino-5-(1-naphthyl)thieno[2,3-b]thiophene-3-carboxylate was found to be the most active com-
Received 26 June 2009
Revised 24 August 2009
Accepted 26 August 2009
Available online 29 August 2009
Keywords:
Thieno[2,3-b]thiophenes
Domino reactions
Ethyl cyanoacetate
Malononitrile
pound with MIC of 1.1 lM against MTB and MDR-TB.
Ó 2009 Elsevier Ltd. All rights reserved.
Morpholine
Sulfur
Antimycobacterial activity
One of the most convenient and well-established protocols for
the synthesis of 2-aminothiophenes is Gewald’s method,1 which
involves the three-component domino reactions of a ketone with
an activated nitrile and elemental sulfur in the presence of mor-
pholine. These 2-aminothiophenes serve as important intermedi-
ates in dye preparations and pharmaceutical industry.2 In
particular, they act as antimitotic agents,3 kinesin spindle protein
(KSP) inhibitors,4 adenosine A1 receptor allosteric enhancers,5
inhibitors of hepatitis C virus NS5B polymerase,6 protein-tyrosine
phosphatases (PTPs) 1B inhibitors7, and human leukocyte elas-
tase.8 The basic framework of these compounds is prevalent in a
variety of natural products,9 besides serving as a building block
for more complex structures which display inhibitory properties
in a variety of biological targets.8,10–15
The World Health Organization estimates that 2 billion people
(about one-third of the world population) are infected with Myco-
bacterium tuberculosis, among which 8 million develop active
tuberculosis (TB) and nearly 2 million die each year, especially in
developing countries.16 In addition, the rising number of people
who contract TB, because their immune systems are compromised
by immunosuppressive drugs or substance abuse or HIV/AIDS, is a
great impediment to TB control and prevention. There is currently
a growing concern about the development and spread of multi-
drug and extensively drug-resistant tuberculosis (MDR/XDR-TB),
which has the potential to paralyze TB care programs. It is also a
serious threat to industrialized nations where individual care and
treatment costs and larger social and economic disruptions could
become major public policy issues.17 In the last 50 years, only a
few drugs have been approved by the Food and Drug Administra-
tion (FDA) to treat TB, which reflects the difficulties rampant in
the discovery and clinical testing of new candidates and the lack
of pharmaceutical industry research in this area. Hence, the discov-
ery of fast-acting new drugs to effectively cure TB, including MDR-
TB, is imperative.
We have recently embarked on a research program to (i) evolve
new methodologies employing tandem/domino multi-component
reactions for the construction of novel heterocycles18 in view of
their distinct advantages of convergence, economy, efficiency,
and eco-friendliness and (ii) unearth new lead molecules with
antimycobacterial activities.19 In this context, we were prompted
to employ Gewald reaction–dehydrogenation domino reactions
for the synthesis of 2-amino-5-arylthieno[2,3-b]thiophenes com-
prising two thiophene rings, screen them for antimycobacterial
activities, and report the results in this Letter. That these 2-ami-
no-5-arylthieno[2,3-b]thiophenes could be significant from
* Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.085

6192
K. Balamurugan et al. / Tetrahedron Letters 50 (2009) 6191–6195
X
S
O
Morpholine
NH2
NC
X
+
+
S
Ar
S
EtOH, MW
S
Ar
X = -COOEt, -CN
3
1
2
Scheme 1. Synthesis of 2-amino-5-arylthieno[2,3-b]thiophenes 3.
Table 1
Synthesis of 2-amino-5-arylthieno[2,3-b]thiophenes 3
Compd
Ar
X
Reaction time
Yield of 3 (%)
MIC (
lM)
Refluxa (80 °C) (h)
MWb (140 °C) (min)
Refluxc
MWc
MTB
MDR-TB
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
C6H5
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
CN
CN
CN
CN
12
12
12
12
12
12
15
15
15
15
15
15
25
25
25
25
25
25
30
30
30
30
30
30
65
60
62
65
63
67
68
62
67
61
58
57
77
74
75
70
69
72
73
71
76
68
65
69
20.6
4.9
9.3
2.3
8.4
41.2
4.9
18.5
2.3
4.2
1.1
>97.5
23.1
21.5
20.9
19.2
5.1
11.4
3.8
61.2
406.1
p-MeC6H4
p-ClC6H4
p-PriC6H4
o,p-Cl2C6H3
1-Naphthyl
C6H5
p-MeC6H4
p-ClC6H4
p-PriC6H4
o,p-Cl2C6H3
1-Naphthyl
1.1
97.5
23.1
43.0
20.9
30.4
10.2
0.4
0.1
7.6
50.8
CN
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide
a
b
c
Refluxed in ethanol.
Irradiated with ethanol.
Isolated yield after purification by column chromatography.
biological and industrial perspectives emerges from the fact
that thieno[2,3-b]thiophenes possess important biological activi-
ties, viz. antiproliferative activity,20 inhibition of non-peptide
GPIIb/IIIa21, and topically active carbonic anhydrase inhibition,22
besides showing good potential as conducting polymers23a and
semiconductors.23b
In the present investigation, the reaction of 5-aryldihydro-
3(2H)-thiophenones 124 with ethyl cyanoacetate or malononitrile
2 and sulfur powder in the presence of morpholine under micro-
wave irradiation and conventional thermal conditions afforded
Table 3
Influence of temperature on the synthesis of 3a under microwave irradiation
S.No.
Temperature (°C)
Irradiation time (min)
Yielda of 3a (%)
1
2
3
100
120
140
75
45
25
64
66
77
a
Isolated yield after purification by column chromatography.
moderate yields of 2-amino-5-arylthieno[2,3-b]thiophenes
3
12–15 h at 80 °C.25 The time for completion of the reactions was
determined by monitoring the reaction by TLC. As the reactions
were conducted under thermal and microwave irradiations at dif-
ferent temperatures, the special influence of microwaves, other
than of heating, was not assessed. It is to be noted, however, that
the microwave reaction affords a slightly higher yield of 2-ami-
no-5-arylthieno[2,3-b]thiophenes 3 (65–77%) in much shorter
reaction times than the thermal reaction (57–68%) under the
conditions employed.
(Scheme 1, Table 1). The microwave reaction was performed in a
focused microwave oven by irradiating the reaction mixture in a
sealed vial at 140 °C at 40 W power level with 5 bar pressure for
25–30 min25 given in Table 1. The data in Tables 2 and 3 disclose
that morpholine catalyzes the reaction efficiently and that the
reaction could be completed rapidly at 140 °C. The reaction vial
after completion of the reaction was cooled and the product was
purified by flash column chromatography. The thermal reaction
was conducted by refluxing the reaction mixture in ethanol for
H
Table 2
CH3
Synthesis of 2-amino-5-phenylthieno[2,3-b]thiophenes, 3a using different bases
H
O
S.No.
Base
Reaction time
MW (min) Thermal (h)
Yield (%)
Thermala
O
MWa
H
4
1
2
3
4
5
6
Morpholine
Diethylamine
DBU
Piperidine
KF–Al2O3
K2CO3
25
25
25
25
15
15
12
12
15
15
10
10
77
70
40
44
72
35
70
62
58
35
60
40
6'
5'
3
3a
NH2
2
4'
5
1'
S
S
6
6a
1
2'
3'
a
Isolated yield after purification by column chromatography.
Figure 1. HMBC correlations in 3a.

K. Balamurugan et al. / Tetrahedron Letters 50 (2009) 6191–6195
6193
X
O
X
N
N
CN
X
S8/B
-S7
B:
+
S
S
Ar
S
Ar
S
Ar
5
4
2
1
X
X
N
NH
H
X
S
S
Ar
NH2
S
S
S
H
S
H
Ar
Ar
6
7
8
B
H
H
X
X
H
X
-H2S8
S8
EtOH
Ar
Ar
NH2
NH2
Ar
..
NH2
S
S
S
S
S
S
S
S7H
3
10
9
X= -CN, -COOEt
Scheme 2. Proposed mechanism for the formation of 2-amino-5-arylthieno-[2,3-b]thiophenes 3.
The structure of the 2-amino-5-arylthieno[2,3-b]thiophenes 3
was established from 1H, 13C, and 2D NMR spectroscopic data as
illustrated for a representative example 3a. In the 1H NMR spec-
trum of 3a, the NH2 protons appear as a singlet at 6.17 ppm, which
shows a HMBC (Fig. 1) with the signal at 100.1 ppm due to C-3. The
phenyl protons and the thiophene proton, H-4, overlap and occur
in the range 7.26–7.62 ppm. The signal of H-4 can, however, be
spotted as a tall peak at 7.59 ppm which has (i) a C,H COSY corre-
lation with the signal at 117.7 ppm assignable to C-4 and (ii)
HMBCs with carbon signals at 118.9, 134.8, 145.6, and 143.3 ppm
ascribable to C-10, C-3a, C-5, and C-6a which are not distinctly as-
signed (Fig. 1). The IR stretching frequencies of 3a, viz. 1657 cmꢀ1
for C@O and 3312 and 3419 cmꢀ1 for NH2, are diagnostic of the thi-
ophene with a 2-amino and 3-ethyl ester functions, as evident
from the comparison of these frequencies with that corresponding
to the ester carbonyl at 1649 cmꢀ1 and NH2 at 3300 and 3403 cmꢀ1
of the model system, viz. 2-amino-8H-indeno[2,1-b]thiophene-3-
carboxylic acid ethyl ester26 with the ester and amino groups at
3- and 2-positions of the thiophene ring.
went dehydrogenation to afford the 2-amino-5-arylthieno
[2,3-b]thiophenes 3. This reaction when performed under N2
atmosphere also led to 3, thereby suggesting that the aroma-
tization to
3 could have been effected by sulfur through
dehydrogenation.
It is pertinent to note that only one report is available in the lit-
erature on the Gewald reaction of tetrahydrothiophen-3(2H)-one
system, wherein 11 upon reaction with 3-(4-chlorophenyl)-3-oxo-
propanenitrile and sulfur furnished 1227 (Scheme 3). Similarly, the
reaction of 11 with ethyl cyanoacetate and sulfur, in our labora-
tory, afforded ethyl 2-amino-4,5-dihydrothieno[2,3-b]thiophene-
3-carboxylate 13 in 67% yield (Scheme 3). It is to be noted that both
12 and 13 have been formed without aromatization, while 3 has
been formed with aromatization. This suggests that the presence
of aryl ring in the intermediate 8 presumably facilitates the aroma-
tization via dehydrogenation as shown in the mechanism (Scheme
2) by forming a stabilized carbanion. From the formation of 3, it is
evident that the reaction of 4 with base gives preferentially 5 in-
stead of the other regioisomer 50 (Scheme 4), as the carbanion
The domino reactions presumably proceed through an initial
Knoevenagel condensation of 5-aryldihydro-3(2H)-thiophenones
formed by the abstraction of proton from the a-methylene adja-
cent to sulfur could be stabilized by conjugation with sulfur of
the five-membered ring as well. This explains the regioselective
formation of 3 in preference to 30.
All the newly synthesized compounds were screened for their
in vitro antimycobacterial activity against MTB and MDR-TB by
1 with activated nitrile 2 yielding an
a,b-unsaturated nitrile 4
(Scheme 2). This intermediate is then thiolated at the methylene
carbon by sulfur, followed by ring closure to afford 2-amino-5-
aryl-4,5-dihydrothieno[2,3-b]thiophenes 8 which further under-
O
CN
O
Cl
O
COOEt
S8
Cl
S
CH 2(CN)(COOEt),
Morpholine
8
NH2
NH2
S
S
S
S
Morpholine
S
11
12
13
Scheme 3. Gewald reactions of 11 with 3-(4-chlorophenyl)-3-oxopropanenitrile and ethyl cyanoacetate.

6194
K. Balamurugan et al. / Tetrahedron Letters 50 (2009) 6191–6195
N
X
X
X
N
S8/B
S
S
NH2
S
S
Ar
Ar
S
Ar
3'
4
5'
Scheme 4. Non-formation of regioisomer 30 from 4.
an agar dilution method and MICs of the synthesized compounds
along with the standard drugs for comparison are reported (Table
1). In the first phase of screening against MTB, all the compounds
showed good in vitro activity with MICs ranging from 1.1 to
chase of a high resolution NMR spectrometer and (ii) FIST program
and the University Grants Commission, New Delhi, for funds under
the DRS and ASIST programs.
97.5
ranging from 1.1 to 43.0
(MIC: 50.8 M). Three compounds (3b, 3d, and 3f) with MICs of
4.9, 2.3, and 1.1 M were more potent than first line anti-TB drug,
ethambutol (MIC: 7.6 M). Ethyl 2-amino-5-(1-naphthyl)thie-
no[2,3-b]thiophene-3-carboxylate (3f), the most active compound
in vitro with MIC of 1.1 M against MTB, was 7 and 45 times more
l
M. All compounds, except 3g, were more active with MICs
Supplementary data
l
M than standard drug pyrazinamide
l
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.085.
l
l
References and notes
l
potent than ethambutol and pyrazinamide, respectively, but less
active than isoniazid and rifampicin.
Subsequently, all the synthesized compounds were evaluated
against MDR-TB which inhibited it with MICs ranging from 1.1 to
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(1) Compounds with X = COOEt (3a–3f) possess more activity
against both MTB and MDR-TB than compounds with
X = CN (3g–3l). In both these sets of compounds, 3f and 3l
with 1-naphthyl ring displayed maximum activity against
both MTB and MDR-TB.
(2) Among the aryl groups in both sets of compounds, the same
order of activity viz. 1-naphthyl > p-PriC6H4 > p-MeC6H4 >
C6H5 is found against MTB as well as MDR-TB which probably
indicates that the lipophilicity and/or steric bulk of the
compounds is an important factor underlying the activity.
In conclusion, the present work describes a facile one-pot
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no-5-arylthieno[2,3-b]thiophenes 3 via domino Gewald reaction–
dehydrogenation sequence. These reactions occur expediently
under microwave irradiation affording a higher yield of the thieno-
thiophenes than the thermal method. These 2-amino-5-arylthieno-
[2,3-b]thiophenes also displayed good in vitro antimycobacterial
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Acknowledgments
S.P. thanks the Department of Science and Technology, New
Delhi, for funding for a major research project (No. SR/S1/OC-70/
2006) and for funds under (i) IRHPA program for funds for the pur-

K. Balamurugan et al. / Tetrahedron Letters 50 (2009) 6191–6195
6195
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3:(1) Conventional method: a mixture of 5-aryldihydro-3(2H)-thiophenones
(1 mmol), ethyl cyanoacetate or malononitrile (1 mmol), powdered sulfur
(2 mmol), and morpholine (1.5 mmol) was refluxed in ethanol (10 ml) for the
time mentioned in Table 1. The reaction mixture during reflux reached a
maximum temperature of 80 °C, which was measured by inserting the
thermometer inside the reaction mixture. After completion of the reaction as
monitored by TLC, the reaction mixture was filtered to remove sulfur powder,
the filtrate was concentrated under vacuum, and the residue was subjected to
column chromatography using petroleum ether/ethyl acetate mixture (4:1) as
eluent to afford the pure product 3.
product 3. Spectroscopic data for representative 2-amino-5-arylthieno[2,3-
b]thiophene 3 are given below.
Ethyl 2-amino-5-phenylthieno[2,3-b]thiophene-3-carboxylate (3a):
(Table 1, entry, 1): isolated as pale yellow solid. Mp 149 °C, yield 77%. IR (KBr):
1657 cmꢀ1 (C@O), 3312, 3419 cmꢀ1 (NH2); 1H NMR (CDCl3, 300 MHz): d 1.45
(t, 3H, J = 7.2 Hz, CH3), 4.40 (q, 2H, J = 7.2 Hz, CH2), 6.17 (s, 2H, NH2), 7.26–7.62
(m, 6H, aromatic and H-4); 13C NMR (CDCl3, 75 MHz): d 14.6 (CH3), 59.9 (CH2),
100.1, 117.7, 118.9, 125.6, 127.5, 128.9, 134.8, 143.3, 145.6, 165.2 (aromatic),
165.8 (C@O). Anal. Calcd for C15H13NO2S2: C, 59.38; H, 4.32; N, 4.62%. Found: C,
59.42; H, 4.38; N, 4.67%.
2-Amino-5-(4-methylphenyl)thieno[2,3-b]thiophene-3-yl cyanide (3h):
(Table 1, entry, 8): Isolated as colorless solid. Mp 225 °C, yield 73%. IR (KBr):
2205 cmꢀ1 (C„N), 3320, 3422 cmꢀ1 (NH2); 1H NMR (CDCl3, 300 MHz): d 2.29
(s, 3H CH3), 7.11 (s, 2H, NH2), 7.14–7.43 (m, 5H, aromatic and H-4); 13C NMR
(CDCl3, 75 MHz): d 19.3 (CH3), 111.8 (CN), 114.3, 116.5, 123.4, 128.0, 129.6,
135.6, 140.7, 144.4, 166.3 (aromatic). Anal. Calcd for C14H10N2S2: C, 62.19; H,
3.73; N, 10.36%. Found: C, 62.28; H, 3.80; N, 10.45%.
Ethyl 2-amino-4, 5 dihydrothieno[2,3-b]thiophene-3-carboxylate (13):
Isolated as a colorless solid. Mp 128 °C, yield 67%. IR (KBr): 1652 cmꢀ1 (C@O),
3330, 3410 cmꢀ1 (NH2); 1H NMR (CDCl3, 300 MHz): d 1.32 (t, 3H, J = 5.1 Hz,
CH3), 3.99 (t, 2H, J = 3.9 Hz, CH2), 4.14 (t, 2H, J = 3.6 Hz, CH2), 4.25 (q, 2H,
J = 7.5 Hz, CH2), 5.99 (s, 2H, NH2); 13C NMR (CDCl3, 75 MHz): d 14.4 (CH3), 33.4
(CH2), 36.1 (CH2), 59.7 CH2), 102.0, 117.8, 139.3, (aromatic) 165.1 (C2), 166.8
(C@O). Anal. Calcd for C9H11NO2S2: C, 47.14; H, 4.83; N, 6.11%. Found: C, 47.20;
H, 4.89; N, 6.16%.
(2) Microwave irradiation:
a mixture of 5-aryldihydro-3(2H)-thiophenones
(1 mmol), ethyl cyanoacetate or malononitrile (1 mmol), and powdered sulfur
(2 mmol) in ethanol (5 ml) was taken in a 10 ml quartz vial and placed in the
Biotage microwave oven. After addition of morpholine (1.5 mmol), the vial was
sealed and subjected to microwave irradiation. The irradiation was programed
at 140 °C, 40 W, 5 bar for the time given in Table 1. After a period of 2–5 min,
the temperature reached
a plateau, 140 °C, and remained constant. After
25 min. the vial was gas jet cooled to room temperature (5 min), the reaction
mixture was filtered to remove sulfur powder, the filtrate was concentrated
under vacuum, and the residue was subjected to column chromatography
using petroleum ether/ethyl acetate mixture (4:1) as eluent to afford the
26. Fu, T. L.; Wang, I. J. Dyes Pigments 2008, 76, 590–595.
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Carrion, M. D.; Cara, C. L.; Shryock, J. C.; Leung, E.; Moorman, A. R.; Gessi, S.;
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