A microwave-assisted facile regioselective Fischer indole synthesis and antitubercular evaluation of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles

Article abstract of DOI:10.1016/j.bmcl.2009.04.029

A series of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles has been synthesised regioselectively in good yields from the reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride. This reaction is found to be assisted by microwaves. T

Full text of DOI:10.1016/j.bmcl.2009.04.029

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3006–3009
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A microwave-assisted facile regioselective Fischer indole synthesis and
antitubercular evaluation of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles
b
Subramanian Vedhanarayanan Karthikeyan a, Subbu Perumal a, , Krithika Arun Shetty ,
*
Perumal Yogeeswari b, Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology and 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-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles has been synthesised regioselectively in
good yields from the reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride.
This reaction is found to be assisted by microwaves. The thieno[3,2-b]indoles were evaluated for their
in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis
(MDR-TB). Among 22 compounds screened, [2-(2,4-dichlorophenyl)-7-fluoro-3,4-dihydro-2H-thieno[3,2-
Received 5 March 2009
Revised 8 April 2009
Accepted 9 April 2009
Available online 14 April 2009
b]indole] (6t) was found to the most active compound with MIC of 0.4 lg/mL against MTB and MDR-TB.
Keywords:
Microwave assisted
Ó 2009 Elsevier Ltd. All rights reserved.
Fischer indole synthesis
Antitubercular activity
Mycobacterium tuberculosis
Multi-drug resistant tuberculosis
Minimum inhibitory concentration
For well over a hundred years, the synthesis and functionaliza-
tion of indoles has been a major area of focus for synthetic organic
chemists, and numerous methods for the preparation of indoles
have been developed.1 Among the synthetic methodologies re-
ported so far for the preparation of the indole analogs, the Fischer
indole synthesis still maintains its prominent role for the large
scale production of biologically active compounds.2 Indoles are of
great significance in view of their (i) occurrence in nature as a
prominent sub-structure of a large number of alkaloids,3 and (ii)
wide-ranging biological activities.4 Some indole derivatives func-
tion as dopamine agonists and/or selective serotonin reuptake
inhibitors (SSRIs), the latter being a class of anti-depressants.5
Acemetacin6 and indometacin7 are clinically used as anti-inflam-
matory drugs and fluvastatin sodium8 is a well-known HMG-CoA
reductase inhibitor.
Thiophene fused nitrogen heterocycles also display important
biological activities. For instance, thienoquinolones display antitu-
mour activities,9 while thienopyrimidinones possess analgesic and
anti-inflammatory activities.10 Thienocarbolines and heteroaryl-
aminobenzothiophenes exhibit antimicrobial11 and anti-oxidant
activities12 respectively. The biological importance of indoles and
thiophene fused nitrogen heterocycles prompted the Fischer indole
synthesis of the hitherto unreported 2-aryl-3,4-dihydro-2H-thie-
no[3,2-b]indoles 6 in excellent yields (Scheme 1) and their screen-
ing for antimycobacterial activities. This study forms part of our
research programme embarked on to evolve new methodologies
for the construction of novel heterocycles13 and to discover new
lead molecules with antimycobacterial activities.14
This study assumes importance as tuberculosis has become one
of the most prevalent diseases that is responsible for the death of
about one billion people during the last two centuries.15 TB re-
mains a serious public health problem in India, accounting for
nearly one-third of the global burden, and it has been estimated
that 3.5 million of the population are infected with TB.15,16 Cur-
rently, the recommended standard chemotherapeutic regimen for
TB treatment prescribed under DOTS comprises an initial 2-month
phase of treatment with isoniazid, rifampicin, pyrazinamide, and
ethambutol followed by a continuation phase of treatment lasting
4 months with isoniazid and rifampicin.17,18 Poor patient compli-
ance can promote the emergence of drug resistance, and this is
particularly true in TB chemotherapy.17,18 The emergence of strains
resistant to either of these drugs causes major concern, as it leaves
only drugs that are far less effective, have more toxic side effects,
and result in higher death rates, especially among HIV-infected
persons. Serial selection of drug resistance, thus, is the predomi-
nant mechanism for the development of MDR strains; the pa-
tients with MDR strains constitute a pool of chronic infections,
* Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.029

S. V. Karthikeyan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3006–3009
3007
NH-NH2.HCl
COOH
COOH
COOH
S
Dioxan, Et3N
Reflux
Ar
Ac2O, NaOAc
Reflux
X
5
HS
COOH
Ar
S
Ar
O
EtOH Reflux
or MW
1
2
3
4
S
Ar
X
N
H
6
Scheme 1.
which propagate primary MDR resistance. In addition to accumu-
lation of mutations in the individual drug target genes, the per-
meability barrier imposed by the MTB cell wall can also
contribute to the development of low-level drug resistance.19,20
In the last 50 years, only a few drugs have been approved by
the Food and Drug Administration (FDA) to treat TB, which re-
flects the inherent difficulties in the discovery and clinical testing
of new agents and the lack of pharmaceutical industry research in
this area.21 Hence, the discovery of fast-acting effective newer
drugs to effectively cure TB, including multidrug resistant tuber-
culosis, is imperative.
reaction mixture reached a temperature of 80 °C during reflux as
measured by inserting a thermometer inside the reaction mixture.
Work up of the reaction mixture after completion of the reaction
(TLC) followed by crystallization afforded the product 6 in a pure
state in good yields (80–95%).
This reaction was further investigated under microwave irradi-
ation with a view to exploring whether, (i) the reaction could be
expedited and, (ii) the yield of 6 could be enhanced. A mixture of
5-aryldihydro-3(2H)-thiophenones 4 and arylhydrazine hydro-
chloride 5 in the molar ratio of 1:1.3 in ethanol taken in a sealed
tube (10 mL) was subjected to microwave irradiation22 at 90 °C
and 2 bar pressure for 3–6 min. The reaction progress was moni-
tored after every 1 min of irradiation by TLC. This reaction also fur-
nished pure product in excellent yields (85–98%; Table 1). The
temperature of 90 °C was chosen to obtain the optimum reaction
In a typical reaction, the synthesis of 2-aryl-3,4-dihydro-2H-thi-
eno[3,2-b]indoles 622 was effected by refluxing a mixture of 5-aryl-
dihydro-3(2H)-thiophenones 413e,h and arylhydrazine hydrochloride
5 (Scheme 1) in a 1:1.3 molar ratio in ethanol for 30–70 min. The
Table 1
Synthesis and antimycobacterial activities of 2-aryl-3,4-dihydro-2H-thieno [3,2-b]indoles 6
Compound
Ar
X
Reaction time (min)
Refluxa (80 °C) MWb (90 °C)
Yield of 6 (%)
Refluxc
MIC (l
g/mL)
MDR-TB
MWc
MTB
d
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
C6H5
H
H
H
H
H
H
H
H
50
50
50
70
70
60
60
65
40
40
30
40
30
30
40
40
40
40
40
30
30
50
3
5
3
6
5
6
6
5
5
5
4
5
4
4
6
5
5
5
5
4
4
6
95
90
92
88
85
80
83
85
80
83
85
85
90
83
80
85
80
80
85
95
85
80
97
95
95
90
93
92
90
88
85
90
90
95
98
90
88
90
95
95
90
97
95
85
25.00
12.50
6.25
1.76
1.76
3.13
6.25
3.13
0.78
12.50
12.50
6.25
0.78
3.13
0.78
3.13
6.25
1.56
3.13
0.40
1.76
0.78
0.05
0.10
1.56
6.25
—
—
d
4-ClC6H4
4-MeC6H4
2,4-Cl2C6H3
3-O2NC6H4
2-BrC6H4
2-ClC6H4
3-FC6H4
12.50
0.78
0.78
3.13
d
—
—
d
4-PriC6H4
C6H5
H
0.40
d
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-F
7-F
7-F
7-F
7-F
7-F
—
—
d
4-ClC6H4
4-MeC6H4
2,4-Cl2C6H3
2-ClC6H4
4-PriC6H4
4-FC6H4
6.25
0.40
1.56
0.78
0.78
12.50
1.56
1.56
0.40
1.56
0.40
1.56
3.13
12.50
50.00
6q
6r
6s
6t
6u
6v
C6H5
4-ClC6H4
4-MeC6H4
2,4-Cl2C6H3
2-ClC6H4
4-PriC6H4
Isoniazid
Rifampicin
Ethambutol
Pyrazinamide
a
Refluxed in ethanol.
Irradiated with ethanol.
Yield after crystallization from chloroform.
Not tested.
b
c
d

3008
S. V. Karthikeyan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3006–3009
37.2 ppm and C-2’ and C-60 at 128.6 ppm. The diastereotopic 3-
5'
Cl
6'
1'
CH2 protons appeared as a doublet of doublets at 3.30 and
3.56 ppm (J = 15.5, 7.7 Hz and 15.5, 8.6 Hz). These protons showed
HMBC correlations with ipso carbons C-3a, C-8b and C-1’, respec-
tively at 140.9, 112.3 and 134.2 ppm. The NH proton gave a broad
singlet at 7.98 ppm.
Although the Fischer indole synthesis is the most widely used
method for the preparation of indoles, it suffers from (i) low yields,
2a,b,24,25 (ii) formation of numerous by-products, and (iii) low
regioselectivity in the case of unsymmetrical ketones.2a,b,26–29 In
contrast, the reaction in the present work led to the exclusive for-
mation of one regioisomer of thienoindoles 6 in very good yield un-
der mild reaction conditions. The other regioisomer 12 (Fig. 2) is
not obtained even in traces in this reaction. The structure of 6 is
readily assigned from the AMX spin system arising from the H-2
and 3-CH2 hydrogens in its 1H NMR spectrum, which distinguishes
from the regioisomer 12.
During the preparation of this manuscript, we came across a lit-
erature report on the synthesis of unsubstituted dihydrothie-
no[3,2-b]indole lacking the aryl ring at 2-position in 60% yield
from the reaction of dihydrothiophen-3(2H)-one and phenylhydr-
azine hydrochloride in ethanol, in contrast to the excellent yields
(88–97%) of 6 obtained in the present work.30 This prompted us
to reexamine the reaction between dihydrothiophen-3(2H)-one
and phenylhydrazine hydrochloride in ethanol, which led to an en-
hanced yield (90%) of the product. It is pertinent to note that there
are only a few reports on the synthesis of dihydrothieno[3,2-b]in-
doles30,31 and thieno[3,2-b]indoles.32
A plausible mechanism for the formation of 6 involving a [3,3]-
sigmatropic rearrangement of the enehydrazine tautomer 8 to 9
with concomitant cyclization and aromatization with the loss of
ammonia is depicted in Scheme 2. The regioselectivity of this reac-
tion is presumably ascribable to the influence of sulfur in favouring
the formation of the tautomer 8 with the double bond involving
the carbon bearing sulfur which ultimately leads to the regioiso-
meric thienoindole 6.
1
S
H
2
8
4'
7
8a 8b
3'
6
2'
3a
3
4a
H
5
N
4 H
H
Figure 1. HMBC correlations in 6b.
time. Any further increase in the temperature failed to enhance the
reaction rate substantially, while lowering the temperature below
90 °C did slow down the reaction.
To enable a comparison of the efficacies of the thermal and
microwave reactions, the reaction under microwave irradiation
was also performed in one representative case, viz. 6a at the tem-
perature of the reaction mixture at reflux under thermal condi-
tions, viz. 80 °C. At 80 °C, the reaction under microwave
irradiation was completed in 5 min, viz. ten times faster than the
thermal reaction (50 min) in the same solvent showing that the
reaction is assisted by microwaves.
5-Aryldihydro-3(2H)-thiophenones 4 were prepared by a litera-
ture method23 with slight modifications described below. Addition
of triethyl amine in dioxan to a mixture of mercaptoacetic acid 2
and cinnamic acid 1 in dioxan yielded the 3-[(carboxymethyl)sul-
fanyl]-3-arylpropanoic acids 3, which upon heating on an oil-bath
at 120 °C with acetic anhydride and sodium acetate (in place of
lithium acetate23 employed in the previous study) to afford 4.
The solid product obtained in both the steps were filtered and
washed well with water to obtain pure product instead of extrac-
tion with ether in the previous study. These modifications resulted
in an enhancement in yield of the product (ꢀ10%) in the present
investigation.
The structure of the 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles
6 was established from 1H, 13C and 2D NMR spectroscopic data as
illustrated for 6b. In the 1H NMR spectrum of 6b, H-2 appeared as a
1H triplet at 5.46 ppm (J = 8.3 Hz) which showed HMBC correla-
tions ( Fig. 1) with the ipso carbon (C-3a) at 140.9 ppm, C-3 at
All the newly synthesized compounds were screened for their
in vitro antimycobacterial activity against MTB and MDR-TB by
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
S
showed good in vitro activity against MTB with MIC of 625
mL. Five compounds (6i, 6m, 6o, 6t and 6v) inhibited MTB with
MIC of <1 g/mL and were more potent than standard ethambutol
g/mL) and pyrazinamide (MIC: 6.25 g/mL). The com-
[2-(2,4-dichlorophenyl)-7-fluoro-3,4-dihydro-2H-thie-
lg/
N
H
Ar
l
(MIC: 1.56
l
l
12
pound,
(not formed)
no[3,2-b]indole] (6t) was found to be the most active in vitro
Figure 2. Regioisomer of 6.
with MIC of 0.4
lg/mL against MTB and was 4 and 16 times more
Ar
NH-NH2
S
H
S
S
Ar
S
H
Ar
Ar
[3,3]
+
O
NH N
NH N
NH2
X
X
X
4
H2
NH
Ar
X
7
5
8
9
S
H
S
S
Ar
Ar
-NH3
NH2
X
X
N
N
NH2
NH2
X
H
H
10
6
11
Scheme 2. Proposed mechanism for the formation 6.

S. V. Karthikeyan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3006–3009
3009
7. Shen, T. Y.; Windholz, T. B.; Rosegay, A.; Witzel, B. E.; Wilson, A. N.; Willett, J.
D.; Holtz, W. J.; Ellis, R. L.; Matzuk, A. R.; Lucas, S.; Stammer, C. H.; Holly, F. W.;
Sarett, L. H.; Risley, E. A.; Nuss, G. W.; Winter, C. A. J. Am. Chem. Soc. 1963, 85,
488.
potent than ethambutol and pyrazinamide respectively. Subse-
quently, sixteen compounds were evaluated against MDR-TB and
all these compounds inhibited MDR-TB with MIC ranging from
8. Hayashi, K.; Kurokawa, J.; Nomura, S.; Kuga, Y.; Ohkura, Y.; Kajiyama, G.
Biochim. Biophys. Acta 1993, 1167, 223.
9. Jarak, I.; Kralj, M.; Piantanida, I.; Suman, L.; Zinic, M.; Pavelic, K.; Karminiski-
Zamola, G. Bioorg. Med. Chem. 2006, 14, 2859.
0.4 to 12.5
and 6v) inhibited MDR-TB with MIC of <1
potent than the currently available anti-TB drugs such as isoniazid
l
g/mL. Eight compounds (6d, 6e, 6i, 6m, 6o, 6p, 6t
lg/mL and were more
10. Alagarsamy, V.; Meena, S.; Ramseshu, K. V.; Solomon, V. R.; Thirumurugan, K.;
Dhanabal, K.; Murugan, M. Eur. J. Med. Chem. 2006, 41, 1293.
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Estevinho, L. M. Bioorg. Med. Chem. 2006, 14, 6827.
12. Queiroz, M. J. R. P.; Ferreira, I. C. F. R.; Estevinho, L. M. Bioorg. Med. Chem. 2007,
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13. (a) Suresh Kumar, R.; Perumal, S.; Kagan, H. B.; Guillot, R. Tetrahedron:
Asymmetry 2007, 18, 170; (b) Indumathi, S.; Ranjith Kumar, R.; Perumal, S.
Tetrahedron 2007, 63, 1411; (c) Srinivasan, M.; Perumal, S. Tetrahedron 2007,
63, 2865; (d) Kamal Nasar, M.; Ranjith Kumar, R.; Perumal, S. Tetrahedron Lett.
2007, 48, 2155; (e) Karthikeyan, S. V.; Perumal, S. Tetrahedron Lett. 2007, 48,
2261; (f) Ranjith Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 12220; (g)
Savitha Devi, N.; Perumal, S. Tetrahedron Lett. 2007, 48, 5627; (h) Karthikeyan,
S. V.; Perumal, S.; Balasubramanian, K. K. Tetrahedron Lett. 2007, 48, 6133.
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J. Med. Chem. 2008, 51, 5731; (b) Ranjith Kumar, R.; Perumal, S.; Senthilkumar,
P.; Yogeeswari, P.; Sriram, D. Tetrahedron 2008, 64, 2962; (c) Ranjith Kumar, R.;
Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett.
2007, 17, 6459.
(MIC: 1.56
(MIC: 12.5
l
g/mL), rifampicin (MIC: 3.13
l
g/mL), ethambutol
lg/mL) and pyrazinamide (MIC: 50.0
lg/mL). Com-
pounds 6i, 6m, 6t and 6v were found to display maximum activity
in vitro with MIC of 0.4 g/mL against MDR-TB, being 4 and 8 times
l
more potent than isoniazid and rifampicin respectively.
With respect to structure–MTB activity relationship, the results
demonstrated that the presence of halogens in the thienoindole
moiety enhances the activity. Among the halogens, fluoro deriva-
tives exhibit greater activity than chloro derivatives. With respect
2-aryl group, aryl ring with halogen or propyl group enhances the
activity. Similarly disubstitution in the aryl ring also amplifies the
activity.
The present work describes a microwave-assisted facile, effi-
cient and rapid regioselective Fischer indole synthesis of new 2-
aryl-3,4-dihydro-2H-thieno[3,2-b]indoles in excellent yields under
mild reaction conditions. These thienoindoles displayed good
in vitro antimycobacterial activity against MTB and MDR-TB.
15. World Health Organization, Tuberculosis Fact Sheet 2006, http://
www.who.int/tb/publications/2006/tb_factsheet_2006_1_en.pdf.
16. Granich, R.; Wares, F.; Suvanand, S.; Chauhan, L. S. Lancet Infect. Dis. 2003, 3,
535.
17. Sharma, D. C. Lancet Infect. Dis. 2003, 3, 265.
Acknowledgments
18. Bass, J. B.; Farer, L. S.; Hopewell, P. C.; O’Brien, R.; Jacobs, R. F.; Ruben, F.; Snider,
D. E.; Thornton, G. Am. J. Respir. Crit. Care Med. 1994, 149, 1359.
19. Bhowruth, V.; Dover, L. G.; Besra, G. S. Prog. Med. Chem. 2007, 45, 169.
20. Rattan, A.; Kalia, A.; Ahmad, N. Emerg. Infect. Dis. 1998, 4, 195.
21. O’Brien, R. J.; Nunn, P. P. Am. J. Respir. Crit. Care Med. 2001, 163, 1055.
22. General procedure for the synthesis of 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles
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-
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. S.V.K. thanks the Council of Scientific
and Industrial Research, New Delhi for the award of a Senior Re-
search Fellowship.
6: Conventional method:
A mixture of 5-aryldihydro-3(2H)-thiophenone
(4.7 mmol) and arylhydrazine hydrochloride (6.1 mmol) was refluxed in
ethanol for 50–70 min. The progress of the reaction was monitored by thin-
layer chromatography. After completion of the reaction, the reaction mixture
was poured onto crushed ice, the resulting solid filtered and crystallized from
chloroform to afford 6.Under microwave irradiation: 5-Aryldihydro-3(2H)-
thiophenone (0.52 mmol) and arylhydrazine hydrochloride (0.68 mmol) was
dissolved in ethanol (5 mL) and subjected to MW irradiation (Biotage
microwave oven, 90 °C, 2 bar pressure) for 3–6 min. The progress of the
reaction was monitored by thin-layer chromatography. After completion of the
reaction, the reaction mixture was poured onto crushed ice, the resulting solid
filtered and crystallized from chloroform to afford 6.Spectroscopic data for
representative dihydrothienoindole is given below.2-(4-Chlorophenyl)-3,4-
dihydro-2H-thieno[3,2-b]indole, 6b: (Table 1, entry 2): Pale yellow solid;
mp = 165–166 °C; 1H NMR (300 MHz, CDCl3) dH 3.30 (dd, 1H, J = 15.5,
7.7 Hz), 3.56 (dd, 1H, J = 15.5, 8.6 Hz), 5.46 (t, 1H, J = 8.3 Hz), 7.10–7.19 (m,
2H), 7.27–7.34 (m, 3H), 7.38–7.43 (m, 3H), 7.98 (br s, 1H). 13C NMR (75 MHz,
CDCl3) dC 37.2, 57.9, 111.7, 112.3, 118.7, 120.1, 121.6, 122.9, 128.6, 128.8,
133.4, 134.2, 140.2, 140.9. Anal. Calcd for C16H12ClNS: C, 67.24; H, 4.23; N, 4.90.
Found: C, 67.30; H, 4.30; N, 4.98.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.029.
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