Synthesis and antimicrobial activities of highly functionalised novel β-lactam and thiazolidine-grafted tetrahydrobenzothiophenes

Article abstract of DOI:10.1007/s00044-012-0259-8

A series of biologically active N-(3-chloro-2-oxo-4-phenylazetidin-1-yl)/3- N-(4-oxo-2-arylthiazolidin-3-yl)-2-(methylsulfonamido)-4,5,6, 7-tetrahydrobenzo[b]thiophene-3-carboxamides derivatives have been synthesised in good yield. The structures of compounds have been established on the basis of IR, ¹H, ¹³C NMR, and elemental analysis. The structure-activity relationships have been studied by screening of antimicrobial activity over a representative panel of bacterial and fungal strains using two-fold serial dilution method. All these synthesised compounds exhibited significant activities against all bacterial and fungal strains.

Full text of DOI:10.1007/s00044-012-0259-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:2964–2974
DOI 10.1007/s00044-012-0259-8
ORIGINAL RESEARCH
Synthesis and antimicrobial activities of highly functionalised
novel b-lactam and thiazolidine-grafted
tetrahydrobenzothiophenes
•
Mariappan Babu Kasi Pitchumani
•
Penugonda Ramesh
Received: 4 May 2012 / Accepted: 22 September 2012 / Published online: 7 November 2012
ꢀ Springer Science+Business Media New York 2012
Abstract A series of biologically active N-(3-chloro-2-
oxo-4-phenylazetidin-1-yl)/3-N-(4-oxo-2-arylthiazolidin-3-
yl)-2-(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxamides derivatives have been synthesised
in good yield. The structures of compounds have been
established on the basis of IR, 1H, 13C NMR, and elemental
analysis. The structure–activity relationships have been
studied by screening of antimicrobial activity over a rep-
resentative panel of bacterial and fungal strains using two-
fold serial dilution method. All these synthesised com-
pounds exhibited significant activities against all bacterial
and fungal strains.
nocardicins and monolactams, which are also used as
chemotherapeutic agents for treating microbial diseases.
(Halve et al., 2007). Derivatives of b-lactam also act as
antihyperglycemic (Jenny, 2006), antitumour (Veinberg
et al., 2004), anti-HIV (Sperka et al., 2005), anti-inflam-
matory, analgesic agents (Saturnino et al., 2000) and ser-
ine-dependent enzyme inhibitors (Clemente et al., 2001).
Hence, there has been renewed interest in the synthesis of
such interesting b-lactam-based heterocycles with potential
applications. Likewise, thiazolidinones also exhibit anti-
microbial, anthelmintic, anti-HIV, antiviral, antiradiation,
anticonvulsant and hypnotic activities (Rao et al., 2004;
Kucukguzel et al., 2006).
Keywords Azetidine ꢀ Thiazolidine ꢀ
Another heterocyclic system which has been the subject
of extensive chemical and pharmacological investigations
in recent times is the tetrahydrobenzothiophene (THBT).
2-Amino-3-ethoxycarbonyl-tetrahydrobenzothiophene core
is a potent pharmacophore and compounds encompassing
this structural core (e.g. tetrahydrothiophene pyrazine car-
boxylate analogues) are reported to be potent inhibitors of
NS5B polymerase (Laporte et al., 2006), an enzyme that is
essential for the replication of hepatitis C (HCV) a positive
single-stranded RNA virus which is responsible for high
mortality due to chronic hepatitis, cirrosis and heptocellu-
lar carcinoma (Cohen, 1999). Further, structure–activity
relationship (SAR) studies disclosed (Laporte et al., 2006)
that the presence of an acidic moiety such as acyl sulfon-
amide on 2-amino group of THBT increases the activity
against HCV polymerase, while maintaining selectivity.
In view of antiviral properties associated with 2-amino-3-
ethoxycarbonyl-tetrahydrobenzothiophene structural core
and in continuation of our interest on antimicrobial properties
of azetidin-2-ones and thiazolidin-4-ones incorporating
coumarin core (Jeyachandran & Ramesh, 2009), we antici-
pated that THBT-grafted azetidinones and thiazolidinones
Antimicrobial screening ꢀ Tetrahydrobenzo[b]thiophene
Introduction
Azetiditine, the b-lactam, as a synthetic intermediate has
been widely recognised in organic synthesis (Alcaide et al.,
2007; Alcaide and Almendros, 2004; Deshmukh et al.,
2004; Claudio et al., 2001; Alcaide and Almentros, 2002)
because it is an active moiety present in most widely used
´
antibiotics such as penicillins (Brynaert and Brule, 2008),
cephalosporins (Alcaide et al., 2008), carbapenems,
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-012-0259-8) contains supplementary
material, which is available to authorized users.
M. Babu ꢀ K. Pitchumani ꢀ P. Ramesh (&)
Department of Natural Products Chemistry,
School of Chemistry, Madurai Kamaraj University,
Madurai 625 021, Tamil Nadu, India
e-mail: npc_ramesh@yahoo.co.in
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Med Chem Res (2013) 22:2964–2974
2965
might exhibit useful biological properties. With this objec-
tive, we have undertaken the synthesis of a series of hitherto
unknown THBT-grafted azetidin-2-ones (5a–j) and thiaz-
olidin-4-ones (6a–j) from 2-methanesulfonamido-2-ethox-
ycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene core. The
attachment of methanesulfonyl moiety (mesyl) to 2-NH2
function serves two purposes: (a) it acts as a versatile pro-
tecting group facilitating chemoselective reactions at the
adjacent ethoxycarbonyl group for assembling azetidinone
and thiazolidinone nuclei. (b) It also modulates the pharma-
cokinetic properties of synthesised compounds by altering
their lipophilicity.
thiazolidinones 6a–j (Scheme 1). The intermediates and
final products have been characterised by their spectro-
1
scopic data (IR, H NMR and 13C NMR.).
Compound 4a (a representative example) was homoge-
neous on TLC and contained nitrogen and sulphur. The
appearance of IR bands at 3410, 3271 and 1673 cm-1 sug-
gested the presence of NHSO2Me, –CONH and amide (car-
1
bonyl) groups in it. In the H NMR spectrum of 4a, the
upfield multiplet (4H) centred at d 1.79–1.92 was assigned to
the methylene protons of C-5 and C-6, while the downfield
multiplet (4H) centred at d 2.35 was ascribed to the methy-
lene protons of C-4 and C-7. The three-proton singlet at d
2.82 was due to methyl group of –NHSO2Me, and the sharp
low intensity signal at d 4.19 integrating for one-proton was
ascribed to the amino proton of –NHSO2Me group. The sharp
low intensity one-proton singlet in the aromatic region at d
8.12 was assigned to N-benzylidene methine proton
(N=CHPh) and the far downfield sharp one-proton singlet
that exchanged with D2O was assigned to the proton of
NHCO. The aromatic protons (5H) resonated as a complex
multiplet in the region d 7.38–7.72. The 13C NMR spectrum
of 4a registered among other signals, a downfield carbon
signal at d 163.9 assignable to carbonyl carbon of CO–NH–
N= unit. On the basis of comparitive spectroscopic data of 4a
with that of its precursor 3, 4a has been formulated as N-(3-
(2-benzylidenehydrazinylcarbonyl)-4,5,6,7-tetrahydrobenzo-
[b]thiophen-2-yl)methanesulfonamide.
The synthetic plan for assembling THBT-grafted azetidi-
nones and thiazolidinones is outlined in Scheme 1. As a pre-
liminary study to assess the biological properties of THBT-
grafted azetidinones/thiazolidinones, we have subjected
5a–j and 6a–j for antibacterial and antifungal screening
(Table 1). The details pertaining to synthesis, characterisa-
tion, and antimicrobial evaluation of THBT-grafted azetidi-
nones/thiazolidinones are presented in this paper.
Results and discussion
Reaction of ethyl 2-(methylsulfonamido)-4,5,6,7-tetra-
hydrobenzo[b]thiophene-3-carboxylate (2), with hydrazine
hydrate in boiling alcohol afforded N-(3-(hydrazinylcar-
bonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)methane-
sulfonamide (3). Condensation of 3 with appropriate
aromatic aldehydes yielded the corresponding Schiff bases
4a–j, which on reaction with chloroacetyl chloride (TEA,
DME) gave azetidinones 5a–j, while similar reaction of
4a–j with thioglycolic acid (ZnCl2/DMF) afforded the
Compound 5a was homogeneous on TLC and answered
for nitrogen, sulphur and chlorine. In the IR spectrum of
5a, a pair of bands of equal intensity at 3324 and
3262 cm-1 were ascribed to N–H stretching vibrations of
CO–NH and NHSO2Me groups. Of the pair of high inten-
sity sharp bands, the one at 1745 cm-1 was assigned to CO
Table 1 Antibacterial activity of compounds 5(a–j) and 6(a–j)
Antibacterial activity of compounds
(zone of inhibition (diameter) mm at 10 lg/mL)
Compounds
5a–j
6a–j
B. subtilis ATCC 6631
E. coli ATCC 35218
B. subtilis ATCC 6631
E. coli ATCC 35218
a (Ph)
6
7
7
6
8
7
8
7
6
6
9
6
7
5
6
7
5
8
6
8
6
7
6
9
6
11
7
b (2-Cl)
c (3-NO2)
10
8
d (4-OMe)
11
8
e (4-Cl)
9
f (3,4-diOMe)
g (4-NO2)
8
7
10
9
10
10
7
h (3-indolyl)
i (3-chromonyl)
j (2-chloro-quinolin-3-yl)
Ciproflaxacin
8
6
8
12
12
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Med Chem Res (2013) 22:2964–2974
Scheme 1 Synthetic route to
title compounds 5a-j and 6a-j
Me
Me
O
O
O
O
MsCl /
TMA / Δ
NH2
NHMs
S
S
1
2
NH2-NH2. H2O /
Δ
Ms = SO2CH3
EtOH
NH2
O
NH
NHMs
S
3
Ar-CHO /
Piperidine
H
O
N
N
Ar
NHMs
S
4 a-j
ClCH 2COCl
TEA / DMF
HSCH2COOH
ZnCl2 / DMF
1'
5'
S
H
O
2'
O
4'
N
Ar
Cl
N
1'
N
4'
4
3
3'
Ar
O
NHMs
5
N
3'
2
H
2'
6
S
O
1
7
NHMs
S
5 a-j
6 a-j
group of the strained azetidine moiety, while the other band
at 1685 cm-1 was ascribed to the C=O of carbamoyl unit.
spectrum of 5a registered only two carbon signals at d
163.1 and 168.4; the downfield signal d 168.4 was assigned
to the carbon of C=O of azetidinone, while the upfield
signal d 163.1 which was also present in the 13C NMR
spectrum of its precursor 4a, was due to CO of –CONH.
TheformationofTHBTgraftedintactazetidinonemolecule
was revealed from the molecular ion peak (m/z 453) and
1
In the H NMR spectrum of 5a, the upfield three-proton
singlet at d 2.76 was due to methyl group of –NHSO2Me
and the low intensity one-proton singlet at d 4.11 was due
to NH of SO2Me. A pair of one-proton doublets
(J = 12.3 Hz) at d 4.73 and 5.16 were assigned to vicinal
methine protons H-4 and H-3, respectively, of azetidinone
moiety (Ar–CH–CH–Cl). The aromatic protons (5H) res-
onated as a complex multiplet in the region d 6.98–7.65
and the downfield one-proton sharp singlet at d 9.68 was
ascribed to NH proton of –CONH–. The 13C NMR
fragment ion peaks at m/z 376 (M?•–C6H5 , 65), m/z 321
•
(M?•–C8H4S, 100), 136 (C8H8S?•). The appearance of frag-
ment ions at m/z 136 (C8H8S?•) and 165 (C9H9S?O) con-
firmed the presence of THBT core in 5a while the prominent
fragment peaks at m/z 195 (C9H8OClN2?•, 25), 181
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Med Chem Res (2013) 22:2964–2974
2967
(C9H8OClN?•, 38) and 103 (C6H5C:N?•) proved beyond
doubt the formation of 3-chloro-4-phenylazetidin-2-one moi-
ety in 5a.
ion peaks at m/z 165 (C9H9OS?) and 136 (C8H8S?•) are
diagnostic of THBT core.
Thus based on the above evidence, 6a has been formulated
as 2-(methylsulfonamido)-N-(4-oxo-2-phenylthiazolidin-3-
yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide.
1
A comparison of spectroscopic data (IR, H NMR, 13C
NMR and DEPT-135) of 5a with that of 4a (Schiff base)
proved the presence of azetidinone moiety in 5a and
established the structure of 5a as N-(3-chloro-2-oxo-4-
phenylazetidin-1-yl)-2-(methylsulfonamido)-4,5,6,7-tetra-
hydrobenzo[b]thiophene-3-carboxamide.
Antimicrobial activity
Compound 6a was homogeneous on TLC and answered
for nitrogen and sulphur. Its IR spectrum displayed a pair
of sharp bands of equal intensity at 3320 and 3261 cm-1
due to N–H stretch (CO–NH and –NHSO2Me) and a low
intensity sharp band at 1740 cm-1 was assigned to CO of
the thiazolidine ring and the strong band at 1672 cm-1 was
ascribed to CO of –NHCO unit. The presence of SO2
moiety of SO2Me was revealed by the characteristic bands
at 1345 (strong) and 1164 cm-1 (medium) (for antisym-
metric and symmetric stretching vibrations of SO2 group).
The 1H NMR spectrum of 6a displayed in addition to
signals due to protons of ring methylene (d 1.52–1.79 and
2.62–2.78) and protons of methyl group of SO2Me (d 3.16),
a pair of one-proton doublets (J = 2.1 Hz) at d 4.81 and
5.08. From the magnitude of the coupling constant
(J = 2.1 Hz), these signals were assigned to the geminal
protons of C–5 of the thiazolidinone ring; such geminal
coupling is generally observed only in rigid cyclopenta-
none ring system, where the geminal hydrogens are adja-
cent to CO group. (Williams and Fleming, 2001) The low
intensity one-proton singlet at d 6.28 was ascribed to N-
benzylic methine proton (–NCHPh) of the thiazolidinone
ring. The far downfield one-proton singlet at d 9.64 was
assigned to the proton of –NH–CO– unit and the aromatic
protons appeared as a complex multiplet (5H) in the region
d 7.26–7.52. The 13C NMR spectrum of 6a registered six
aliphatic carbon signals, which were grouped into four
methylene, one methine and one methyl carbon based on
DEPT experiment; of the two downfield carbon signals, the
one at d 168 was ascribed to carbon of CO of thiazolidi-
none ring, while the upfield signal at d 164.8, which was
also present in the 13C NMR spectrum of its precursor 4a,
was assigned to the carbon of C=O of –NHCO– unit. A
Antibacterial activity
The newly synthesised compounds 5a–j and 6a–j were
evaluated for in vitro antibacterial activity against micro-
organisms, Bacillus subtilis ATCC 6631 and Escherichia
coli ATCC 35218 which were obtained from Bose Clinical
Laboratory, Madurai.
The agar diffusion method (Nogrady, 2004) was used
for the determination of antibacterial activity of synthes-
ised compounds 5a–j and 6a–j against microorganism
listed above. The results of antibacterial activity of the
synthesised b-lactam and thiazolidine compounds 5a–j and
6a–j against human bacterial pathogens with ciprofloxacin
as reference control were presented in Table 1.
Antibacterial screening data (Table 1) revealed that all the
tested compounds, 5a–j and 6a–j registered significant
activity against both Gram-positive and Gram-negative
bacteria at a concentration of 10 lg/mL. Compounds 5b (2-
Cl), 5c (3-NO2), 5e (4-Cl), 5f (3,4-diOMe), 5g (4-NO2) and
5h (3-indolyl) showed significant activity in the order
5e = 5g [ 5b = 5c = 5f = 5h against B. subtilis, whereas
compounds 5b (2-Cl), 5c (3-NO2), 5d (4-OMe), 5e (4-Cl), 5f
(3,4-diOMe), 5 g (4-NO2), 5 h (3-indolyl), 5i (3-chromonyl)
registered significant inhibition in the order 5c = 5g [
5h = 5e [ 5d = 5f = 5i [ 5b [ 5j against E. coli.
Among compounds of 6a–j series, 6e (4-Cl), 6g (4-
NO2), 6c (3-NO2), 6i (3-chromonyl) showed high activity
against B. subtillis, while 6b (2-Cl), 6d (4-OMe), 6g (4-
NO2), 6h (3-indolyl) and 6j (2-chloroquinolin-2-yl) regis-
tered high activity against E. coli. Compounds 5/6e and 5/
6g registered very high activity against both Gram-positive
(B. subtillis) and Gram-negative (E. coli) organisms; the
level of activity is almost comparable to that of the stan-
dard (ciprofloxacin) and they turn out to be the most potent
antibacterial compounds of 5 and 6 series.
1
comparison of the spectroscopic data (IR, H NMR, 13C
NMR and DEPT) of 6a with that of its precursor 4a
established the formation of the thiazolidinone ring in 6a.
The formation of intact THBT grafted 4-oxo-2-phenyl-
thiazolidine is evident by the appearance of parent ion peak
of moderate intensity at m/z 451 (20) and fragment ion
A scrutiny of results of antibacterial activity disclosed
that electron-withdrawing groups of aryl moiety increased
the antibacterial activity. The significant activity shown by
compounds 5d (4-OMe) and 6f (3,4-diOMe) is under-
standable on the assumption that in the absence of direct
conjugation between the aryl and b-lactam/thiazolidinone
rings, the OMe group which has opposing -I and ?M
effects, can exert only -I effect and not ?M effect.
•
peaks at m/z 374 (M?•–C6H5 , 65) and 258 (M?•–193,
100). The presence of prominent fragmentation peak in the
mass spectrum of 6a at m/z 178 (C9H8NOS?•, 50) and 193
(C9H9N2OS?, 45) proved beyond doubt the formation of
4-oxo-2-phenylthiazolidine moiety and the appearance of
123

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Med Chem Res (2013) 22:2964–2974
Table 2 Antifungal activities of the compounds 5(a–j) and 6(a–j)
Antifungal activities of the compounds
zone of inhibition (diameter) mm at 10 lg/mL
Compound 5
A. fumigatus
ATCC 28212
A.niger
ATCC 16404
Compound 6
A. fumigatus
ATCC 28212
A.niger
ATCC 16404
a (Ph)
4
13
15
18
12
13
21
16
12
14
22
25
21
a (Ph)
5
9
20
14
14
13
12
15
18
12
19
25
21
b (2-Cl)
6
b (2-Cl)
6
c (3-NO2)
8
c (3-NO2)
6
d (4-OMe)
6
d (4-OMe)
6
e (4-Cl)
5
e (4-Cl)
7
f (3,4-OMe)
9
f (3,4-OMe)
g (4-NO2)
6
g (4-NO2)
6
8
h (3-Indolyl)
7
h (3-Indolyl)
i (3-Chromonyl)
j (2-Chloro-quinolin-3-yl)
Ketoconazole
Clotrimazole (10 lg/mL)
6
i (3-Chromonyl)
j (2-Chloro-quinolin-3-yl)
Ketoconazole (10 lg/mL)
Clotrimazole (10 lg/mL)
7
4
6
8
10
10
20 (2)
20 (2)
Antifungal activity
Conclusions
Antifungal activity was assessed against fungal strains
(Aspergillus fumigatus ATCC 28212 and Aspergillus niger
ATCC 16404) by agar cup plate method in a modified manner
(Kucukguzel et al., 2006,). Ketoconazole (10 lg/mL) and
Clotrimazole (10 lg/mL) were used as standard fungicides
and the inhibitory activities were expressed as percentage
inhibition (Table 2). All the tested compounds showed sig-
nificant fungal inhibition at a concentration of 10 lg/mL.
Among tested compounds 5a–j, 5c (3-NO2), and 5f (3,
4-diOMe) exhibited high activity against fungal strains, A.
fumigatus and A. niger, while compound 5j (2-chloro-
quinolin-3-yl) registered very high activity; the level of
activity was comparable to that of the standards (Keto-
conazole and Clotrimazole).
This paper reports the synthesis and antimicrobial activity
of novel and new THBT derivatives incorporating 2-aze-
tidinone and 4-thiazolidinone moieties. All the synthesised
compounds have been characterised beyond doubt by
modern spectroscopic techniques. Most of the compounds
registered excellent antimicrobial activity, and the level of
activity of some of them is comparable to that of the
standard. Our preliminary results on the antimicrobial
properties of THBT grafted azetidinones and thiazolidi-
nones are promising enough to explore their role as
potential inhibitors of HCVB polymerase.
Experimental section
Among 6 series of compounds, 6j (2-chloroquinolin-3-
yl) registered very high activity against both A. fumigatus
and A. niger, while 6h (3-indolyl) and 6b (2-Cl) registered
very high activity against A. niger; compounds 6g (4-NO2)
and 6e (4-Cl) showed high activity against A. fumigatus.
A close examination of the data generated on antifungal
activity (Table 2) suggested that although electron-with-
drawing groups of aryl moiety promoted the activity as in
case of antibacterial activity, the trend is less clear-cut in
case of antifungal activity exhibited by 5/6a–j. It appears
that the steric nature of the attached aryl/heterocyclic ring
system controls the antifungal activity, although most
electron-withdrawing groups are also sterically bulky.
SAR study of the substitution pattern of the aryl group
towards antibacterial and antifungal activity has shown that
electron-withdrawing groups have more impact on the
activities.
General
Melting points were determined on sulphuric acid bath in
open capillaries and were uncorrected. Elemental analysis
was carried out on Perkin-Elmer 2400 Series-II instrument.
The IR spectra were recorded on 8400 S Shimadzu-FT IR
Spectrophotometer and JASCO-410 IR Spectrophotometer
using KBr pellets/chloroform. The 1H NMR and 13C NMR
spectra were recorded on Bruker Avance 300 MHz
instrument with TMS as internal standard.
In vitro antibacterial and antifungal activity
Discs measuring 6.25 mm in diameter were punched from
Whatmann no. 1 filtre paper. Batches of 10 discs were
dispensed to each screw-capped bottle and sterilised by dry
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Med Chem Res (2013) 22:2964–2974
2969
heat at 140 ꢁC for an hour. The test compounds were
prepared with a concentration of 0.5 % using methanol.
The discs of each concentration were placed in triplicate in
meat peptone agar medium and seeded with fresh bacterial
culture separately and incubated at 37 ꢁC for 24 h. The
zone of inhibition was measured in millimetres using
10 lg/mL concentrations of synthesised compounds
(5a–j and 6a–j); methanol was used both as a solvent and
as a control. No zone of inhibition was observed in control
(i.e., in methanol).
(m, 4H, H-5,6), 2.53–2.68 (m, 4H, H-4,7), 1.75–2.24 (m,
8H, 49 CH2), 2.97 (s, 3H, SO2Me), 4.16 (s, 1H,
NHSO2Me), 4.32 (q, 2H, –OCH2CH3). 13C NMR (75 MHZ,
CDCl3):14.72 (OCH2CH3), 23.5, 24.9, 39.8 (SO2CH3),
62.49 (OCH2CH3), 114.3, 128.3, 131.6, 139.0, 164.4
(C=O).
Synthesis of N-[3-(hydrazinylcarbonyl)-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl] methanesulfonamide, (3)
Potato dextrose agar (PDA) was used as basal medium
for test fungi. Glass Petri dishes were sterilised, and ster-
ilised melted PDA medium (*45 ꢁC) was poured at the
rate of 15 mL into each petridish (90 mm). After solidifi-
cation of the medium, small portions of the mycelium of
each fungus were spread carefully over the centre of each
PDA plate with the help of sterilised needles. Then, each
fungus was transferred to a number of PDA plates, which
were then incubated and ready for use after 5 days of
incubation. Prepared discs of samples were placed gently
on solidified agar plates, freshly seeded with the test
organisms with sterile forceps.
To an alcoholic solution of 2 (0.01 mol), hydrazine hydrate
(0.02 mol) was added and the reaction mixture was
refluxed on a water bath for 3 h and the course of the
reaction was monitored by TLC. The solid that separated
on evaporation of the solvent was filtered, washed with
water and dried; crystallisation from aq. ethanol gave N-[3-
(hydrazinylcarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-
2-yl] methanesulfonamide 3.
Mp 134–135 ꢁC (aq. ethanol); yield: 76 %. IR
(KBr,cm-1): 3425 (CONHNH2 str.), 3394 (CONHNH2
str.), 3218 (SO2NH str.), 1683 (CONH str.), 1357 (SO2Me
unsym. str.), 1154 (SO2Me sym. str.). 1H NMR (300 MHZ,
CDCl3): d 1.78–1.93 (m, 4H, H-5,6), 2.65–2.84 (m, 4H, H-
4,7), 2.95 (s, 3H, SO2CH3), 4.14 (s, 1H, NHSO2Me), 4.54
(s, 2H, NHNH2), 9.68 (s, 1H, CONH). 13C NMR (75 MHZ,
CDCl3): 22.4, 23.7, 24.9, 39.4 (SO2CH3), 115.3, 125.3,
134.6, 139.0, 164.4 (CONH)
A control disc was also placed on the test plates to
compare the effect of the test samples and to nullify the
effect of solvent, respectively. The plates were then kept in
a refrigerator at 4 ꢁC for 24 h, so that the materials had
sufficient time to diffuse over a considerable area of the
plates. After this process, the plates were incubated at
25 ꢁC for 72 h. Methanol (0.5 %) was used as solvent to
prepare desired solutions of the compounds initially and
also to maintain proper control. The zone of inhibition was
measured in millimetres at 10 lg/mL concentration of the
synthesised compounds 5a–j and 6a–j; no zone of inhibi-
tion was observed in control (i.e. in methanol).
General procedure for the synthesis of N-[3-(2-
arylidenehydrazinyl-carbonyl)-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl]methanesulfonamide
(Schiff base), (4a–j)
To an alcoholic solution of 3 (0.01 mol), appropriate aro-
matic aldehydes (0.01 mol) and 5 % NaOH (20 mL) were
added and stirred at room temperature for about 3 h; then
the reaction mixture was carefully neutralised with 1:1 HCl
under ice cold condition, the solid 4a–j that separated was
filtered, washed with water, dried and crystallised from aq.
alcohol.
Synthesis of ethyl 2-(methylsulfonamido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (2)
To a mixture of cyclohexanone (0.01 mol), ethyl cya-
noacetate (0.01 mol), and sulphur (0.01 mol) in ethanol
(30 mL), diethylamine (0.01 mol) was added dropwise.
The crystals of ethyl 2-amino-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate 1 (Zeng et al., 2010) that sep-
arated were filtered and crystallised from ethanol. A solu-
tion of 1 (0.01 mol) in triethylamine (10 mL) was treated
with methanesulfonyl chloride (0.05 mol) and the reaction
mixture was warmed on a water bath for 30 min and left
overnight. The solid that separated on adding ice-water was
filtered, dried and crystallised from aq. ethanol.
4a: Mp 192–194 ꢁC (aq. ethanol); yield: 71 %. IR (KBr,
cm-1): 3410 (CONH str.), 3271 (NHSO2Me str.), 1673
(CONH str.), 1361 (SO2Me unsym. str.), 1176 (SO2Me
1
sym. str.). H NMR (300 MHZ, CDCl3): d 1.79–1.92 (m,
4H, CH2-5,6), 2.35–2.48 (m, 4H, CH2-4,7), 2.82 (s, 3H,
SO2CH3), 4.19 (s, 1H, NHSO2Me), 7.32–7.72 (m, 5H,
ArH), 8.12 (s, 1H, N=CHPh), 9.81 (s, 1H, CONH). 13C
NMR (75 MHZ, CDCl3): 24.5, 25.1, 28.4, 40.7 (SO2CH3),
114.3, 124.6, 127.8, 132.3, 133.6, 136.2, 140.7, 147.8
(N=CH), 163.9 (CONH). DEPT-135: d 22.98 (;), 24.49
(;), 25.12 (;), 39.55 (:), 125.91 (:), 127.28 (:), 130.02 (:),
146.12 (:) (N=CH/).
Mp 146–148 ꢁC (aq. ethanol); yield: 72 %. IR (KBr,
cm-1): 3223 (NHSO2 str.), 1730 (ester C=O), 1351
1
(SO2Me unsym. str.), 1148 (SO2Me sym. str.). H NMR
(300 MHZ, CDCl3): d 1.36 (t, 3H, –OCH2CH3), 1.85–1.98
123

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Med Chem Res (2013) 22:2964–2974
General procedure for the synthesis of azetidinones (5a–j)
–SO2CH3), 4.10 (s, 1H, NHSO2Me), 4.88 (d, 1H,
J = 8.7 Hz, CHAr), 5.26 (d, 1H, J = 8.7 Hz, CHCl),
7.16–7.45 (m, 4H, ArH), 9.85 (s, 1H, CONH). 13C NMR (75
MHZ, CDCl3): 23.1, 23.8, 24.6, 39.4 (COCH2S), 62.3, 65.1,
114.9, 122.4, 125.2, 128.6, 133.8, 135.2, 139.6, 145.6, 163.8
(–NCOCH), 168.7 (CONH). DEPT-135: d 21.37 (;), 25.32
(;), 27.12 (;), 40.38 (:) (SO2CH3), 62.08 (:), 67.48 (:),
121.30 (:), 127.32 (:), 128.74 (:). Anal. Calcd for
C19H19ClN4O6S2: C, 45.74; H, 3.84;. Found: C, 45.70; H,
3.85.
To a solution of Schiff bases (0.01 mol) 4a–j in DMF
(10 mL), chloroacetyl chloride (0.01 mol) and triethylamine
(0.05 mol) were added and the reaction mixture was stirred
at room temperature for 24 h; after completion of the reac-
tion (TLC) the reaction mixture was poured into cold water
and the liberated compounds were extracted with chloro-
form. Evaporation of the solvent in vacuo afforded the cor-
responding azetidinones 5a–j.
N-(3-Chloro-2-oxo-4-phenylazetidin-1-yl)-2-(methylsulfo-
namido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
amide (5a) Mp 137 ꢁC (aq. alcohol); Yield: 76 %. IR
(KBr, cm-1): 3324 (br. CONH), 3262 (br. NHSO2), 1745
(NCOCH), 1685 (CONH), 1361 (SO2Me unsym. str.), 1159
(SO2Me sym. str.). 1H NMR (300 MHZ, CDCl3): 1.76–1.93
(m, 4H, CH2-5,6), 2.29–2.43 (m, 4H, CH2-4,7), 2.76 (s, 3H,
–SO2CH3), 4.11 (s, 1H, NHSO2Me), 4.73 (d, 1H,
J = 12.3 Hz, CHAr), 5.16 (d, 1H, J = 12.3 Hz, CHCl),
6.93–7.26 (m, 5H, Ph), 9.68 (s, 1H, NH). 13C NMR (75
MHZ, CDCl3): 21.6, 25.5, 25.9, 40.7 (SO2CH3), 58.8, 62.9,
113.6, 123.1, 129.6, 131.9, 134.8, 142.3, 163.1 (–NCOCH),
168.4 (CONH). DEPT-135: d 21.44 (;), 23.09 (;), 30.49
(;), 37.94 (:) (SO2CH3), 52.90 (:), 64.13 (:), 126. 97 (:),
128.91 (:). Anal. Calcd for C19H20ClN3O4S2: C, 50.27 %;
H, 4.44 %. Found: C 50.28 %; H 4.40 %.
N-[3-Chloro-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-2-
(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide (5d) Viscous liquid; Yield: 65 %.IR (KBr,
cm-1): 3317 (br. CONH), 3253 (br. NHSO2), 1744
(NCOCH), 1672 (CONH), 1350 (SO2Me unsym. str.), 1154
(SO2Me sym. str.).1H NMR (300 MHZ, CDCl3): 1.58–1.72
(m, 4H, CH2-5,6), 2.61–2.74 (m, 4H, CH2-4,7), 2.77 (s, 3H,
–SO2CH3), 3.96 (s, 3H, –OCH3), 4.12 (s, 1H, NHSO2Me),
5.06 (d, 1H, J = 9.0 Hz, CHAr), 5.43 (d, 1H, J = 9.0 Hz,
CHCl), 6.94–7.27 (m, 4H, ArH), 9.78 (s, 1H, NH). 13C NMR
(75 MHZ, CDCl3): 21.4, 24.6, 25.5, 39.8 (SO2CH3), 55.1
(–OCH3), 62.4, 67.5, 112.9, 113.3, 122.7, 126.0, 135.6,
139.1, 157.3, 162.8 (–NCOCH), 164.7 (CONH). DEPT-135:
d 21.24 (;), 24.32 (;), 25.71 (;), 39.16 (:) (SO2CH3), 55.74
(:) (–OCH3), 61.53 (:), 66.38 (:), 127.47 (:), 129.38 (:).
Anal. Calcd for C20H22ClN3O5S2: C, 49.63; H, 4.58. Found:
C, 49.61; H, 4.60.
N-[3-Chloro-2-(2-chlorophenyl)-4-oxoazetidin-1-yl]-2-(meth-
ylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxamide (5b) Mp 148 ꢁC (aq. alcohol); Yield: 69 %. IR
(KBr, cm-1): 3320 (br. CONH), 3265 (br. NHSO2), 1749
(NCOCH), 1642 (CONH), 1354 (SO2Me unsym. str.), 1163
(SO2Me sym. str.). 1H NMR (300 MHZ, CDCl3): 1.62–1.79
(m, 4H, CH2-5,6), 2.65–2.78 (m, 4H, CH2-4,7), 2.79 (s, 3H,
–SO2CH3), 4.08 (s, 1H, NHSO2Me), 4.93 (d, 1H, J =
9.6 Hz, CHAr), 5.36 (d, 1H, J = 9.6 Hz, CHCl), 7.20–7.80
(m, 4H, ArH), 9.84 (s, 1H, CONH). 13C NMR (75 MHZ,
CDCl3): 23.6, 25.4, 26.4, 40.7 (SO2CH3), 58.8, 62.9, 113.6,
124.1, 129.6, 131.9, 134.8, 142.3, 163.1 (–NCOCH), 168.4
(CONH). DEPT-135: d 23.41 (;), 24.90 (;), 28.05 (;), 38.96
(:) (SO2CH3), 59.65 (:), 67.86 (:), 124.92 (:), 129.06 (:).
Anal. Calcd for C19H19Cl2N3O4S2: C, 46.72; H, 3.92.
Found: C 46.70 %; H 3.95 %.
N-[3-Chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-yl]-2-(meth-
ylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxamide (5e) Mp 122 ꢁC (aq. alcohol); Yield: 69 %. IR
(KBr, cm-1): 3320 (br. CONH), 3260 (br. NHSO2Me), 1748
(NCOCH), 1684 (CONH), 1353 (SO2Me unsym. str.), 1159
(SO2Me sym. str.). 1H NMR (300 MHZ, CDCl3): 1.64–1.87
(m, 4H, CH2-5,6), 2.64–2.86 (m, 4H, CH2-4,7), 2.84 (s, 3H,
–SO2CH3), 4.05 (s, 1H, NHSO2Me), 4.90 (d, 1H, J = 9.3
Hz, CHAr), 5.35 (d, 1H, J = 9.3 Hz, CHCl), 7.42–7.76 (m,
4H, ArH), 9.69 (s, 1H, NH). 13C NMR (75 MHZ, CDCl3):
23.6, 25.5, 25.9, 40.2 (SO2CH3), 59.8, 62.9, 119.6, 121.1,
125.6, 131.9, 134.8, 142.3, 163.1 (–NCOCH), 168.4
(CONH). DEPT-135: d 23.44 (;), 25.29 (;), 26.49 (;), 39.95
(:) (SO2CH3), 59.40 (:), 63.14 (:), 118.97 (:), 121.91 (:).
Anal. Calcd for C19H19Cl2N3O4S2: C, 46.72; H, 3.92.
Found: C, 46.70; H, 3.94.
N-[3-Chloro-2-(3-nitrophenyl)-4-oxoazetidin-1-yl]-2-(meth-
ylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxamide (5c) Mp 129 ꢁC (methanol); Yield: 68 %.IR
(KBr, cm-1): 3346 (br. CONH), 3268 (br. NHSO2), 1741
(NCOCH), 1669 (CONH), 1538 (NO2 asym. str.), 1324
(NO2 sym. str.,), 1345 (SO2Me unsym. str.), 1159 (SO2Me
sym. str.). 1H NMR (300 MHZ, CDCl3): 1.65–1.83 (m, 4H,
CH2-5,6), 2.71–2.82 (m, 4H, CH2-4,7), 2.89 (s, 3H,
N-[3-Chloro-2-(3,4-dimethoxyphenyl)-4-oxoazetidin-1-yl]-
2-(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxamide (5f) Mp 126 ꢁC (aq. alcohol);
Yield: 72 %. IR (KBr, cm-1): 3317 (br. CONH), 3254 (br.
NHSO2Me), 1744 (NCOCH), 1667 (CONH), 1343 (SO2Me
unsym. str.), 1146 (SO2Me sym. str.). 1H NMR (300 MHZ,
CDCl3): 1.71–1.82 (m, 4H, CH2-5,6), 2.69–2.78 (m, 4H,
123

Med Chem Res (2013) 22:2964–2974
2971
CH2-4,7), 2.93 (s, 3H, –SO2CH3), 3.97 (s, 6H, 2xCH3),
4.10 (s, 1H, NHSO2Me), 4.95 (d, 1H, J = 9.0 Hz, CHAr),
5.26 (d, 1H, J = 9.0 Hz, CHCl), 6.93–7.49 (m, 3H, ArH),
9.87 (s, 1H, NH). 13C NMR (75 MHZ, CDCl3): 22.4, 24.6,
25.5, 39.8 (SO2CH3), 55.1 (–OCH3), 62.9, 65.5, 112.9,
119.3, 121.7, 126.0, 135.6, 139.1, 157.3, 162.8 (–NCOCH),
164.7 (CONH). DEPT-135: d 21.94 (;), 24.19 (;), 25.32 (;),
39.58 (:) (SO2CH3), 54.34 (:) (–OCH3), 63.17 (:), 67.14 (:),
118.63 (:), 121.86 (:). Anal. Calcd for C21H24ClN3O6S2: C,
49.07; H, 4.71. Found: C, 49.04; H, 4.76.
2.67–2.80 (m, 4H, CH2-4,7), 2.87 (s, 3H, –SO2CH3), 4.09
(s, 1H, NHSO2Me), 4.91 (d, 1H, J = 8.7 Hz, CHAr), 5.36
(d, 1H, J = 8.7 Hz, CHCl), 7.14–8.25 (m, 5H, ArH), 9.87
(s, 1H, NH). 13C NMR (75 MHZ, CDCl3): 23.4, 25.9, 27.9,
41.8 (SO2CH3), 62.3, 65.9, 116.7, 117.3, 120.7, 124.2,
129.4, 134.2, 135.7, 139.7, 149.3, 160.1(–NCOCH), 161.7
(CONH). Anal. Calcd for C22H20ClN3O6S2: C, 50.62; H,
3.86. Found: C, 50.64; H, 3.87.
N-[3-Chloro-2-(2-chloroquinolin-3-yl)-4-oxoazetidin-1-yl]-
2-(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thi-
ophene-3-carboxamide (5j) Mp 154 ꢁC (aq. alcohol);
Yield: 77 %. IR (KBr, cm-1): 3312 (br. CONH), 3255
(br. NHSO2Me), 1762 (NCOCH), 1672 (CONH), 1340
N-[3-Chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-yl]-2-(methyl
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
amide (5g) Mp 137–138 ꢁC (aq. alcohol); Yield: 62 %.
IR (KBr, cm-1): 3322 br. CONH), 3256 (br. NHSO2Me),
1756 (NCOCH), 1680 (CONH), 1359 (SO2 Me unsym.
str.), 1159 (SO2Me sym. str.). 1H NMR (300 MHZ, CDCl3):
1.71–1.81 (m, 4H, CH2-5,6), 2.67–2.85 (m, 4H, CH2-4,7),
2.96 (s, 3H, -SO2CH3), 4.10 (s, 1H, NHSO2Me), 4.95 (d,
1H, J = 8.4 Hz, CHAr), 5.38 (d, 1H, J = 8.4 Hz, CHCl),
7.41–8.28 (m, 4H, ArH), 9.79 (s, 1H, CONH). 13C NMR
(75 MHZ, CDCl3): 23.4, 25.9, 26.3, 40.2 (SO2CH3), 62.3,
65.9, 116.7, 117.3, 120.7, 124.3, 129.4, 134.2, 135.7,
139.7, 149.3, 160.1 (–NCOCH), 166.7 (CONH).DEPT-
135: d 23.26 (;), 23.45 (;), 31.73 (;), 36.49 (:) (SO2CH3),
62.53 (:), 66.31 (:), 127.62 (:), 128.53 (:). Anal. Calcd for
C19H19ClN4O6S2: C, 45.74; H, 3.84;. Found: C, 45.76; H,
3.86.
1
(SO2Me unsym. str.), 1159 (SO2Me sym. str.). H NMR
(300 MHZ, CDCl3): 1.62–1.79 (m, 4H, CH2-5,6),
2.72–2.84 (m, 4H, CH2-4,7), 2.96 (s, 3H, –SO2CH3), 4.12
(s, 1H, NHSO2Me), 5.10 (d, 1H, J = 8.4 Hz, CHAr), 5.45
(d, 1H, J = 8.4 Hz, CHCl), 7.35–8.30 (m, 5H, ArH), 9.85
(s, 1H, CONH).13C NMR (75 MHZ, CDCl3): 23.5, 25.7,
26.4, 39.2 (SO2CH3), 52.0, 61.9, 112.7, 121.7, 123.6,
127.5, 129.6, 134.8, 137.1, 139.6, 142.8, 145.2, 155.3,
161.8 (–NCOCH), 167.7 (CONH). DEPT-135: d 23.38
(;), 24.37 (;), 25.89 (;), 39.57 (:) (SO2CH3), 56.20 (:),
61.22 (:), 126.10 (:), 129.59 (:), 143.5 (:). Anal. Calcd
for C22H23Cl2N4O4S2: C, 48.71; H, 4.27. Found: C, 48.70;
H, 4.25.
General procedure for the synthesis of
thiazolidinones (6a–j)
N-[3-Chloro-2-(indol-3-yl)-4-oxoazetidin-1-yl]-2-(methyl
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxamide (5h) Mp 152 ꢁC (aq. alcohol); Yield: 68 %. IR
(KBr, cm-1): 3317 (br. CONH), 3253 (br. NHSO2Me),
1744 (NCOCH), 1665 (CONH), 3329 (–NH of indol-3-yl),
To a solution of Schiff bases (0.01 mol) 4a–j in DMF
(10 mL), thioglycolic acid (0.01 mol) and anhydrous zinc
chloride (0.02 mol) were added and the contents were
refluxed for 5 h. The reaction mixture was poured into cold
water and the liberated compounds were extracted with
chloroform. Evaporation of the solvent in vacuo afforded
the corresponding thiazolidinones 6a–j.
1
1350 (SO2Me unsym. str.), 1159 (SO2Me sym. str.). H
NMR (300 MHZ, CDCl3): 1.61–1.77 (m, 4H, CH2-5,6),
2.64–2.82 (m, 4H, CH2-4,7), 2.94 (s, 3H, –SO2CH3), 4.05
(s, 1H, NHSO2Me), 5.14 (d, 1H, J = 9.3 Hz, CHAr), 5.49
(d, 1H, J = 9.3 Hz, CHCl), 7.10–7.73 (m, 5H, ArH), 9.62
(s, 1H, NH), 10.45 (s, 1H, –NH of indol-3-yl). 13C NMR
(75 MHZ, CDCl3): 21.4, 25.6, 26.5, 39.8 (SO2CH3), 58.1,
67.5, 112.9, 113.3, 121.7, 123.0, 126.7, 130.3, 133.6,
139.1, 157.3, 162.8 (–NCOCH), 164.5 (CONH). DEPT-
135: 23.41 (;), 24.90 (;), 25.05 (;), 39.68 (:) (SO2CH3),
59.65 (:), 67.86 (:), 127.92 (:), 129.06 (:).
N-(2-phenyl-4-oxo-thiazolidin-3-yl)-2-(methylsulfonamido)-
4,5,6,7-tetrahydrobenzo[b]-thiophene-3-carboxamide,
(6a) Mp 144 ꢁC (aq. alcohol); Yield: 74 %. IR (KBr,
cm-1): 3320 (br. CONH), 3261 (br. NHSO2), 1740
(NCOCH2), 1672 (CONH), 1345 (SO2Me unsym. str.),
1
1164 (SO2Me unsym. str.). H NMR (300 MHZ, CDCl3):
1.52–1.79 (m, 4H, CH2-5,6), 2.62–2.78 (m, 4H, CH2-4,7),
3.16 (s, 3H, –SO2CH3), 4.10 (s, 1H, NHSO2Me), 4.81 (d,
1H, J = 2.1 Hz, SCHa), 5.08 (d, 1H, J = 2.1 Hz, SCHb),
6.28 (s, 1H, NCH/), 7.26–7.52(m, 5H, ArH), 9.64 (s, 1H,
CONH). 13C NMR (75 MHZ, CDCl3): 22.3, 23.4, 25.1,
37.0 (COCH2S), 39.8 (SO2CH3), 54.6, 112.5, 114.9, 126.3,
127.5, 128.6, 134.8, 139.6, 164.8 (COCH2S), 168.0
(CONH). DEPT-135: d 19.57 (;), 23.71 (;), 27.25 (;),
N-[3-Chloro-2-(4-oxo-4H-chromen-2-yl)-4-oxoazetidin-1-yl]
-2-(methylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide (5i) Mp 139 ꢁC (aq. alcohol), Yield: 74 %.
IR (KBr, cm-1): 3321(br. CONH), 3258 (br. NHSO2Me),
1760 (NCOCH), 1742 (CO of chromone), 1662 (CONH),
1
1352 (SO2Me unsym. str.), 1159 (SO2Me sym. str.). H
NMR (300 MHZ, CDCl3): 1.52–1.76 (m, 4H, CH2-5,6),
123

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Med Chem Res (2013) 22:2964–2974
36.41 (;) (COCH2S), 39.82 (:) (SO2CH3), 59.32 (:)
(SO2CH3), 63.06 (:), 109.27 (:), 112.20 (:), 120.39 (:),
124.17 (:), 126.15 (:). Anal. Calcd for C19H21N3O4S3: C,
50.53; H, 4.69. Found: C, 50.52; H, 4.70.
(s, 1H, CONH). 13C NMR (75 MHZ, CDCl3): 23.6, 24.1,
24.7, 36.1 (COCH2S), 40.9 (SO2CH3), 55.9 (OCH3), 58.4
(NCH/), 114.5, 116.2, 125.3, 129.6, 131.2, 136.2, 139.3,
159.1, 164.5 (COCH2S), 168.2 (CONH). DEPT-135: d
23.41 (;), 24.90 (;), 28.05 (;), 37.05 (;) (COCH2S), 38.96
(:) (SO2CH3), 59.65 (:) (NCH/), 117.92 (:), 128.92 (:),
129.06 (:). Anal. Calcd for C20H23N3O5S3: C, 49.88; H,
4.81. Found: C, 49.85; H, 4.80.
N-[2-(2-Chlorophenyl)-4-oxothiazolidin-3-yl]-2-(methylsulfo-
namido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
amide (6b) Mp 119–120 ꢁC (aq. alcohol); Yield: 71 %. IR
(KBr, cm-1): 3345 (br. CONH), 3264 (br. NHSO2), 1724
([NCOCH2), 1656 (CONH), 1354 (SO2Me unsym. str.),
N-[2-(4-Chlorophenyl)-4-oxothiazolidin-3-yl]-2-(methyl
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbox-
amide (6e) Mp 132 ꢁC (aq. alcohol); Yield: 73 %. IR
(KBr, cm-1): 3320 (br. CONH), 3261 (br. NHSO2Me), 1741
(NCOCH2), 1672 (CONH), 1353 (SO2Me unsym. str.),
1
1158 (SO2Me unsym. str.). H NMR (300 MHZ, CDCl3):
1.77–1.94 (m, 4H, CH2-5,6), 2.56–2.69 (m, 4H, CH2-4,7),
2.97 (s, 3H, SO2CH3), 4.26 (s, 1H, NHSO2Me), 4.88 (d, 1H,
J = 2.1 Hz, SCHa), 4.91 (d, 1H, J = 2.1 Hz, SCHb), 6.13
(s, 1H, NCH/), 7.08–7.64 (m, 4H, ArH), 9.76 (s, 1H,
CONH). 13C NMR (75 MHZ, CDCl3): 22.3, 23.4, 25.1, 37.0
(COCH2S), 39.8 (SO2CH3), 54.6, 112.5, 114.7, 126.3, 127.5,
128.6, 134.8, 139.6, 164.8 (COCH2S), 167.8 (CONH).
DEPT-135: d 23.41 (;), 24.90 (;), 28.05 (;), 37.05 (;)
(COCH2S), 38.96 (:) (SO2CH3), 59.65 (:), 127.92 (:),
128.92 (:), 129.06 (:). Anal. Calcd for C19H20ClN3O4S3: C,
46.95; H, 4.15. Found: C, 46.93; H, 4.17.
1
1162 (SO2Me unsym. str.). H NMR (300 MHZ, CDCl3):
1.82–1.94 (m, 4H, CH2-5,6), 2.58–2.74 (m, 4H, CH2-4,7),
2.97 (s, 3H, –SO2CH3), 4.17 (s, 1H, NHSO2Me), 4.86 (d,
1H, J = 2.1 Hz, SCHa), 4.98 (d, 1H, J = 2.1 Hz, SCHb),
6.36 (s, 1H, NCH/), 7.23–7.67 (m, 4H, ArH), 9.63 (s, 1H,
CONH). 13C NMR (75 MHZ, CDCl3): 23.3, 23.9, 24.4, 36.2
(COCH2S), 39.3 (SO2CH3), 57.7 (NCH/), 115.5, 123.4,
125.1, 128.4, 130.2, 132.8, 136.9, 138.2, 139.0, 163.8
(COCH2S), 168.7 (CONH). DEPT-135: d 23.32 (;), 24.05
(;), 28.35 (;), 37.42 (;) (COCH2S), 38.96 (:) (SO2CH3),
59.60 (:) (NCH/), 128.61 (:), 130.29 (:), 132.06 (:). Anal.
Calcd for C19H20ClN3O4S3: C, 46.95; H, 4.15. Found: C,
46.96; H, 4.18.
N-[2-(3-Nitrophenyl)-4-oxo-2-thiazolidin-3-yl]-2-(Methane
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxamide, (6c) Viscous liquid; Yield: 70 %. IR (KBr,
cm-1): 3328 (br. CONH), 3265 (br. NHSO2), 1758
(NCOCH2), 1667 (CONH), 1530 (N=O unsym. str.), 1320
(N=O sym. str.), 1341 (SO2Me unsym. str.), 1164 (SO2Me
N-[2-(3,4-Dimethoxyphenyl)-4-oxothiazolidin-3-yl]-2-(meth-
ylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
boxamide (6f) Mp 124 ꢁC (aq. alcohol); Yield: 71 %. IR
(KBr, cm-1): 3311 (br. CONH), 3267 (br. NHSO2Me), 1723
(NCOCH2), 1680 (CONH), 1338 (SO2Me unsym. str.),
1
unsym. str.). H NMR (300 MHZ, CDCl3): 1.59–1.79 (m,
4H, CH2-5,6), 2.53–2.69 (m, 4H, CH2-4,7), 2.90 (s, 3H,
–SO2CH3), 4.19 (s, 1H, NHSO2Me), 4.66 (d, 1H,
J = 1.8 Hz, SCHa), 4.74 (d, 1H, J = 1.8 Hz, SCHb), 6.23
(s, 1H, NCH/), 7.17–7.42 (m, 4H, ArH), 9.69 (s, 1H,
CONH). 13C NMR (75 MHZ, CDCl3): 23.4, 25.9, 27.9,
35.8 (COCH2S), 40.8 (SO2CH3), 62.3, 65.9, 116.7, 120.7,
124.3, 129.4, 134.2, 135.7, 139.7, 149.3, 160.1 (COCH2S),
161.7 (CONH). DEPT-135: d 23.41 (;), 24.90 (;), 28.05
(;), 37.05 (;) (COCH2S), 38.96 (:) (SO2CH3), 59.65 (:),
121.92 (:), 128.78 (:), 133.06 (:). Anal. Calcd for
C19H20N4O6S3: C, 45.95; H, 4.06. Found: C, 45.96; H,
4.08.
1
1154 (SO2Me unsym. str.). H NMR (300 MHZ, CDCl3):
1.64–1.81 (m, 4H, CH2-5,6), 2.59–2.87 (m, 4H, CH2-4,7),
2.85 (s, 3H, –SO2CH3), 3.84 (s, 2H, OCH3), 4.16 (s, 1H,
NHSO2Me), 4.64 (d, 1H, J = 2.7 Hz, SCHa), 4.87 (d, 1H,
J = 2.7 Hz, SCHb), 6.63 (s, 1H, NCH/), 6.84–7.61 (m, 3H,
ArH), 9.85 (s, 1H, CONH). 13C NMR (75 MHZ, CDCl3):
23.3, 23.8, 24.3, 35.9 (COCH2S), 39.8 (SO2CH3), 56.3
(OCH3), 58.4 (NCH/), 114.5, 116.2, 123.4, 125.3, 132.6,
136.2, 139.3, 146.7, 149.1, 164.5 (COCH2S), 168.2
(CONH). DEPT-135: d 23.41 (;), 24.90 (;), 28.05 (;), 37.05
(;) (COCH2S), 38.96 (:) (SO2CH3), 59.65 (:) (NCH/),
117.92 (:), 128.92 (:), 129.06 (:). Anal. Calcd for
C21H25N3O6S3: C, 49.30; H, 4.93. Found: C, 49.33; H, 4.90.
N-[2-(4-Methoxyphenyl)-4-oxothiazolidin-3-yl]-2-(methyl-
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxamide (6d) Mp 152 ꢁC (aq. alcohol); Yield: 65 %.
IR (KBr, cm-1): 3314 (br. CONH), 3267 (br. NHSO2),
1741 (NCOCH2), 1664 (CONH), 1337 (SO2Me unsym.
str.), 1168 (SO2Me unsym. str.). 1H NMR (300 MHZ,
CDCl3): 1.52–1.79 (m, 4H, CH2-5,6), 2.62–2.78 (m, 4H,
CH2-4,7), 2.78 (s, 3H, –SO2CH3), 4.18 (s, 1H, NHSO2Me),
4.78 (d, 1H, J = 2.7 Hz, SCHa), 4.81(d, 1H, J = 2.7 Hz,
SCHb), 6.34 (s, 1H, NCH/), 7.10–7.54 (m, 4H, ArH), 9.83
N-[2-(4-Nitrophenyl)-4-oxo-thiazolidin-3-yl]-2-(methanes
ulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxamide, (6g) Mp 149 ꢁC (aq. alcohol); Yield: 79 %.
IR (KBr, cm-1): 3341 br. CONH), 3268 (br. NHSO2Me),
1752 (NCOCH2), 1668 (CONH), 1347 (SO2Me unsym.
str.), 1149 (SO2Me unsym. str.). 1352 (NO2 unsym. str.),
123

Med Chem Res (2013) 22:2964–2974
2973
1327 (NO2 sym. str.). 1H NMR (300 MHZ, CDCl3):
1.65–1.89 (m, 4H, CH2-5,6), 2.58–2.88 (m, 4H, CH2-4,7),
2.90 (s, 3H, –SO2CH3), 4.19 (s, 1H, NHSO2Me), 4.93 (d,
1H, J = 2.4 Hz, SCHa), 4.98 (d, 1H, J = 2.4 Hz, SCHb),
6.31 (s, 1H, NCH/), 7.02–8.12 (m, 4H, ArH), 9.80 (s, 1H,
CONH). 13C NMR (75 MHZ, CDCl3): 23.3, 23.6, 24.4,
36.1 (COCH2S), 39.7 (SO2CH3), 56.1 (NCH/), 114.9,
123.4, 125.2, 128.6, 132.7, 135.8, 139.6, 146.5, 163.8
(COCH2S), 168.7 (CONH). DEPT-135: d 23.41 (;), 24.90
(;), 28.05 (;), 37.05 (;) (COCH2S), 38.96 (:) (SO2CH3),
59.65 (:), 121.92 (:), 128.78 (:), 131.06 (:), 134.53 (:).
Anal. Calcd for C19H20N4O6S3: C, 45.95; H, 4.06. Found:
C, 45.96; H, 4.08
N-[2-(2-Chloroquinolin-3-yl)-4-oxo-thiazolidin-3-yl]-2-
(Methanesulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxamide, (6j) Mp 165 ꢁC (aq. alcohol); Yield:
65 %. IR (KBr, cm-1): 3320 (br. CONH), 3265 (br.
NHSO2Me), 1741 (NCOCH2), 1665 (CONH), 1337
(SO2Me unsym. str.), 1156 (SO2Me unsym. str.).1H NMR
(300 MHZ, CDCl3): 1.52–1.79 (m, 4H, CH2-5,6), 2.62–2.78
(m, 4H, CH2-4,7), 2.92 (s, 3H, –SO2CH3), 4.01 (s, 1H,
NHSO2Me), 4.76 (d, 1H, J = 2.4 Hz, SCHa), 4.84 (d, 1H,
J = 2.4 Hz, SCHb), 6.18 (s, 1H, NCH/), 7.61–8.42 (m, 5H,
ArH), 9.86 (s, 1H, CONH). 13C NMR (75 MHZ, CDCl3):
23.1, 23.8, 24.6, 35.9 (COCH2S), 39.7 (SO2CH3), 53.1
(NCH/), 114.9, 125.2, 126.4, 127.3, 129.6, 130.2, 135.8,
136.8, 139.6, 145.6, 163.8 (COCH2S), 168.7 (CONH).
DEPT-135: d 23.41 (;), 24.90 (;), 28.05 (;), 37.12 (;)
(COCH2S), 39.86 (:) (SO2CH3), 54.65 (:) (NCH/), 114.92
(:), 124.78 (:), 125.78 (:), 126.78 (:), 127.48 (:), 129.48
(:), 131.92 (:). Anal. Calcd for C22H22ClN4O4S3: C, 49.11;
H, 4.12. Found: C, 49.07; H, 4.15.
N-[2-(Indol-3-yl)-4-oxo-thiazolidin-3-yl]-2-(methane-
sulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxamide, (6h) Mp 135 ꢁC (aq. alcohol); Yield:
73 %. IR (KBr, cm-1): 3320 (br. CONH), 3261 (br.
NHSO2Me), 1741 (NCOCH2), 1673 (CONH), 1452 (–NH
of indol-3-yl), 1334 (SO2Me unsym. str.), 1146 (SO2Me
1
Acknowledgments The authors thank DST for providing FT-NMR
under IRHPA programme and one of the authors (M. Babu) is grateful
to UGC for UGC-JRF fellowship.
unsym. str.). H NMR (300 MHZ, CDCl3): 1.66–1.79 (m,
4H, CH2-5,6), 2.72–2.85 (m, 4H, CH2-4,7), 2.84 (s, 3H,
–SO2CH3), 4.20 (s, 1H, NHSO2Me), 4.81 (d, 1H,
J = 2.1 Hz, SCHa), 4.97 (d, 1H, J = 2.1 Hz, SCHb), 6.38
(s, 1H, NCH/), 6.80–7.43 (m, 5H, ArH), 9.89 (s, 1H,
CONH), 11.32 (s, 1H, NH-indol-3-yl). 13C NMR (75 MHZ,
CDCl3): 23.1, 23.8, 24.6, 35.9 (COCH2S), 39.7 (SO2CH3),
55.9 (NCH/), 111.2, 114.5, 119.3, 122.8, 123.4, 125.2,
128.0, 130.2, 135.8, 136.9, 139.4, 164.5 (COCH2S), 168.3
(CONH).DEPT-135: 23.41 (;), 24.90 (;), 28.05 (;), 37.05
(;) (COCH2S), 38.96 (:) (SO2CH3), 59.65 (:) (NCH/),
111.92 (:), 118.78 (:), 119.78 (:), 122.78 (:), 124.78 (:),
127.87 (:).
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