Synthesis and antimicrobial activity of 5-chloroindoline-2,3-dione derivatives

Article abstract of DOI:10.1007/s00044-011-9644-y

A series of 3-(5-chloro-2-oxoindolin-3-ylideneamino)-2-arylthiazolidin-4- ones 4a-k and 5-chloro-3-(3- chloro-2-oxo-4-arylazetidin-1-ylimino)indolin-2- ones 5a-k was synthesized. The structures of final compounds were confirmed by analytical (C, H, N) and spectral (FT-IR, ¹H NMR, ¹³C NMR and Mass) data. The synthesized compounds were screened for possible antibacterial and antifungal activity. Compounds 4c, 4f, 4g, 4h, 4i, 4j, 5c, 5f, 5g, 5h, 5i and 5j showed substantially significant activity. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9644-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1302–1312
DOI 10.1007/s00044-011-9644-y
ORIGINAL RESEARCH
Synthesis and antimicrobial activity of 5-chloroindoline-2,3-dione
derivatives
•
S. G. Shingade Sanjaykumar B. Bari
•
U. B. Waghmare
Received: 24 September 2010 / Accepted: 12 April 2011 / Published online: 23 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 3-(5-chloro-2-oxoindolin-3-ylide-
neamino)-2-arylthiazolidin-4-ones 4a–k and 5-chloro-3-(3-
chloro-2-oxo-4-arylazetidin-1-ylimino)indolin-2-ones 5a–k
was synthesized. The structures of final compounds were
ring system is a common structural feature in number of
broad spectrum b-lactam antibiotics like penicillins and
cephalosporins which have been widely used as chemother-
apeuticagentstotreat bacterialinfectionsanddiseases. These
molecules operate by forming a covalent adduct with mem-
brane-bound bacterial transpeptidases, which are also known
as penicillin binding proteins (PBPs), involved in the bio-
synthesis of cell wall. These therapeutic agents prevent the
construction of cell wall and eventually lead to cell lysis and
death. Moreover, due to their b-lactamase inhibitory action,
2-azetidinone-based heterocycles represent an attractive
target of contemporary organic synthesis. A large numbers of
2-azetidinones (Arnould et al., 1992; Halve et al., 2007; Keri
et al., 2009) were reported to possess antibacterial and anti-
fungal activity. The 4-thiazoldinone nucleus has drawn many
attentions due to its various activities like antimicrobial
(Vicini et al., 2008), anti-HIV (Chen et al., 2009; Rao et al.,
2004; Rawalet al., 2005) anticancer (Abdel-Aziz et al., 2010;
Lv et al., 2010) and antihypertensive (Bhandari et al., 2009).
Various chemotherapeutic drugs are in use but due to
increase in microbial resistance against these drugs, there is
a need to develop new, potent and fast-acting antimicrobial
drugs. In the light of these observations, it was planned to
synthesize a series of isatin derivatives by incorporating the
azetidinone/thiazolidinone moiety at third position of isatin
nucleus with an aim to get better antibacterial as well as
antifungal activity.
1
confirmed by analytical (C, H, N) and spectral (FT-IR, H
NMR, 13C NMR and Mass) data. The synthesized com-
pounds were screened for possible antibacterial and anti-
fungal activity. Compounds 4c, 4f, 4g, 4h, 4i, 4j, 5c, 5f, 5g,
5h, 5i and 5j showed substantially significant activity.
Keywords 5-Chloroindoline-2,3-dione ꢀ Azetidinone ꢀ
Thiazolidinone ꢀ Antibacterial and antifungal activity
Introduction
Isatin derivatives have been found to possess potent wide
spectrum of activities like antibacterial, antifungal (Bondock
et al., 2008; Gupta and Narayana, 1997; Pandeya et al., 1999;
Sridhar et al., 2001), antitubercular (Aboul-Fadl et al., 2003;
Karali et al., 2007), anticonvulsant (Verma et al., 2004; Sri-
dhar et al., 2002), anticancer (Vine et al., 2007) and antiox-
idant (Andreani et al., 2010). The 2-azetidinone (b-lactam)
S. G. Shingade (&) ꢀ S. B. Bari
Department of Pharmaceutical Chemistry, R. C. Patel Institute
of Pharmaceutical Education & Research, Dhule, Shirpur
425405, Maharashtra, India
e-mail: sunilshingade@gmail.com
Results and discussion
S. B. Bari
e-mail: sbbari@rediffmail.com
Chemistry
U. B. Waghmare
Department of Microbiology, Shreemati Kasturbai Walchand
College of Arts and Science, Sangli 416416, Maharashtra, India
e-mail: ubwaghmare@gmail.com
The synthetic routes of compounds are outlined in Scheme 1.
The compound 5-chloroindoline-2,3-dione 1 was prepared
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Med Chem Res (2012) 21:1302–1312
1303
O
Scheme 1 3a–k, 4a–k and 5a–
k. Ar = phenyl,2-chlorophenyl,
4-chlorophenyl,3-
NH2
N
Cl
ethanol
Cl
O
NH2NH2
methoxyphenyl,2-
hydorxyphenyl,
O
N
H
N
4-hydorxyphenyl,4-
dimethylaminophenyl,
4-methoxyphenyl,4-
fluorophenyl,4-nitorphenyl and
2-furan
H
2
1
Absolute ethanol
Ar-CHO
O
S
Ar
N
N
Ar
Cl
SHCH2COOH
anhy. ZnCl2
N
O
N
N
H
Cl
4 a-k
O
N
H
3 a-k
ClCH2COCl
Et3N
O
Cl
Ar
N
N
Cl
O
N
H
5 a-k
according to reported method (Marvel and Hiers, 1941).
The condensation of 5-chloroindoline-2,3-dione 1 with
hydrazine hydrate in ethanol afforded 5-chloro-3-hydra-
zonoindolin-2-one 2 (Khan et al., 2002, 2009). Compound
2 on further reaction with different substituted aromatic
aldehydes in presence of 2–3 drops of glacial acetic acid in
ethanol yielded the corresponding 5-chloro-3-[(arylid-
ene)hydrazono]indoline-2-ones 3a–3k. Compounds 3a–3k,
further undergoes cyclization with thioglycolic acid in
presence of anhydrous ZnCl2 and with chloroacetylchloride
in presence of triethylamine (Et3N) to afford 3-(5-chloro-
2-oxoindolin-3-ylideneamino)-2-arylthiazolidin-4-ones
4a–4k (Agarwal et al., 2006) and 5-chloro-3-(3-chloro-2-
oxo-4-arylazetidin-1-ylimino)indolin-2-ones 5a–5k (Bhati
and Kumar, 2008), respectively.
spectrum and appearance of a singlet between d 8.58–9.1
for one proton of –N=CH–Ar in the H NMR spectra also
1
supports their structures. Cycloaddition of thioglycolic acid
to 3a–3k resulted into compounds 4a–4k which was con-
firmed by the presence of a band between 1760 and
1771 cm-1 (C=O of b-thialactum ring) in the IR spectra
and a singlet in between d 3.1–3.5 of two protons of CH2 of
thiazolidinone ring and 4.3–4.8 of –CH–Ar in the 1H NMR
spectra. Cycloaddition of chloroacetylchloride to 3a–3k
resulted into compounds 5a–5k which was confirmed by
the presence of a band between 1745 and 1760 cm-1 (C=O
of b-lactam ring) in the IR spectra and a singlet in between
1
d 4.25–4.9 of –CH–Cl and 5.2–5.5 of –CH–Ar in the H
NMR spectra.
The thiazolidi-4-ones and azetidi-2-ones are formed by
cycloaddition mechanism (Soleiman, 2011). The formation
of compounds 3a–k was evidenced by appearance of a
band between 1675 and 1703 cm-1 (N=CH) in the IR
Antimicrobial activity
All the synthesized compounds were screened for their
possible antibacterial and antifungal activities by
123

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Med Chem Res (2012) 21:1302–1312
determining minimum inhibitory concentrations (MICs) in
lg ml-1 against selected strains. The MICs was deter-
mined by broth dilution method (Srinivas et al., 2006). The
MIC was determined for each compound along with cip-
rofloxacin as standard control and the results are presented
in Tables 1 and 2. The MIC values of 12 derivatives
against tested organisms exhibited significant activity with
a degree of variation. It was found that 4-thiazolidinone
derivatives of 5-chloroisatin displayed substantially sig-
nificant activity: compound 4c against S. hominis,
B. pumilus, B. cereus, S. typhi, E. coli and P. aeroginosa;
4f against S. epiderimidis, S. hominis, B. pumilus, P. vul-
garis, S. typhi, K. pneumonia and P. aeroginosa; 4g against
S. aureus, S. hominis, B. pumilus, P. mirabilis and S. typhi;
4h against B. subtilis, S. epidermidis, P. mirabilis, S. typhi
and K. pneumonia; 4i against S. epiderimidis, S. hominis,
B. pumilus, B. cereus, S. typhi and P. aeroginosa; 4j
against M. luteus, S. aureus, S. hominis, S. typhi and
P. aeroginosa.
arylthiazolidin-4-one and 5-chloro-3-(3-chloro-2-oxo-4-
arylazetidin-1-ylimino)indolin-2-one from 5-chloro-3-
[(arylidene)hydrazono]indoline-2-one although the synthesis
of spirothiazolidinone (Bhambi et al., 2009; Dandia et al.,
2006) and spiroazetidinone (Dandia et al., 2007; Singh and
Luntha, 2009) derivatives of isatin are reported previously.
The activity data reveals that the compounds 4c, 4f, 4g, 4h,
4i, 4j, 5c, 5f, 5g, 5h, 5i and 5j having electron withdrawing
as well as electron releasing substitution at fourth position
of the phenyl ring exhibits good antibacterial as well as
antifungal activities. The compounds 4d and 5d having
electron releasing substituents at third position of the
phenyl ring exhibits moderate activity. In compounds 4b,
4e, 5b and 5e electron withdrawing substituents at second
position of phenyl ring are found to be inactive. In con-
clusion, the substitution at the fourth position may enhance
activity and substitution at second position may decrease
the activity.
In case of 2-azetidinone derivatives of 5-chloroisatin, the
substantially significant activity is exhibited by: compound
5c against B. subtilis, S. hominis, B. pumilus, P. vulgaris,
S. typhi and K. pneumonia; 5f against B. subtilis, S. epi-
derimidis, B. pumilus, B. cereus, P. vulgaris, P. mirabilis,
S. typhi, E. coli and P. aeroginosa; 5g against S. epider-
imidis, B. pumilus, P. vulgaris, S. typhi, K. pneumonia,
E. coli and P. aeroginosa; 5h against S. epiderimidis,
M. luteus, B. pumilus, B. cereus, S. typhi, K. pneumonia,
E. coli and P. aeroginosa; 5i against B. subtilis, S. hominis,
P. mirabilis and S. typhi; 5j against B. subtilis, M. luteus,
B. pumilus, B. cereus, P. vulgaris, P. mirabilis, S. typhi,
K. pneumonia and P. aeroginosa.
Experimental protocols
General
All reagents and solvents used in study are of analytical
grade and have been procured locally. The progress of the
reaction is monitored by TLC and the products are purified
through recrystallization. The melting points (m. p.) were
determined in one-end-open capillary method and are
uncorrected. The CATA-2R microwave was used for
microwave assisted reaction. IR spectra were recorded on
Shimadzu FT-IR 8400-S spectrophotometer using potas-
sium bromide (KBr) pellet. The 1H NMR spectra were
acquired on Varian AMX 300 NMR instrument using
CDCl3 or DMSO-d6 as the solvent and TMS as the internal
reference (chemical shifts in d, ppm); 13C NMR was per-
formed on Varian AMX 300 (100 MHz) spectrometer
using solutions in CDCl3 or DMSO-d6 and mass spectra
were acquired on API 2000 spectrometer. The elemental
analysis (C, H, N) of compounds was performed on Ele-
mentar Vario EL III elemental analyzer.
The antifungal activity (MIC) of all the synthesized
compounds was determined by using clotrimazole as
standard control. From the series of 4-thiazolidinone,
derivatives 4c, 4f, 4g, 4h, 4i and 4j exhibited substantially
significant activity against A. niger, A. Awamori, C. albi-
cans, A. alternate, M. canis, R. solani, T. longiformis,
A. flavus, F. solani, T. viride, A. flavus and A. fumigatus.
Also, the compounds 5c, 5f, 5g, 5h, 5i and 5j of 2-aze-
tidinone series showed substantially significant activity
against A. niger, A. Awamori, C. albicans, A. alternate,
M. canis, R. solani, T. longiformis, A. flavus, F. solani,
T. viride, A. flavus and A. fumigatus. The compounds 4a,
4d, 4k, 5a, 5d and 5k showed significant activity and 4b,
4e, 5b and 5e are found to be inactive against all screened
strains of bacteria and fungi.
General procedure for the synthesis of 5-chloro-3-
[(arylidene)hydrazono] indoline-2-one (3a–k)
5-Chloro-3-hydrazonoindolin-2-one (2, 0.1 mol), various
substituted aromatic aldehydes (0.1 mol) and two drops of
glacial acetic acid in 50 ml absolute alcohol was refluxed
for 2 h. The reaction mixture was cooled at room tem-
perature. The solid mass thus obtained was recrystallized
from suitable solvent to obtain compounds 3a–k.
Conclusions
In this study, we report synthesis and characterization of a
series of 3-(5-chloro-2-oxoindolin-3-ylideneamino)-2-
3-(Benzylidenehydrazono)-5-chloroindolin-2-one (3a)
Yield 82% (ethanol); m. p. 268–270°C. IR (KBr, cm-1):
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Med Chem Res (2012) 21:1302–1312
1305
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1306
Med Chem Res (2012) 21:1302–1312
Table 2 Antifungal activity of the compounds: MIC in lg ml-1
Comp. code Name of microorganism (MIC in lg ml-1
)
A. niger A. awamori C. albicans A. alternate M. canis R. Solani T. longiformis F. solani T. viride A. flavus A. fumigatus
4a
4b
4c
18.75
75.0
4.68
37.5
18.75
150
9.37
37.5
150
9.37
150
37.5
150
4.68
37.5
75.0
37.5
75.0
18.75
150
4.68
37.5
150
18.75
150
37.5
75.0
37.5
150
4.68
18.75
150
4.68
37.5
150
4.68
18.75
75.0
4.68
9.37
4.68
9.37
9.37
18.75
37.5
75.0
4.68
18.75
75.0
4.68
4.68
4.68
4.68
4.68
18.75
0.58
4.68
9.37
18.75
150
9.37
9.37
18.75
150
4d
4e
18.75
75.0
9.37
4.68
9.37
9.37
4.68
37.5
18.75
18.75
75.0
9.37
9.37
9.37
9.37
4.68
37.5
37.5
75.0
9.37
37.5
18.75
18.75
75.0
9.37
4.68
9.37
9.37
4.68
37.5
18.75
150
150
4f
4.68
4.68
4.68
9.37
4.68
4.68
9.37
4.68
9.37
9.37
9.37
4.68
4.68
4.68
4.68
4.68
4.68
18.75
37.5
4.68
4.68
4.68
4.68
9.37
4.68
4.68
4.68
4.68
9.37
4.68
4.68
4.68
4.68
4.68
18.75
37.5
4g
4h
4i
9.37
4.68
4j
9.37
4k
5a
5b
5c
37.5
18.75
150
4.68
37.5
75.0
4.68
37.5
37.5
150
4.68
37.5
150
4.68
18.75
18.75
37.5
18.75
150
4.68
37.5
75.0
9.37
37.5
18.75
150
4.68
37.5
150
150
150
150
150
150
9.37
9.37
4.68
9.37
4.68
5d
5e
18.75
18.75
18.75
18.75
18.75
150
150
150
150
150
150
5f
4.68
4.68
9.37
4.68
4.68
4.68
4.68
9.37
9.37
4.68
4.68
9.37
9.37
9.37
9.37
4.68
4.68
4.68
9.37
9.37
18.75
2.34
4.68
4.68
4.68
9.37
9.37
4.68
4.68
9.37
4.68
4.68
4.68
4.68
4.68
9.37
9.37
18.75
2.34
5g
5h
5i
9.37
4.68
4.68
4.68
18.75
2.34
9.37
4.68
4.68
9.37
9.37
4.68
9.37
9.37
5j
5k
Standard*
37.5
2.34
37.5
2.34
37.5
1.17
37.5
1.17
37.5
1.17
37.5
1.17
37.5
2.34
Standard*—clotrimazole
MIC minimum inhibitory concentration
5-Chloro-3-[(4-chlorobenzylidene)hydrazono]indolin-2-
one (3c) Yield 85% (ethanol); m. p. 185–187°C. IR (KBr,
cm-1): 3280 (NH), 3068 (CH aromatic), 1685 (C=O), 1623
(C=N), 755 (C–Cl); 1H NMR (DMSO-d6) d in ppm:
6.9–7.0 (s, 1H, Ar–H), 7.35–7.95 (m, 6H, Ar–H), 8.58 (s,
1H, –N=CH), 11.0 (s, 1H, Het-NH); 13C NMR (DMSO-d6)
d in ppm: 169.2, 149.3, 142.2, 140.5, 138.6, 136.5, 134.8,
132.3, 130.6, 129.2, 126.4, 123.9, 118.9. Anal. Calcd. for
C15H9Cl2N3O: C 56.63, H 2.85, N 13.21; Found: C 56.75,
H 2.79, N 13.24%.
3246 (NH), 3023 (CH aromatic), 1685 (C=O), 1616 (C=N),
1
752 (C–Cl); H NMR (CDCl3) d in ppm: 6.8–6.9 (d, 1H,
Ar–H), 7.4–7.8 (m, 7H, Ar–H), 8.7 (s, 1H, –N=CH), 11.0
(s, 1H, Het-NH); 13C NMR (CDCl3) d in ppm: 169.1,
149.5, 145.8, 143.2, 141.1, 138.4, 135.6, 133.7, 130.8,
128.2, 125.9, 123.5, 119.1. Anal. Calcd. for C15H10ClN3O:
C 63.50, H 3.55, N 14.81; Found: C 63.57, H 3.47, N
14.89%.
5-Chloro-3-[(2-chlorobenzylidene)hydrazono]indolin-2-one
(3b) Yield 78% (ethanol); m. p. 236–238°C. IR (KBr,
cm-1): 3250 (NH), 3064 (CH aromatic), 1703 (C=O), 1617
5-Chloro-3-[(3-methoxybenzylidene)hydrazono]indolin-2-
one (3d) Yield 87% (methanol); m. p. 198–200°C. IR
(KBr, cm-1): 3242 (NH), 3065 (CH aromatic), 1684
(C=O), 1640 (C=N), 1267 (C–O–C), 745 (C–Cl); 1H NMR
(CDCl3) d in ppm: 3.9 (s, 3H, –OCH3), 6.85–7.57 (m, 5H,
Ar–H), 8.65 (s, 1H, –N=CH), 11.2 (s, 1H, Het-NH); 13C
NMR (CDCl3) d in ppm: 169.4, 160.7, 150.8, 142.2, 139.7,
136.8, 134.5, 131.6, 129.1, 127.0, 124.7, 120.8, 118.2,
1
(C=N), 743 (C–Cl); H NMR (CDCl3) d in ppm: 6.9–7.0
(d, 1H, Ar–H), 7.2–7.4 (m, 5H, Ar–H), 8.25–8.35 (m, 1H,
Ar–H), 9.1 (s, 1H, –N=CH), 11.1 (s, 1H, Het-NH); 13C
NMR (CDCl3) d in ppm: 169.0, 151.1, 146.5, 144.2, 142.2,
140.1, 138.0, 136.1, 133.6, 131.8, 129.7, 127.8, 125.5,
123.1, 119.2. Anal. Calcd. for C15H9Cl2N3O: C 56.63, H
2.85, N 13.21; Found: C 56.71, H 2.80, N 13.27%.
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Med Chem Res (2012) 21:1302–1312
1307
116.1, 111.0, 54.9. Anal. Calcd. for C16H12ClN3O2: C
61.25, H 3.86, N 13.39; Found: C 61.33, H 3.75, N 13.34%.
5-chloro-3-[(2-hydroxybenzylidene)hydrazono]indolin-
2-one (3e) Khan et al. (2009).
C15H9ClN4O3: C 54.81, H 2.76, Cl 10.79, N 17.04; Found:
C 54.89, H 2.69, N 10.83%.
5-Chloro-3-[(furan-2-ylmethylene)hydrazono]indolin-2-
one (3k) Yield 89% (ethanol); m. p. 265°C. IR (KBr,
cm-1): 3300 (NH), 3072 (CH aromatic), 1685 (C=O), 1635
5-Chloro-3-[(4-hydroxybenzylidene)hydrazono]indolin-2-
one (3f) Yield 88% (ethanol); m. p. 238–240°C. IR (KBr,
cm-1): 3410 (Ar–OH), 3290 (NH), 3055 (CH aromatic),
1
(C=N), 1258 (C–O–C), 753 (C–Cl); H NMR (DMSO-d6)
d in ppm: 6.6 (d, 1H, Ar–H), 6.88–6.96 (m, 1H, Ar–H), 7.2
(d, 1H, Ar–H), 7.68–7.77 (t, 3H, Ar–H), 8.58 (s, 1H,
–N=CH), 11.2 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in
ppm: 169.1, 163.9, 149.2, 144.2, 140.9, 137.4, 132.0,
130.0, 127.2, 123.3, 120.2, 118.1, 112.6. Anal. Calcd. for
C13H8ClN3O2 : C 57.05, H 2.95, N 15.35; Found: C 57.13,
H 2.97, N 15.29%.
1
1675 (C=O), 1639 (C=N), 751 (C–Cl); H NMR (DMSO-
d6) d in ppm: 6.7–6.8 (d, 1H, Ar–H), 6.8–6.9 (d, 2H, Ar–
H), 7.6–7.8 (m, 4H, Ar–H), 8.58 (s, 1H, –N=CH), 10.1 (s,
1H OH), 11.1 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in
ppm: 169.2, 161.0, 149.6, 141.1, 138.1, 134.9, 132.7,
130.8, 127.5, 125.5, 123.0, 119.8, 116.1. Anal. Calcd. for
C15H10ClN3O2: C 60.11, H 3.36, N 14.02; Found: C 60.15,
H 3.47, N 14.13%.
General procedure for the synthesis of 3-(5-chloro-2-
oxoindolin-3-ylideneamino)-2-arylthiazolidin-4-one (4a–k)
5-Chloro-3-[(4-dimethylaminobenzylidene)hydrazono]in-
dolin-2-one (3g) Yield 83% (ethanol); m. p. 228–230°C.
IR (KBr, cm-1): 3306 (NH), 3077 (CH aromatic), 2846
The mixture of 5-chloro-3-[(arylidene)hydrazono] indo-
line-2-one (3a–k, 0.1 mol) and thioglycolic acid (0.1 mol)
in ethanol (100 ml) in presence of anhydrous ZnCl2
(a pinch) was refluxed for 10–12 h on water bath. The
reaction mixture was poured into ice-cold water, filtered
and finally recrystallized from appropriate solvents to give
compounds 4a–k.
1
(CH aliphatic), 1688 (C=O), 1626 (C=N), 748 (C–Cl); H
NMR (CDCl3) d in ppm: 2.4 (s, 6H, –N(CH3)2), 6.7–6.8 (d,
2H, Ar–H), 6.9–7.0 (d, 1H, Ar–H), 7.58–7.8 (m, 4H, Ar–
H), 8.6 (s, 1H, –N=CH), 11.1 (s, 1H, Het-NH); 13C NMR
(CDCl3) d in ppm: 169.9, 153.4, 149.4, 140.2, 138.1, 136.0,
133.7, 131.8, 129.5, 125.4, 122.1, 119.3, 111.8, 40.1. Anal.
Calcd. for C17H15ClN4O: C 62.48, H 4.63, N 17.15; Found:
C 62.55, H 4.52, N 17.20%.
3-(5-Chloro-2-oxoindolin-3-ylidendeamino)-2-phenylthia-
zolidin-4-one (4a) Yield 69% (methanol); m. p. 124–
126°C. IR (KBr, cm-1): 3310 (NH), 3070 (CH aromatic),
1771, 1680 (C=O), 1632 (C=N), 750 (C–Cl), 700 (C–S–C);
1H NMR (DMSO-d6) d in ppm: 3.1 (s, 2H, CH2 of thia-
zolidinone ring), 4.3 (s, 1H, –N–CH–Ar), 6.9–6.94 (d, 1H,
Ar–H), 7.24–7.3 (t, 3H, Ar–H), 7.54–7.66 (m, 2H, Ar–H),
7.86–7.94 (t, 2H, Ar–H), 11.1 (s, 1H, Het-NH); 13C NMR
(DMSO-d6) d in ppm: 171.0, 167.7, 146.2, 144.1, 141.6,
139.3, 136.7, 134.6, 132.0, 129.4, 127.1, 124.8, 118.9,
56.5, 35.6. Anal. Calcd. for C17H12ClN3O2S: C 57.06, H
3.38, N 11.74, S 8.96; Found: C 56.97, H 3.43, N 11.66, S
8.88%. MS: [M]? at m/z 357.81.
5-Chloro-3-[(4-methoxybenzylidene)hydrazono]indolin-2-
one (3h) Yield 90% (ethanol); m. p. 243–244°C. IR
(KBr, cm-1): 3310 (NH), 3061 (CH aromatic), 1695
(C=O), 1625 (C=N), 1251 (C–O–C), 750 (C–Cl); 1H NMR
(CDCl3) d in ppm: 3.85 (s, 3H, –OCH3), 6.79–6.85 (d, 1H,
Ar–H), 6.92–7.0 (d, 2H, Ar–H), 7.75–7.98 (m, 4H, Ar–H),
8.6 (s, 1H, –N=CH), 11.2 (s, 1H, Het-NH); 13C NMR
(CDCl3) d in ppm: 169.5, 162.6, 150.2, 142.6, 140.2, 137.7,
135.3, 132.7, 130.0, 127.2, 124.5, 119.6, 114.5, 55.9. Anal.
Calcd. for C16H12ClN3O2: C 61.25, H 3.86, N 13.39;
Found: C 61.33, H 3.81, N 13.46%.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(2-chloro-
phenyl)thiazolidin-4-one (4b) Yield 78% (ethanol); m.
p. 188–189°C. IR (KBr, cm-1): 3302 (NH), 3080 (CH
aromatic), 1762, 1688 (C=O), 1627 (C=N), 750 (C–Cl),
5-chloro-3-[(4-fluorobenzylidene)hydrazono]indolin-2-
one (3i) Khan et al. (2009).
1
5-Chloro-3-[(4-nitrobenzylidene)hydrazono]indolin-2-one
(3j) Yield 75% (ethanol); m. p. 280°C. IR (KBr, cm-1):
3316 (NH), 3073 (CH aromatic), 1686 (C=O), 1638 (C=N),
695 (C–S-C); H NMR (DMSO-d6) d in ppm: 3.22 (s, 2H,
CH2 of thiazolidinone ring), 4.8 (s, 1H, –N–CH–Ar), 6.9–7
(d, 1H, Ar–H), 7.2–7.45 (m, 5H, Ar–H), 8.2–8.35 (m, 1H,
Ar–H), 11.1 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in
ppm: 171.3, 167.9, 150.4, 148.9, 145.5, 142.8, 140.3,
137.8, 135.2, 132.8, 130.5, 127.8, 125.6, 119.1, 102.3,
51.2, 35.9. Anal. Calcd. For C17H11Cl2N3O2S: C 52.05, H
2.83, N 10.71, S 8.17; Found: C 52.11, H 2.89, N 10.66, S
8.12%. MS: [M]? at m/z 392.26.
1
1535, 1350 (NO2), 754 (C–Cl); H NMR (DMSO-d6) d in
ppm: 6.85–6.95 (m, 1H, Ar–H), 7.53–7.7 (m, 2H, Ar–H),
8.1 (d, 2H, Ar–H), 8.4 (d, 2H, Ar–H), 8.7 (s, 1H, –N=CH),
11.1 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm:
169.1, 152.0, 149.7, 142.3, 140.0, 137.9, 134.0, 132.1,
130.1, 128.6, 126.5, 124.3, 119.7. Anal. Calcd. for
123

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Med Chem Res (2012) 21:1302–1312
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(4-chloro-
phenyl)thiazolidin-4-one (4c) Yield 66% (chloroform);
m. p. 138–140°C. IR (KBr, cm-1): 3306 (NH), 307 6 (CH
aromatic), 1760, 1685 (C=O), 1624 (C=N), 745 (C–Cl),
131.9, 129.9, 127.6, 125.3, 119.1, 115.6, 56.9, 35.7. Anal.
Calcd. for C17H12ClN3O3S: C 54.62, H 3.24, N 11.24, S
8.58; Found: C 54.58, H 3.16, N 11.18, S 8.47%. MS: [M]?
at m/z 373.81.
1
689 (C–S–C); H NMR (DMSO-d6) d in ppm: 3.2 (s, 2H,
CH2 of thiazolidinone ring), 4.3 (s, 1H, –N–CH–Ar),
6.8–7.0 (d, 1H, Ar–H), 7.35–7.45 (d, 2H, Ar–H), 7.5–7.68
(m, 2H, Ar–H), 7.86–7.95 (d, 2H, Ar–H), 11.0 (s, 1H, Het-
NH); 13C NMR (DMSO-d6) d in ppm: 171.2, 168.4, 145.1,
142.4, 140.3, 137.8, 135.6, 133.1, 130.5, 128.0, 125.7,
123.3, 119.1, 56.5, 35.1. Anal. Calcd. for C17H11Cl2N3O2S:
C 52.05, H 2.83, N 10.71, S 8.17; Found: C 51.97, H 2.89,
N 10.67, S 8.12%. MS: [M]? at m/z 392.26.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-[4-(dimethyl-
amino)phenyl]thiazolidin-4-one (4g) Yield 75% (dioxan);
m. p. 245–247°C. IR (KBr, cm-1): 3304 (NH), 3075 (CH
aromatic), 2852 (CH aliphatic), 1765, 1689 (C=O), 1616
1
(C=N), 749 (C–Cl), 692 (C–S–C); H NMR (DMSO-d6) d
in ppm: 2.4 (s, 6H, –N(CH3)2), 3.5 (s, 2H, CH2 of thia-
zolidinone ring), 4.3 (s, 1H, –N–CH–Ar), 6.7–6.8 (d, 2H,
Ar–H), 6.9–7.0 (d, 1H, Ar–H), 7.55–7.93 (m, 4H, Ar–H),
11.1 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm:
171.4, 168.8, 149.3, 142.9, 140.3, 137.8, 135.3, 132.4,
130.1, 127.5, 125.6, 119.3, 112.7, 56.2, 40.5, 35.6. Anal.
Calcd. for C19H17ClN4O2S: C 56.93, H 4.27, N 13.98, S
8.00; Found: C 57.10, H 4.20, N 13.86, S 7.93%. MS: [M]?
at m/z 400.88.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(3-methoxy-
phenyl)thiazolidin-4-one (4d) Yield 74% (ethanol); m.
p. 148–150°C. IR (KBr, cm-1): 3315 (NH), 3074 (CH aro-
matic), 1764, 1682 (C=O), 1615 (C=N), 1250 (C–O–C), 748
(C–Cl), 682 (C–S–C); 1H NMR (DMSO-d6) d in ppm: 3.18
(s, 2H, CH2 of thiazolidinone ring), 3.9 (s, 3H, –OCH3), 4.62
(s, 1H, –N–CH–Ar), 6.9–6.94 (d, 1H, Ar–H), 7.02–7.06 (d,
2H, Ar–H), 7.22–7.32 (m, 3H, Ar–H), 7.54–7.64 (m, 2H, Ar–
H), 11.1 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm:
171.2, 168.6, 160.3, 141.7, 139.5, 137.0, 134.9, 132.5, 130.2,
127.7, 125.5, 119.8, 117.1, 114.3, 112.1, 58.3, 56.2, 35.7.
Anal. Calcd. for C18H14ClN3O3S: C 55.74, H 3.64, N 10.83,
S 8.27; Found: C 55.82, H 3.57, N 10.75, S 8.18%. MS: [M]?
at m/z 387.84.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(4-methoxy-
phenyl)thiazolidin-4-one (4h) Yield 70% (toluene); m.
p. 324°C. IR (KBr, cm-1): 3315 (NH), 3074 (CH aro-
matic), 1760, 1688 (C=O), 1627 (C=N), 1248 (C–O–C),
748 (C–Cl), 691 (C–S–C); 1H NMR (DMSO-d6) d in ppm:
3.2 (s, 2H, CH2 of thiazolidinone ring), 3.9 (s, 3H, –OCH3),
4.6 (s, 1H, –N–CH–Ar), 6.68–6.73 (d, 2H, Ar–H), 6.9–6.94
(d, 1H, Ar–H), 7.44–7.64 (m, 2H, Ar–H), 7.83–7.88 (d, 2H,
Ar–H), 11.1 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d in
ppm: 171.5, 168.6, 159.3, 145.2, 142.5, 139.4, 137.0,
133.9, 131.3, 129.2, 125.4, 119.5, 114.2, 57.5, 55.0, 35.8.
Anal. Calcd. for C18H14ClN3O3S: C 55.74, H 3.64, N
10.83, S 8.27; Found: C 55.79, H 3.59, N 10.77%. MS:
[M]? at m/z 387.84.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(2-hydroxy-
phenyl)thiazolidin-4-one (4e) Yield 65% (ethanol); m.
p. 240–242°C. IR (KBr, cm-1): 3435 (Ar–OH), 3312 (NH),
3075 (CH aromatic), 1763, 1688 (C=O), 1622 (C=N), 750
(C–Cl), 690 (C–S–C); 1H NMR (DMSO-d6) d in ppm: 3.3 (s,
2H, CH2 of thiazolidinone ring), 4.6 (s, 1H, –N–CH–Ar),
6.7–6.9 (d, 1H, Ar–H), 7.03–7.4 (m, 4H, Ar–H), 7.5–7.8 (m,
2H, Ar–H), 11.1 (s, 1H, Het-NH), 11.4 (s, 1H, OH); 13C
NMR (DMSO-d6) d in ppm: 171.4, 168.1, 153.2, 142.4,
140.0, 137.6, 135.4, 132.9, 130.6, 128.1, 125.7, 122.8, 120.4,
117.9, 115.6, 50.2, 35.6. Anal. Calcd. for C17H12ClN3O3S: C
54.62, H 3.24, N 11.24, S 8.58; Found: C 54.69, H 3.21, N
11.18, S 8.49%. MS: [M]? at m/z 373.81.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(4-fluoro-
phenyl)thiazolidin-4-one (4i) Yield 67% (benzene); m.
p. 176–178°C. IR (KBr, cm-1): 3310 (NH), 3080 (CH
aromatic), 1762, 1690 (C=O), 1626 (C=N), 1150 (C–F),
750 (C–Cl), 690 (C–S–C); 1H NMR (DMSO-d6) d in ppm:
3.2 (s, 2H, CH2 of thiazolidinone ring), 4.6 (s, 1H, –N–CH–
Ar), 6.8–7.0 (d, 1H, Ar–H), 7.25–7.38 (d, 2H, Ar–H),
7.49–7.7 (m, 2H, Ar–H), 7.85–7.98 (m, 2H, Ar–H), 11.1 (s,
1H, Het-NH); 13C NMR (DMSO-d6) d in ppm: 171.1,
168.7, 161.3, 141.5, 139.2, 136.8, 134.4, 132.3, 129.9,
127.5, 125.2, 119.4, 115.2, 56.3, 36.1. Anal. Calcd. for
C17H11ClFN3O2S: C 54.33, H 2.95, N 11.18, S 8.53;
Found: C 54.41, H 3.10, N 11.09, S 8.45%. MS: [M]? at
m/z 374.5.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(4-hydroxy-
phenyl)thiazolidin-4-one (4f) Yield 72% (ethanol); m.
p. 271–272°C. IR (KBr, cm-1): 3440 (Ar–OH), 3310 (NH),
3078 (CH aromatic), 1764, 1690 (C=O), 1624 (C=N), 751
1
(C–Cl), 689 (C–S-C); H NMR (DMSO-d6) d in ppm: 3.3
(s, 2H, CH2 of thiazolidinone ring), 4.4 (s, 1H, –N–CH–
Ar), 6.7–6.9 (m, 3H, Ar–H), 7.56–7.8 (m, 4H, Ar–H), 10.1
(s, 1H, OH), 11.0 (s, 1H, Het-NH); 13C NMR (DMSO-d6) d
in ppm: 171.3, 168.5, 156.7, 141.1, 138.9, 136.7, 134.4,
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(4-nitro-
phenyl)thiazolidin-4-one (4j) Yield 57% (benzene); m.
123

Med Chem Res (2012) 21:1302–1312
1309
p. 196–198°C. IR (KBr, cm-1): 3310 (NH), 3075 (CH
aromatic), 1762, 1685 (C=O), 1627 (C=N), 1540, 1346
C 56.69, H 3.08, N 11.67; Found: C 56.77, H 2.98, N
11.58%. MS: [M]? at m/z 359.00.
1
(NO2), 748 (C–Cl), 690 (C–S–C); H NMR (DMSO-d6) d
in ppm: 3.2 (s, 2H, CH2 of thiazolidinone ring), 4.4 (s, 1H,
–N–CH–Ar), 6.8–7.0 (m, 1H, Ar–H), 7.5–7.7 (m, 2H, Ar–
H), 8.0–8.25 (d, 2H, Ar–H), 8.75–8.92 (d, 2H, Ar–H), 11.1
(s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm: 170.7,
168.3, 147.6, 145.3, 139.4, 137.1, 134.9, 132.6, 130.4,
128.3, 126.0, 123.6, 119.1, 56.7, 35.8. Anal. Calcd. for
C17H11ClN4O4S: C 50.69, H 2.75, N 13.91, S 7.96; Found:
C 50.74, H 2.67, N 13.83, S 7.89%. MS: [M]? at m/
z 402.81.
5-Chloro-3-[3-chloro-2-(2-chlorophenyl)-4-oxazetidin-1-yli-
mino]indolin-2-one (5b) Yield 76% (ethanol); m.
p. 120°C. IR (KBr, cm-1): 3312 (NH), 3078 (CH aro-
1
matic), 1760, 1728 (C=O), 1622 (C=N), 744 (C–Cl); H
NMR (DMSO-d6) d in ppm: 4.25 (s, 1H, CHCl), 5.2 (s, 1H,
–N–CHAr), 6.8–7.0 (d, 1H, Ar–H), 7.15–7.4 (m, 5H, Ar–
H), 7.95–8.05 (m, 1H, Ar–H), 11.1 (s, 1H, Het-NH); 13C
NMR (DMSO-d6) d in ppm: 168.2, 165.5, 146.2, 144.7,
142.5, 140.9, 139.0, 136,8, 135.1, 133.0, 131.4, 129.5,
127.2, 125.3, 119.1, 63.8, 56.2. Anal. Calcd. for
C17H10Cl3N3O2: C 51.74, H 2.55, N 10.65; Found: C
51.81, H 2.59, N 10.74%. MS: [M]? at m/z 392.98.
3-(5-Chloro-2-oxoindolin-3-ylideneamino)-2-(furan-2-yl)
thiazolidin-4-one (4k) Yield 63% (methanol); m. p. 310°C.
IR (KBr, cm-1): 3308 (NH), 3080 (CH aromatic), 1760,
1690 (C=O), 1624 (C=N), 1250 (C–O–C), 750 (C–Cl), 692
5-Chloro-3-[3-chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-
ylimino]indolin-2-one (5c) Yield 82% (ethanol); m.
p. 170–172°C. IR (KBr, cm-1): 3309 (NH), 3075 (CH
aromatic), 1750, 1720 (C=O), 1626 (C=N), 750 (C–Cl); 1H
NMR (DMSO-d6) d in ppm: 4.38 (s, 1H, CHCl), 5.4 (s, 1H,
–N–CHAr), 6.9–7.0 (d, 1H, Ar–H), 7.2–7.3 (d, 2H, Ar–H),
7.35–7.5 (m, 2H, Ar–H), 7.7–7.8 (d, 2H, Ar–H), 11.0 (s,
1H, Het-NH); 13C NMR (DMSO-d6) d in ppm: 168.0,
166.2, 142.3, 140.4, 138.0, 136.3, 134.4, 132.2, 130.2,
128.1, 126.2, 124.2, 119.1, 64.5, 61.3. Anal. Calcd. For
C17H10Cl3N3O2: C 51.74, H 2.55, N 10.65; Found: C
51.83, H 2.48, N 10.57%. MS: [M]? at m/z 392.98.
1
(C–S–C); H NMR (DMSO-d6) d in ppm: 3.3 (s, 2H, CH2
of thiazolidinone ring), 4.52 (s, 1H, –N–CH–Ar), 6.5–6.7
(d, 1H, Ar–H), 6.85–6.98 (m, 1H, Ar–H), 7.15–7.28 (d, 1H,
Ar–H), 7.68–7.78 (t, 3H, Ar–H), 11.2 (s, 1H, Het-NH); 13
C
NMR (DMSO-d6) d in ppm: 171.4, 168.9, 151.5, 141.7,
139.3, 136.9, 134.4, 131.9, 129.6, 125.5, 119.5, 109.6,
107.2, 55.8, 33.6. Anal. Calcd. for C15H10ClN3O3S: C
51.80, H 2.90, N 12.08, S 9.22; Found: C 51.91, H 2.96, N
11.98, S 9.12%. MS: [M]? at m/z 347.78.
General procedure for the preparation of 5-chloro-3-(3-
chloro-2-oxo-4-arylazetidin-1-ylimino)indolin-2-one
(5a–k)
5-Chloro-3-[3-chloro-2-(3-methoxyphenyl)-4-oxoazetidin-
1-ylimino]indolin-2-one (5d) Yield 80% (ethanol); m.
p. 138°C. IR (KBr, cm-1): 3312 (NH), 3078 (CH aro-
matic), 1753, 1721 (C=O), 1618 (C=N), 1252 (C–O–C),
To a stirred solution of 5-chloro-3-[(arylidene)hydrazono]
indoline-2-one (3a–k, 0.1 mol) in dioxan (100 ml), chlo-
roacetylchloride (0.1 mol) was added dropwise at 0–5°C
temperature in presence of triethylamine. The reaction
mixture was stirred for about 8 h and the precipitate of
amine hydrochloride was filtered off. The excess of dioxan
was distilled off. The mass thus obtained was cooled,
poured in ice-cold water, filtered, washed, dried and
recrystallized from appropriate solvents to furnish com-
pounds 5a–k.
1
749 (C–Cl); H NMR (DMSO-d6) d in ppm: 3.9 (s, 3H,
–OCH3), 4.8 (s, 1H, CHCl), 5.2 (s, 1H, –N–CHAr),
6.98–7.2 (d, 1H, Ar–H), 7.1–7.14 (d, 1H, Ar–H), 7.3–7.4
(m, 3H, Ar–H), 7.62–7.72 (m, 2H, Ar–H), 11.1 (s, 1H, Het-
NH); 13C NMR (DMSO-d6) d in ppm: 168.7, 166.5, 160.6,
144.7, 139.3, 134.2, 132.3, 130.2, 128.6, 126.8, 124.9,
121.1, 119.2, 113.9, 112.0, 64.5, 61.7, 55.6. Anal. Calcd.
for C18H13Cl2N3O3: C 55.40, H 3.36, N 10.77; Found: C
55.49, H 3.31, N 10.68%. MS: [M]? at m/z 390.22.
5-Chloro-3-(3-chloro-2-oxo-4-pheylazetidin-1-ylimino)in-
dolin-2-one (5a) Yield 85% (ethanol); m. p. 140–142°C.
IR (KBr, cm-1): 3315 (NH), 3080 (CH aromatic), 1745,
5-Chloro-3-[3-chloro-2-(2-hydroxyphenyl)-4-oxoazetidin-
1-ylimino]indolin-2-one (5e) Yield 75% (dioxan); m.
p. 109°C. IR (KBr, cm-1): 3430 (Ar–OH), 3310 (NH),
3075 (CH aromatic), 1748, 1726 (C=O), 1624 (C=N), 746
(C–Cl); 1H NMR (DMSO-d6) d in ppm: 4.8 (s, 1H, CHCl),
5.5 (s, 1H, –N–CHAr), 6.96–7.2 (d, 1H, Ar–H), 7.22–7.3
(m, 4H, Ar–H), 7.62–7.72 (m, 2H, Ar–H), 11.1 (s, 1H, Het-
NH), 11.5 (s, 1H, OH); 13C NMR (DMSO-d6) d in ppm:
168.0, 166.1, 154.2, 140.8, 138.4, 136.5, 134.6, 132.7,
1
1720 (C=O), 1625 (C=N), 740 (C–Cl); H NMR (DMSO-
d6) d in ppm: 4.6 (s, 1H, CHCl), 5.2 (s, 1H, –N–CHAr),
6.9–6.94 (d, 1H, Ar–H), 7.18–7.24 (t, 3H, Ar–H), 7.4–7.5
(m, 2H, Ar–H), 7.8–7.86 (t, 2H, Ar–H), 11.1 (s, 1H, Het-
NH); 13C NMR (DMSO-d6) d in ppm: 169.3, 166.5, 144.1,
140.0, 138.0, 136.1, 134.2, 132.4, 130.6, 128.9, 127.1,
125.3, 119.6, 64.5, 61.4. Anal. Calcd. for C17H11Cl2N3O2:
123

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Med Chem Res (2012) 21:1302–1312
130.9, 129.0, 127.1, 125.2, 121.2, 119.3, 115.5, 64.8, 55.2.
Anal. Calcd. for C17H11Cl2N3O3: C 54.28, H 2.95, N
11.17; Found: C 54.36, H 3.10, N 11.06%. MS: [M]? at m/
z 376.19.
(C–Cl); 1H NMR (DMSO-d6) d in ppm: 4.78 (s, 1H,
CHCl), 5.19 (s, 1H, –N–CHAr), 6.95–7.05 (d, 1H, Ar–H),
7.25–7.35 (t, 2H, Ar–H), 7.5–7.7 (m, 2H, Ar–H), 7.85–7.95
(m, 2H, Ar–H), 11.0 (s, 1H, Het-NH); 13C NMR (DMSO-
d6) d in ppm: 168.4, 166.1, 161.0, 141.4, 139.3, 133.9,
132.0, 130.1, 128.0, 126.3, 124.2, 119.1, 115.5, 64.4, 61.2.
Anal. Calcd. for C17H10Cl2FN3O2: C 53.99, H 2.67, N
11.11; Found: C 54.08, H 2.59, N 11.04%. MS: [M]? at m/
z 378.18.
5-Chloro-3-[3-chloro-2-(4-hydroxyphenyl)-4-oxoazetidin-
1-ylimino]indolin-2-one (5f) Yield 84% (chloroform); m.
p. 160–162°C. IR (KBr, cm-1): 3438 (Ar–OH), 3315 (NH),
3080 (CH aromatic), 1759, 1720 (C=O), 1620 (C=N), 752
(C–Cl); 1H NMR (DMSO-d6) d in ppm: 4.8 (s, 1H, CHCl),
5.4 (s, 1H, –N–CHAr), 6.98–7.1 (d, 1H, Ar–H), 7.1–7.2 (d,
2H, Ar–H), 7.4–7.65 (m, 4H, Ar–H), 10.1 (s, 1H, OH), 11.0
(s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm: 168.3,
166.0, 156.7, 139.4, 135.2, 133.2, 131.3, 129.9, 128.3,
126.7, 125.1, 119.2, 115.8, 64.6, 61.2. Anal. Calcd. for
C17H11Cl2N3O3: C 54.28, H 2.95, N 11.17; Found: C
54.36, H 3.04, N 11.09%. MS: [M]? at m/z 376.19.
5-Chloro-3-[3-chloro-2-(4-nitrophenyl)-4-oxoazetidin-1-
ylimino]indolin-2-one (5j) Yield 81% (toluene); m.
p. 212°C. IR (KBr, cm-1): 3315 (NH), 3082 (CH aro-
matic), 1759, 1728 (C=O), 1625 (C=N), 1544, 1348 (NO2),
1
742 (C–Cl); H NMR (DMSO-d6) d in ppm: 4.9 (s, 1H,
CHCl), 5.19 (s, 1H, –N–CHAr), 6.95–7.08 (m, 1H, Ar–H),
7.65–7.8 (m, 2H, Ar–H), 8.05–8.15 (d, 2H, Ar–H),
8.35–8.5 (d, 2H, Ar–H), 11.0 (s, 1H, Het-NH); 13C NMR
(DMSO-d6) d in ppm: 168.2, 166.1, 149.6, 145.8, 139.5,
133.7, 131.6, 129.5, 127.6, 125.5, 123.5, 121.7, 119.2,
64.0, 61.5. Anal. Calcd. for C17H10Cl2N4O4: C 50.39, H
2.49, N 13.83; Found: C 50.48, H 2.41, N 13.74%. MS:
[M]? at m/z 405.19.
5-Chloro-3-[3-chloro-2-{4-(dimethylamino)phenyl}-4-oxoaz-
etidin-1-ylimino]indolin-2-one (5g) Yield 78% (ethyl-
acetate); m. p. 149–150°C. IR (KBr, cm-1): 3308 (NH),
3082 (CH aromatic), 2860 (CH aliphatic), 1750, 1722
(C=O), 1620 (C=N), 748 (C–Cl); 1H NMR (DMSO-d6) d in
ppm: 2.4 (s, 6H, –N(CH3)2), 4.8 (s, 1H, CHCl), 5.3 (s, 1H,
–N–CHAr), 6.75–6.85 (d, 2H, Ar–H), 6.9–7.1 (d, 1H, Ar–
H), 7.7–8.0 (m, 4H, Ar–H), 11.0 (s, 1H, Het-NH); 13C
NMR (DMSO-d6) d in ppm: 168.8, 166.3, 149.2, 139.0,
136.0, 133.7, 131.8, 129.5, 127.2, 125.1, 119.3, 112.4,
64.1, 61.6, 40.5. Anal. Calcd. for C19H16Cl2N4O2: C 56.59,
H 4.00, N 13.89; Found: C 56.66, H 3.95, N 13.81%. MS:
[M]? at m/z 403.26.
5-Chloro-3-[3-chloro-2-(furan-2-yl)-4-oxoazetidin-1-ylimino]
indolin-2-one (5k) Yield 85% (methanol); m. p. 102°C.
IR (KBr, cm-1): 3312 (NH), 3080 (CH aromatic), 1760,
1
1725 (C=O), 1620 (C=N), 1253 (C–O–C), 746 (C–Cl); H
NMR (DMSO-d6) d in ppm: 4.7 (s, 1H, CHCl), 5.18 (s, 1H,
–N–CHAr), 6.7–6.9 (d, 1H, Ar–H), 6.95–7.1 (m, 1H, Ar–
H), 7.25–7.4 (d, 1H, Ar–H), 7.75–7.9 (t, 3H, Ar–H), 11.1
(s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm: 168.4,
166.3, 151.1, 141.6, 139.5, 134.7, 132.6, 130.8, 128.9,
125.2, 119.1, 111.3, 109.1, 62.2, 59.3. Anal. Calcd. for
C15H9Cl2N3O3: C 51.45, H 2.59, N 12.00; Found: C 51.56,
H 2.48, N 11.94%. MS: [M]? at m/z 350.16.
5-Chloro-3-[3-chloro-2-(4-methoxyphenyl)-4-oxoazetidin-
1-ylimino]indolin-2-one (5h) Yield 87% (ethanol); m.
p. 112°C. IR (KBr, cm-1): 3310 (NH), 3080 (CH aro-
matic), 1747, 1721 (C=O), 1625 (C=N), 1250 (C–O–C),
Antibacterial and antifungal activity (MIC)
1
750 (C–Cl); H NMR (DMSO-d6) d in ppm: 3.85 (s, 3H,
The bacterial and fungal strains were procured from
National Chemical Laboratory (NCL), Pune, India. The
antibacterial activity of the synthesized compounds was
screened against the following bacterial strains: Bacillus
subtilis ATCC 6633, Staphylococcus epidermidis ATCC
12228, Micrococcus luteus ATCC 4698, Staphylococcus
aureus ATCC 25923, Staphylococcus hominis ATCC
27844, Bacillus pumilus ATCC 14884, Bacillus cereus
ATCC 11778, Proteus vulgaris ATCC 13315, Proteus
mirabilis ATCC 49565, Salmonella typhi ATCC 19430,
Klebsiella pneumonia ATCC 13883, Escherichia coli
ATCC 25922 and Pseudomonas aeroginosa ATCC 10145.
The compounds were also screened against the follow-
ing fungal strains: Aspergillus niger ATCC 9142,
–OCH3), 4.6 (s, 1H, CHCl), 5.42 (s, 1H, –N–CHAr),
6.68–6.74 (d, 2H, Ar–H), 6.9–6.94 (d, 1H, Ar–H),
7.38–7.48 (m, 2H, Ar–H), 7.66–7.72 (d, 2H, Ar–H), 11.1
(s, 1H, Het-NH); 13C NMR (DMSO-d6) d in ppm: 168.0,
166.1, 158.4, 139.5, 136.6, 134.7, 133.0, 131.1, 129.1,
127.2, 125.3, 119.5, 114.0, 64.8, 61.4, 55.5. Anal. Calcd.
for C18H13Cl2N3O3: C 55.40, H 3.36, N 10.77; Found: C
55.49, H 3.42, N 10.69%. MS: [M]? at m/z 390.22.
5-Chloro-3-[3-chloro-2-(4-fluorophenyl)-4-oxoazetidin-1-
ylimino]indolin-2-one (5i) Yield 76% (benzene); m.
p. 154°C. IR (KBr, cm-1): 3313 (NH), 3078 (CH aro-
matic), 1752, 1720 (C=O), 1620 (C=N), 1140 (C–F), 740
123

Med Chem Res (2012) 21:1302–1312
1311
Dandia A, Singh R, Khaturia S, Merienne C, Morgantc G, Loupy A
(2006) Efficient microwave enhanced regioselective synthesis of
a series of benzimidazolyl/triazolyl spiro [indole-thiazolidinon-
es] as potent antifungal agents and crystal structure of spiro[3H-
indole-3,20-thiazolidine]-30(1,2,4-triazol-3-yl)-2,40(1H)-dione.
Bio Med Chem 14:2409–2417
Dandia A, Singh R, Khaturia S (2007) Efficient microwave enhanced
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Aspergillus awamori ATCC 22342, Candida albicans
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porum canis ATCC 11622, Rhizoctonia solani ATCC
76131, Trichophyton longiformis ATCC 22397, Aspergil-
lus flavus ATCC 15517, Fusarium solani ATCC 38136 and
Trichoderma viride ATCC 52440.
The MIC was done by broth dilution method. Nutrient
broth and potato dextrose broth was procured from
Himedia Laboratories. A set of sterilized test tubes with
nutrient broth medium capped with cotton plugs were taken
(1–12). The test compounds were dissolved in suitable
solvent (DMF) and at the concentration of 600 lg ml-1
,
which were serially diluted from 1 to 12. A fixed volume of
0.5 ml culture was added in all the test tubes and was
incubated at 37°C for 24 h. After 24 h, tubes were
observed visually for turbidity.
Keri RS, Hosamani KM, Shingalapur RV, Reddy HRS (2009)
2-Azetidinone derivatives: design, synthesis, in vitro anti-
microbial, cytotoxic activities and DNA cleavage study. Eur J
Med Chem 44:5123–5130
Acknowledgment Sunil G. Shingade is thankful to UGC New
Delhi, India for the award of J. R. F.—Rajiv Gandhi National Junior
Research Fellowship and financial support for this work.
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