Synthesis and antimicrobial activity of some 1,3-disubstituted indeno[1,2-c]pyrazoles

Article abstract of DOI:10.1002/jhet.1081

Synthesis of new 3-alkyl indeno[1,2-c]pyrazoles, possessing 4-substituted thiazole moiety at position-1 derived from 2-acyl indane-1,3-diones, has been described. These compounds and their precursor were screened for their antibacterial (Staphylococcus au

Full text of DOI:10.1002/jhet.1081

Month 2013
Synthesis and Antimicrobial Activity of Some 1,3‐Disubstituted
Indeno[1,2‐c]pyrazoles
*
Rajni Mohil, Devinder Kumar, and Satbir Mor
Department of Chemistry, Guru Jambheshwar University of Science and Technology,
Hisar‐125001 Haryana, India
*
E-mail: satbir_mor@yahoo.co.in
Received April 30, 2011
DOI 10.1002/jhet.1081
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of new 3‐alkyl indeno[1,2‐c]pyrazoles, possessing 4‐substituted thiazole moiety at position‐1
derived from 2‐acyl indane‐1,3‐diones, has been described. These compounds and their precursor were
screened for their antibacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli) and antifungal
(Aspergillus niger, Candida albicans) activities.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
products [11]. Thiazoles and their derivatives were espe-
cially reported to possess analgesic [12], antitumor [13],
antimicrobial [14], anti‐inflammatory [15], antipyretic
[16], antitubercular [17], antiHIV [18], diuretic [19],
anticonvulsant [20] activities, and so on. Antimicrobial
activities of some substituted thiazoles are well established,
because they possess (S C N) toxophoric unit. The designing
of new types of polyheterocyclic compounds along with the
refining of procedures for synthesis of these known
substances is an urgent target of the modern heterocyclic
chemistry. The need of making a large number of variously
substituted indenopyrazoles for biological screening led the
chemist to develop numerous methods of synthesis [21, 22]
in the past. Realizing the importance of the above biodynamic
heteryl nuclei, and in continuation of our interest in designing
the synthesis of biologically active nitrogen and sulfur
heterocycles, it was planned to synthesize a system thiazolyl
indenopyrazole that combines together two biolabile
components, which are indenopyrazole and 4‐substituted
thiazole, therefore, report herein, the synthesis and
antimicrobial (antibacterial and antifungal) activity of 16
Pyrazole derivatives have played a crucial role in the
history of heterocyclic chemistry and have been used exten-
sively as important pharmacophores and synthons, because
they are known to possess a broad spectrum of biological
properties such as antimalarial [1], antidepressant [2],
hypoglycemic [3], and so on. Introducing a pyrazolidinone
ring [4] in place of the β‐lactam ring (in penicillins and
cephalosporins) [5] results in enhanced activity. Owing to
their versatile chemotherapeutic importance, a significant
amount of research effort has been focused on pyrazole
nucleus. Among the pyrazoles fused to carbocyclic and
heterocyclic ring systems, indenopyrazoles occupy a unique
position because of wide ranging biological activities such
as antihypertensive [6], anticancer [7], herbicidal [8],
antibacterial [9], antiviral [10], and so on associated with
them. On the other hand, sulfur and/or nitrogen heterocycles
that possess pharmaceutical activities widely occur in nature
in the form of alkaloids, vitamins, pigments, as constituents
of plant and animal cells and other bioactive natural
© 2013 HeteroCorporation

R. Mohil, D. Kumar, and S. Mor
Vol 000
Scheme 1
new 3‐alkyl indeno[1,2‐c]pyrazoles, possessing 4‐substituted
thiazole moiety at position‐1 (5 and 6) and eight key
hydrazones (4) derived from 2‐acyl indane‐1,3‐diones (1).
bromides afforded the corresponding key hydrazones (4)
[25] in high yields. The hydrazones on cyclization in
boiling absolute alcohol in presence of glacial acetic
acid furnished pyrazoles (5) in good yields. The
indenopyrazoles (5) have also been obtained by the
condensation of the 2‐acylindane‐1,3‐dione (1) with
2‐hydrazino‐4‐substituted thiazoles, which first afforded
hydrazones (4) and then underwent cyclization in presence
of glacial acetic acid to afford pyrazoles (5). The assumption
that the condensation of the thiosemicarbazide/hydrazine
has occurred on the side chain carbonyl and not on 1‐ or
3‐position of indan‐1,3‐dione moiety finds support from
the results reported the literature [21b–d,26]. The
indenopyrazoles (5) on Wolf–Kishner reduction [27]
RESULTS AND DISCUSSION
2‐Acyl indane‐1,3‐diones (1) needed for the purpose were
prepared by the Claisen condensation of RCOCH3 and
diethylphthlate under the influence of sodium methoxide
according to the literature procedure [23]. Condensation of
equimolar quantities of 2‐acylindane‐1,3‐dione (1) with
thiosemicarbazide in boiling absolute ethanol yielded the
corresponding thiosemicarbazones [24] in excellent yields,
which on treatment with different 4‐substituted phenacyl
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Synthesis and Antimicrobial Activity of Some 1,3-Disubstituted Indeno[1,2-c]pyrazoles
Journal of Heterocyclic Chemistry
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R. Mohil, D. Kumar, and S. Mor
Vol 000
Table 2
In vitro antimicrobial activity (*pMIC) of compounds 4a–h, 5a–h, and 6a–h.
Antibacterial activity
Antifungal activity
C. albicans A. niger
Compounds
B. subtilis
S. aureus
E. coli
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
6d
6e
6f
1.159
1.477
0.893
1.184
1.176
1.493
0.908
1.213
1.137
1.15
1.173
1.479
1.455
1.171
1.189
1.194
1.420
1.438
1.458
1.764
1.739
1.455
1.474
1.479
2.698
–
1.460
1.778
1.495
1.786
1.176
1.493
1.510
1.815
1.438
1.150
1.474
1.479
1.455
1.472
1.490
2.098
1.119
1.438
1.458
1.462
1.739
1.756
1.775
1.780
2.698
–
1.460
1.477
1.495
1.786
1.176
1.493
1.510
1.514
1.438
1.455
1.474
1.479
1.455
1.171
1.490
1.796
1.420
1.438
1.458
1.462
1.438
1.756
1.474
1.780
2.698
–
1.460
1.176
1.194
1.485
1.477
1.493
1.510
1.514
1.137
1.455
1.474
1.479
1.455
1.472
1.490
1.796
1.420
1.438
1.458
1.462
1.438
1.455
1.474
1.780
–
1.460
1.477
1.495
1.485
1.477
1.493
1.510
1.514
1.438
1.455
1.474
1.479
1.455
1.472
1.496
1.495
1.420
1.739
1.759
1.462
1.438
1.455
1.775
1.479
–
6g
6h
Norfloxacin
Fluconazole
3.000
3.000
*pMIC = −log MIC.
yielded the corresponding indenopyrazoles (6) in moderate
yields (Scheme 1).
shifting of C8 H (δ 8.38–8.46) when compared with other
aromatic protons due to anisotropic‐diamagnetic effect of
lone pair of electrons present on nitrogen and sulfur of
N1‐thiazole moiety [28]. The C3 CH3 and C3 CH2 protons
of ethyl group were observed in the region at δ 2.38–2.41
and 2.67–2.79, respectively. The other aromatic and aliphatic
protons were observed in the expected regions. The C3 CH3
and C3 CH2CH3 protons showed upfield shift [29] relative to
the corresponding protons in the hydrazones (4) coupled
with the observation that the IR spectra displayed strong
absorption bands in the region 1708 1702 cm−1 unequivocally
proves that cyclization of the hydrazones (4) has led to the
formation of indenopyrazoles (5). An examination of
13C‐NMR spectra of indenopyrazoles (5) displayed signals
in most downfield region at δ 183.66–184.12 corresponding
to the C4 carbons [30] and the signals in the regions at δ
148.17–153.29, δ 121.70–123.43, and δ 157.37–157.80 are
in agreement with the value recorded for the carbon atoms
C3, C3a, and C8b of pyrazole ring [31], respectively. The
chemical shifts in regions at δ 159.61–160.10(C2′), δ
153.26–154.32(C4′), and δ 109.13–110.49(C5′) corroborate
the thiazole character of N1‐thiazole moiety [32]. The
chemical shift signals in aromatic regions at δ 123.64–124.12,
δ 127.61–130.50, δ 132.59–133.71, and δ 123.91–124.87
corresponds to C5, C6, C7, and C8, respectively, which are
All the newly synthesized compounds, hydrazones (4)
and indenopyrazoles (5 and 6), were well characterized
by satisfactory spectroscopic (IR, 1H‐NMR, 13C‐NMR,
and mass) and analytical data (vide experimental). The
most characteristic feature of the IR spectra of hydrazones
(4) was that they displayed absorption bands of medium
intensity in the region at 3365–3271 cm−1 (N H and O H
stretch) and >C O and >C N sharp absorptions in region
1689–1682 cm−1 and 1641–1629 cm−1, respectively. The
1
1H‐NMR spectra of hydrazones (4) displayed H signal
due to NH (exchangeable with deuterium oxide) in the
region δ 12.33–13.03; however, the signal due to C2 H
could not be located. The aromatic protons were observed
in the region δ 6.91–8.10 and aliphatic CH3 protons of
ethyl group and CH2 protons of propyl group present on
C2‐1H‐indene‐1,3(2H)‐diones appeared in the regions at
δ 2.81–2.91 and 3.19–3.23, respectively. Further, the ratio
of aromatic to aliphatic protons was found satisfactory
(vide experimental). The IR spectra of indenopyrazoles (5)
exhibited strong >C O stretching in the region 1708–1702
cm−1 due to conjugated five‐membered cyclic ketone
[27a,28a]. The main characteristic feature of 1H‐NMR
spectra of these indenopyrazoles (5) is the downfield
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Synthesis and Antimicrobial Activity of Some 1,3-Disubstituted Indeno[1,2-c]pyrazoles
In vitro antimicrobial activity (pMIC) of compounds 4a-h, 5a-h & 6a-h
B. subtilis
S. aureus
E. coli
C. albicans
A. niger
3
2.5
2
1.5
1
0.5
0
Compounds
Figure 1. In vitro antimicrobial activity (pMIC) of compounds 4a–h, 5a–h, and 6a–h. [Color figure can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
in agreement with the results reported in literature [30]. The
signals of other aliphatic and aromatic carbons were
observed in the expected region (Table 1).
activity almost similar to Norfloxacin against S. aureus,
whereas compounds 4e, 5b, and 6a exhibited moderate
level of activity. Compounds 4c and 4g were less effective
against B. subtilis, whereas compounds 4a, 4d, 4e, 4h, 5f,
5g, and 5h were found moderatively active in comparison
with Norfloxacin. All the newly synthesized compounds
(4a–h, 5a–h, and 6a–h) were assayed for antifungal
activity. Compounds 5h and 6h exhibited strong antifungal
activity against C. albicans and compounds 4b, 4c, and 5a
showed moderate activity in comparing their pMIC with
Fluconazole, whereas compounds 6b, 6c, and 6g displayed
very strong activity against A. niger. A careful analysis of
pMIC data shows some interesting trends. Comparison of
pMIC data of N1‐thiazolyl hydrazones (4a–h) and
N1‐thiazolylindenopyrazoles (5a–h and 6a–h) revealed that
the cyclization of hydrazones (4) to pyrazoles (5,6) leads to
significant increase in their antimicrobial activity (Fig. 1).
The potent antimicrobial activity exhibited by 4d, 4h, 5d,
5h, 6d, and 6h may be due to the presence of 4‐chlorophenyl
pharmacophore at C4 of the thiazole moiety. The present
study highlights the importance of indenopyrazole and
4‐substituted thiazole ring features responsible for the
inhibitory action against the microorganisms and, therefore,
may serve as a lead molecule for further modifications to
obtain clinically useful novel entities.
The IR spectra of indenopyrazoles (6) displayed strong
absorptions in the region at 1544–1534 cm−1 presumably
due to endo CN, which is supported by the values assigned
in literature [33]. The disappearance of >C O stretch due
to conjugated five‐membered cyclic ketone in IR spectra of
indenopyrazoles (6) as exhibited by indenopyrazoles (5)
and appearance of singlets in 1H‐NMR spectra in the region
δ 3.63–3.67 (2H) assignable to C4 protons along with
downfield shifting of C8 H (δ 8.64–8.84) presumably due
to increased anisotropic‐diamagnetic effect of N1‐thiazole
moiety as the hybridization state of C4 changes from sp2 to sp3
confirms Wolf–Kishner reduction of 5→ 6 (>C O → >CH2).
The other aromatic protons, however, appeared in the
expected regions (vide experimental). Further, the mass
spectral data and analytical data of 4, 5, and 6 are in
agreement with their molecular formula.
All the 24 newly synthesized compounds 4a–h, 5a–h,
and 6a–h were tested in vitro for their antimicrobial activity
against two Gram‐positive bacteria, that is, Bacillus subtilis
(MTCC 441) and Staphylococcus aureus (MTCC 7443),
one Gram‐negative bacteria, that is, Escherichia coli
(MTCC 42), and two fungi, that is, Candida albicans
(MTCC 183) and Aspergillus niger (MTCC 282). Serial
tube dilution technique [34] was used to determine minimum
inhibitory concentration (MIC). pMIC equals to negative
logarithm of MIC was calculated (Table 2).
CONCLUSION
In conclusion, we have prepared successfully eight new
N1‐thiazolyl hydrazones (4a–h) and 16 indenopyrazoles
(5a–h and 6a–h) using easily obtainable compounds
1‐, 2‐, 3‐, and 4‐substituted phenacyl bromides under
environmentally benign conditions and their in vitro
antimicrobial activities were evaluated. The compounds
containing 4‐chlorophenyl pharmacophore at C4 of the
thiazole moiety (4d, 4h, 5d, 5h, 6d, and 6h) exhibited
significant antimicrobial activities.
Most of the compounds exhibited moderate to good
antimicrobial activity against the tested microorganisms.
In comparing their pMIC values with Norfloxacin, all the
compounds were effective against E. coli, and compounds
4d, 5h, and 6f especially showed very high activity. All
the compounds were effective against S. aureus but
compounds 4b, 4d, 4h, 5h, 6e, 6f, 6g, and 6h exhibited
very high activity. Compound 5h displayed inhibitory
Journal of Heterocyclic Chemistry
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R. Mohil, D. Kumar, and S. Mor
Vol 000
1
NH 3271, CO 1684, CN 1637 cm−1; H‐NMR (CDCl3): δ 2.85
(s, 3H, CH3), 3.83 (s, 3H, OCH3), 6.92–7.74 ( m, 7H, ArH, and
5′‐thiazole H), 8.03‐8.06 (m, 2H, 4‐ and 7‐H), 13.03 (br s, 1H,
NH, deuterium oxide exchangeable); ms: (TOF MS ES+) m/z
392.12 (M+H)+. Anal. Calcd. for C21H17N3O3S: C, 64.43;
H, 4.38; N, 10.73; S, 8.19. Found: C, 64.29; H, 4.27; N, 11.03;
S, 8.57.
EXPERIMENTAL
Melting points were determined in open capillaries and are
uncorrected. The IR absorption spectra were scanned on Perkin
Elmer Spectrum, BX II FTIR spectrometer using potassium
bromide (KBr) pellets, and the wave numbers were given in cm−1.
The 1H‐NMR spectra and 13C‐NMR were recorded on Bruker
Avance II 400 spectrometer at 400 and 100 MHz, respectively,
in CDCl3 or CDCl3 + DMSO‐d6 or DMSO‐d6. The chemical shifts
are reported in parts per million (δ, ppm) using tetramethylsilane
(TMS) as an internal standard. Coupling constants J are valued
in Hertz (Hz). Mass spectra were recorded on Waters Micromass
Q‐Tof Micro (ESI) spectrometer. Elemental analysis was carried
out using Vario Micro Cube Elementar CHNS analyser. Analyti-
cal results for C, H, N, and S were within 0.4% of the
theoretical values. The purities of the compounds were checked
by thin layer chromatography (TLC) using readymade silica gel
(SIL G/UV254, ALUGRAM) plates. The spots were visualized
under ultraviolet (UV) lamp. Solvents were dried using standard
literature procedures. 2‐Acyl indane‐1,3‐diones (1) [23] and
2‐hydrazino‐4‐substituted thiazoles (3) [35] were prepared
according to literature procedures. Norfloxacin (GMH Laboratories,
Baddi, H. P., India) and fluconazole (Aurobindo Pharmaceuticals,
Mandal, A. P., India) were used as reference antimicrobial agents
against the tested microorganisms.
2‐(1‐(2‐(4‐(4‐Chlorophenyl)thiazol‐2‐yl)hydrazono)ethyl)‐
1H‐indene‐1,3(2H)‐dione (4d). The compound 4d was obtained
as yellow solid, 80% yield, mp 250–252°C; IR (KBr): NH 3290
CO 1687, CN 1633 cm−1; H‐NMR (DMSO‐d6): δ 2.91 (s, 3H,
1
CH3), 7.33–7.74 ( m, 7H, ArH and 5′‐thiazole H), 8.08–8.10
(m, 2H, 4‐, and 7‐H), 13.01 (br s, 1H, NH, deuterium oxide
exchangeable); ms: (TOF MS ES+) m/z 395.05 (M)+, 396.11 (M
+1)+, 397.21 (M+2)+. Anal. Calcd. for C20H14ClN3O2S: C,
60.68; H, 3.56; N, 10.61; S, 8.10. Found: C,60.35; H, 3.86;
N,10.95; S, 8.32.
2‐(1‐(2‐(4‐Phenylthiazol‐2‐yl)hydrazono)propyl)‐1H‐indene‐
1,3(2H)‐dione (4e). The compound 4e was obtained as orange
yellow solid, 84% yield, mp 184–186°C; IR (KBr): NH 3353,
CO 1686, CN 1629 cm−1 1H‐NMR (CDCl3): δ 1.29 (t, 3H,
;
ethyl‐CH3), 3.23 (q, 2H, ethyl‐CH2), 7.60 (m, 8H, ArH, and
5′‐thiazole H), 8.07–8.09 (m, 2H, 4‐ and 7‐H), 12.98 (br s, 1H,
NH, deuterium oxide exchangeable); ms: (TOF MS ES+) m/z
375.1 (M)+. Anal. Calcd. for C21H17N3O2S: C, 67.18; H, 4.56;
N, 11.19; S, 8.54. Found: C, 66.79; H, 4.17; N, 11.05; S, 8.73.
2‐(1‐(2‐(4‐p‐Tolylthiazol‐2‐yl)hydrazono)propyl)‐1H‐indene‐
1,3(2H)‐dione (4f). The compound 4f was obtained as orange
yellow solid, 81% yield, mp 206–208°C; IR (KBr): NH 3365,
Synthesis of thiosemicarbazone of 2‐acyl indane‐1,3‐diones
(2a and 2b). The thiosemicarbazones 2 were prepared by
condensation of equimolar quantities of 2‐acyl indane‐1,3‐dione
(1) and thiosemicabazide in absolute alcohol as per literature
procedure [24].
CO 1683, CN 1638 cm−1 1H‐NMR (DMSO‐d6): δ 1.28
;
Synthesis of 2‐(1‐(2‐(4‐phenylthiazol‐2‐yl)hydrazono)
ethyl)‐1H‐indene‐1,3(2H)‐dione (4a). To a suspension of 2a
(1.30 g, 5 mmol) and sodium acetate (0.41 g, 5 mmol) in
absolute ethanol (25 mL), phencyl bromide (0.99 g, 5 mmol)
was added slowly with stirring, and the reaction mixture was
gently refluxed for 30 min and then allowed to stand at room
temperature. The yellowish solid thus obtained was filtered and
washed with ethanol to give 4a in excellent yield 1.49 g (83%),
(t, 3H, ethyl‐CH3), 2.35 (s, 3H, CH3), 3.20 (q, 2H, ethyl‐CH2),
7.18–7.62 ( m, 7H, ArH, and 5′‐thiazole H), 7.64–7.66 (m, 2H,
4‐ and 7‐H), 12.34 (br s, 1H, NH, deuterium oxide
exchangeable); ms: (TOF MS ES+) m/z 390.1 (M+H)+. Anal.
Calcd. for C22H19N3O2S: C, 67.84; H, 4.92; N, 10.79; S,
8.23. Found: C, 68.07; H, 4.72; N, 10.43; S, 7.87.
2‐(1‐(2‐(4‐(4‐Methoxyphenyl)thiazol‐2‐yl)hydrazono)propyl)‐
1H‐indene‐1,3(2H)‐dione (4g). The compound 4g was
obtained as orange yellow solid, 81% yield, mp 200–202°C;
mp 202–204°C; IR (KBr): NH 3357, CO 1687, CN 1643 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.81 (s, 3H, CH3), 7.22–7.69 ( m, 8H,
ArH and 5′‐thiazole H), 7.73–7.76 (m, 2H, 4‐, and 7‐H), 12.33
(br s, 1H, NH, deuterium oxide exchangeable); ms: (TOF MS
ES+) m/z 360.09 (M)+. Anal. Calcd. for C20H15N3O2S: C,
66.46; H, 4.18; N, 11.63; S, 8.87. Found: C, 66.74; H, 3.83; N,
11.70; S, 9.26.
IR (KBr): NH 3267, CO 1683, CN 1633 cm−1 1H‐NMR
;
(DMSO‐d6): δ 1.28 (t, 3H, ethyl‐CH3), 3.23 (q, 2H, ethyl‐
CH2), 3.82 (s, 3H, OCH3), 6.91–7.78 ( m, 9H, ArH, and
5′‐thiazole H), 12.39 (br s, 1H, NH, deuterium oxide
exchangeable); ms: (TOF MS ES+) m/z 406.11 (M+H)+. Anal.
Calcd. for C22H19N3O3S: C, 65.17; H, 4.72; N, 10.36; S,
7.91. Found: C, 65.07; H, 4.39; N, 10.21; S, 7.82.
Following exactly the same procedure as detailed in 4a, the
other hydrazones 4b–h were prepared from the corresponding
p‐substituted phenacyl bromides and thiosemicarbazones of
2‐acyl indane‐1,3‐dione (2). The physical, spectral, and analytical
data for these compounds are given as follows.
2‐(1‐(2‐(4‐(4‐Chlorophenyl)thiazol‐2‐yl)hydrazono)propyl)‐
1H‐indene‐1,3(2H)‐dione (4h). The compound 4h was
obtained as orange yellow solid, 83% yield, mp 216–218°
C; IR (KBr): NH 3346, CO 1689, CN 1637 cm−1
;
2‐(1‐(2‐(4‐p‐Tolylthiazol‐2‐yl)hydrazono)ethyl)‐1H‐indene‐
1,3(2H)‐dione (4b). The compound 4b was obtained as orange
yellow solid, 79% yield, mp 214–216°C; IR (KBr): NH 3354,
1H‐NMR (DMSO‐d6):
δ 1.28 (t, 3H, ethyl‐CH3), 3.19
(q, 2H, ethyl‐CH2), 7.36–7.65 ( m, 7H, ArH, and 5′‐thiazole
H), 7.78–7.80 (m, 2H, 4‐ and 7‐H), 12.98 (br s, 1H, NH,
deuterium oxide exchangeable); ms: (TOF MS ES+) m/z
409.07 (M)+, 410.07 (M+1)+, 411.07 (M+2)+. Anal. Calcd. for
C21H16ClN3O2S: C, 61.53; H, 3.93; N, 10.25; S, 7.82. Found:
C, 61.47; H, 4.21; N, 9.98; S, 8.01.
1
CO 1682, CN 1641 cm−1; H‐NMR (DMSO‐d6): δ 2.45 (s, 3H,
CH3), 2.91 (s, 3H, CH3), 7.23–7.74 ( m, 7H, ArH, and 5′‐thiazole
H), 7.99–8.02 (m, 2H, 4‐ and 7‐H), 13.03 (br s, 1H, NH,
deuterium oxide exchangeable); ms: (TOF MS ES+) m/z 398.21
(M+Na)+. Anal. Calcd. for C21H17N3O2S: C, 67.18; H, 4.56; N,
11.19; S, 8.54. Found: C, 66.84; H, 4.33; N, 10.85; S, 8.93.
2‐(1‐(2‐(4‐(4‐Methoxyphenyl)thiazol‐2‐yl)hydrazono)ethyl)‐
1H‐indene‐1,3(2H)‐dione (4c). The compound 4c was obtained
as orange yellow solid, 84% yield, mp 230–232°C; IR (KBr):
The thiazolyl hydrazones 4a–h were also prepared by refluxing
the equimolar mixture of 2‐acyl indane‐1,3‐dione (1; 5 mmol) and
2‐hydrazino‐4‐substituted thiazoles (3; 5 mmol) in dry ethanol for
15–20 min. The mixture was cooled, filtered, washed with cold
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Synthesis and Antimicrobial Activity of Some 1,3-Disubstituted Indeno[1,2-c]pyrazoles
ethanol, and air‐dried to give yellow solid, yield 1.66 g (92%) of
4a, 1.67 g (89%) of 4b, 1.77 g (91%) of 4c, 1.71 g (91%) of 4d,
1.70 g (91%) of 5e, 1.75 g (90%) of 5f, 1.80 g (89%) of 5g, and
1.91 g (93%) of 5h. The physical, spectral, and analytical data for
these compounds correspond to thiazolyl hydrazones 4a–h syn-
thesized by earlier method.
ES+) m/z 377.01 (M)+, 378.3 (M+1)+, 379.04 (M+2)+; Anal.
Calcd. for C20H12ClN3OS: C, 63.57; H, 3.20; N, 11.12; S, 8.49.
Found: C, 63.21; H, 3.57; N, 10.92; S, 8.59.
3‐Ethyl‐1‐(4‐phenylthiazol‐2‐yl)indeno[1,2‐c]pyrazol‐4
(1H)‐one (5e). The compound 5e was obtained as yellow needles
(chloroform), 74% yield, mp 148–150°C; IR (KBr): CO 1703
cm−1, CN 1610 cm−1; 1H‐NMR (CDCl3): δ 1.35 (t, 3H, ethyl‐CH3),
2.67 (q, 2H, ethyl‐CH2), 7.14–7.41 (m, 7H, 5′‐thiazole H and ArH),
7.74 (d, 2H, 2″‐, 6″‐H, J = 7.12 Hz), 8.41 (dd, 1H, 8‐H, J = 7.32,
2.27 Hz); 13C‐NMR (CDCl3): δ 12.40, 21.05, 110.49, 122.91,
123.79, 124.02, 125.97, 128.45, 128.86, 130.28, 132.59, 133.14,
133.87, 140.02, 153.0, 154.09, 157.55, 159.78, 183.67; ms:
(TOF MS ES+) m/z 358.6 (M+H)+; Anal. Calcd. for
C21H15N3OS: C, 70.57; H, 4.23; N, 11.76; S, 8.97. Found: C,
70.69; H, 4.07; N, 11.60; S, 8.69.
3‐Ethyl‐1‐(4‐p‐tolylthiazol‐2‐yl)indeno[1,2‐c]pyrazol‐4
(1H)‐one (5f). The compound 5f was obtained as yellow needles
(chloroform), 65% yield, mp 160–162°C; IR (KBr): CO 1702,
CN 1609 cm−1; 1H‐NMR (CDCl3): δ 1.39 (t, 3H, ethyl‐CH3),
2.41 (s, 3H, CH3), 2.75 (q, 2H, ethyl‐CH2), 7.21–7.31 (m, 4H,
5′‐thiazole H and ArH), 7.40 (m, 1H, 7‐H), 7.53 (d, 1H, 5‐H,
J = 7.24 Hz), 7.75 (d, 2H, 2″‐, 6″‐H, J = 8.16 Hz), 8.39 (dd,
1H, 8‐H, J = 7.40, 2.32 Hz); 13C‐NMR (CDCl3): δ 12.50,
21.10, 21.35, 109.82, 122.96, 123.91, 124.17, 126.0, 129.63,
130.42, 131.33, 132.81, 133.31, 138.50, 140.23, 153.29,
154.32, 157.80, 159.82, 183.90; ms: (TOF MS ES+) m/z
394.3 (M+Na)+. Anal. Calcd. for C22H17N3OS: C, 71.14; H,
4.61; N, 11.31; S, 8.63. Found: C, 69.99; H, 4.47; N, 10.98;
S, 8.33.
Synthesis of 3‐methyl‐1‐(4‐phenylthiazol‐2‐yl)indeno
[1,2‐c]pyrazol‐4(1H)‐one (5a). The hydrazone 4a (1.80 g,
5 mmol) was refluxed in a solution of 75 mL ethanol‐acetic
acid (2:1) for 5 h. The reaction mixture was concentrated, and
the precipitates thus obtained were separated by filtration,
which on recrystallization from chloroform afforded yellow
needles of 5a, yield 1.25 g (73%); mp 210–212°C; IR (KBr):
CO 1702, CN 1607 cm−1 1H‐NMR (DMSO‐d6): δ 2.39
;
(s, 3H, CH3), 7.39–7.59 (m, 6H, ArH), 7.76 (s, 1H,
5′‐Thiazole H), 7.97 (d, 2H, 2″‐, 6″‐H, J = 7.76 Hz ), 8.46 (dd, 1H,
8‐H, J = 7.16, 2.41 Hz); 13C‐NMR (DMSO‐d6): δ 12.61, 109.88,
122.96, 123.64, 123.91, 126.01, 128.72, 128.93 130.23, 132.25,
133.71, 133.89, 140.27, 149.07, 154.29, 157.37, 159.7, 184.22; ms:
(TOF MS ES+) m/z 344.09 (M+H)+. Anal. Calcd. for C20H13N3OS:
C, 69.95; H, 3.82; N, 12.24; S, 9.34. Found: C, 69.73; H, 3.46; N,
11.96; S, 9.22.
Following exactly the procedure as employed for 5a, the
indenopyrazoles 5b–h were synthesized from the corresponding
hydrazones 4b–h. The physical, spectral, and analytical data for
these compounds are given as follows.
3‐Methyl‐1‐(4‐p‐tolylthiazol‐2‐yl)indeno[1,2‐c]pyrazol‐4
(1H)‐one (5b). The compound 5b was obtained as yellow
needles (chloroform), 71% yield, mp 208–210°C; IR (KBr): CO
1707, CN 1621 cm−1; 1H‐NMR (DMSO‐d6): δ 2.38 (s, 3H, CH3),
2.41 (s, 3H, CH3), 7.30 (d, 2H, 3″‐, 5″‐H, J = 7.95 Hz), 7.39–7.41
(m, 1H, 6‐H), 7.51–7.55 (m, 2H, 5‐, 7‐H), 7.62 (s, 1H, 5′‐H), 7.83
(d, 2H, 2″‐, 6″‐H, J = 7.96 Hz), 8.42 (dd, 1H, 8‐H, J = 7.56, 2.40
Hz); 13C‐NMR (CDCl3): δ 12.66, 21.34, 109.78, 123.41, 123.93,
124.14, 125.97, 129.61, 130.40, 131.25, 132.59, 133.30, 138.49,
140.13, 148.17, 153.26, 157.41, 159.61, 184.14; ms: (TOF MS
ES+) m/z 380.3 (M+Na)+. Anal. Calcd. for C21H15N3OS: C,
70.57; H, 4.23; N, 11.76; S, 8.97. Found: C, 70.31; H, 4.13;
N,12.15; S, 9.29.
3‐Ethyl‐1‐(4‐(4‐methoxyphenyl)thiazol‐2‐yl)indeno[1,2‐c]
pyrazol‐4(1H)‐one (5g).. The compound 5g was obtained as
yellow needles (chloroform), 73% yield, mp 154–156°C; IR
1
(KBr): CO 1702, CN 1610 cm−1; H‐NMR (DMSO‐d6): δ 1.32
(t, 3H, ethyl‐CH3), 2.76 (q, 2H, ethyl‐CH2), 3.88 (s, 3H,
OCH3), 7.00 (d, 2H, 3″‐, 5″‐H, J = 8.22 Hz), 7.25–7.52 (m, 4H,
5′‐thiazole H and ArH), 7.82 (d, 2H, 2″‐, 6″‐H, J = 8.24 Hz),
8.40 (dd, 1H, 8‐H, J = 7.12, 2.29 Hz); 13C‐NMR (DMSO‐d6): δ
12.44, 21.01, 55.37, 109.13, 114.30, 122.77, 123.30, 123.81,
124.07, 127.35, 130.50, 132.72, 133.42, 140.11, 152.99,
154.08, 157.66, 159.84, 159.95, 183.69; ms: (TOF MS ES+)
m/z 388.4 (M+H)+. Anal. Calcd. for C22H17N3O2S: C, 68.20;
H, 4.42; N, 10.85; S, 8.28.Found: C, 68.57; H, 4.21; N, 10.73;
S, 8.39.
1‐(4‐(4‐Methoxyphenyl)thiazol‐2‐yl)‐3‐methylindeno
[1,2‐c]pyrazol‐4(1H)‐one (5c). The compound 5c was obtained as
yellow needles (chloroform), 75% yield, mp 204–206°C; IR (KBr):
1
CO 1708, CN 1606 cm−1; H‐NMR (DMSO‐d6): δ 2.38 (s, 3H,
CH3), 3.87 (s, 3H, OCH3), 7.03 (d, 2H, 3″‐, 5″‐H, J = 8.40 Hz),
7.39–7.42 (m, 1H, 6‐H), 7.53–7.57 (m, 3H, 5‐, 7‐, and 5′‐thiazole
H), 7.88 (d, 2H, 2″‐, 6″‐H, J = 8.44 Hz), 8.42 (dd, 1H, 8‐H, J
= 7.4, 2.41 Hz); 13C‐NMR (CDCl3): δ 12.68, 55.40, 108.81,
114.29, 123.43, 123.90, 124.21, 126.89, 127.38, 130.44,
132.65, 133.34, 140.20, 148.23, 153.04, 157.45, 159.70,
159.89, 184.20; ms: (TOF MS ES+) m/z 396.3 (M+Na)+. Anal.
Calcd. for C21H15N3O2S: C, 67.54; H, 4.05; N, 11.25; S, 8.59.
Found: C, 67.32; H, 4.11; N, 11.57; S, 8.78.
1‐(4‐(4‐Chlorophenyl)thiazol‐2‐yl)‐3‐ethylindeno[1,2‐c]
pyrazol‐4(1H)‐one (5h). The compound 5h was obtained as
yellow needles (chloroform), 72% yield, mp 210–212°C; IR
(KBr): CO 1702, CN 1629 cm−1 1H‐NMR (DMSO‐d6): δ
;
1.34 (t, 3H, ethyl‐CH3), 2.79 (q, 2H, ethyl‐CH2), 7.39–7.57
(m, 6H, 5′‐thiazole H, and ArH), 7.88 (d, 2H, 3″‐, 5″‐H, J =
8.12Hz), 8.39 (d, 1H, 8‐H, J = 7.54, 2.32 Hz); 13C‐NMR
(DMSO‐d6): δ 12.51, 21.2, 109.7, 121.7, 124.12, 124.87,
127.70, 128.86, 129.84, 131.44, 133.21, 133.92, 135.50,
140.02, 153.12, 154.13, 157.43, 160.10, 183.99; ms: (TOF
MS ES+) m/z 392.3 (M+1)+, 393.04 (M+2)+, 394.3(M+3)+.
Anal. Calcd. for C21H14ClN3OS: C, 64.36; H, 3.60; N,
10.72; S, 8.18. Found: C, 64.26; H, 3.87; N, 11.17; S, 8.53.
Synthesis of 2‐(3‐methylindeno[1,2‐c]pyrazol‐1(4H)‐yl)‐4‐
phenylthiazole (6a). The solution of indenopyrazole 5a (0.34 g,
1 mmol), ethylene glycol (5 mL), hydrazine hydrate (1 mL),
and KOH (0.5 mL) was heated to 120°C for 1 h and at 180°C
for 4 h. Thereafter, the reaction mixture was poured in cold
water, the solid thus obtained was filtered, washed with water,
1‐(4‐(4‐Chlorophenyl)thiazol‐2‐yl)‐3‐methylindeno[1,2‐c]
pyrazol‐4(1H)‐one (5d). The compound 5d was obtained as
yellow needles (chloroform), 69% yield, mp 240–242°C; IR
1
(KBr): CO 1708, CN 1635 cm−1; H‐NMR (DMSO‐d6): δ 2.41
(s, 3H, CH3), 7.37–7.40 (m, 1H, 6‐H), 7.48 (d, 2H, 2″‐, 6″‐H,
J = 8.24 Hz), 7.52–7.57 (m, 3H, 5‐,7‐, and, 5′‐thiazole H),
7.89 (d, 2H, 3″‐, 5″‐H, J = 8.2 Hz), 8.38 (dd, 1H, 8‐H, J = 7.20,
2.43 Hz); 13C‐NMR (DMSO‐d6): δ 12.7, 109.5, 123.09, 123.68,
124.42, 127.61, 128.40, 129.12, 131.79, 132.93, 133.78, 134.10,
140.12, 148.91, 153.65, 157.37, 159.89, 184.91; ms: (TOF MS
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Mohil, D. Kumar, and S. Mor
Vol 000
dried and recrystallized from benzene to give colorless needles of
2‐(3‐Ethylindeno[1,2‐c]pyrazol‐1(4H)‐yl)‐4‐(4‐methoxyphenyl)
thiazole (6g). The compound 6g was obtained as colorless
crystals (benzene), 57% yield, mp 196–198°C; IR (KBr): CN
6a in moderate yield 174 mg (53%); mp 160–162°C; IR (KBr):
1
CN 1535 cm−1; H‐NMR (CDCl3): δ 2.39 (s, 3H, CH3), 3.63 (s,
2H, 4‐H), 7.18–7.60 (m, 7H, 5′‐thiazole H and ArH), 7.93 (d,
2H, 2″‐, 6″‐H, J = 7.8 Hz), 8.79 (dd, 1H, 8‐H, J = 7.5, 2.37
Hz); ms: (TOF MS ES+) m/z 352.1 (M+Na)+. Anal. Calcd. for
C20H15N3S: C, 72.92; H, 4.59; N, 12.76; S, 9.73. Found: 73.04;
H, 4.28; N, 12.46; S, 9.76.
Following exactly the procedure as detailed for synthesis of 6a,
the indenopyrazoles 6b–h were prepared from the corresponding
indenopyrazoles 5b–h. The physical, spectral, and analytical data
of these compounds are given as follows.
1534 cm−1 1H‐NMR (DMSO‐d6): δ 1.39 (t, 3H, ethyl‐CH3),
;
2.83 (q, 2H, ethyl‐CH2), 3.66 (s, 2H, 4‐H), 3.81 (s, 3H, OCH3),
7.17–7.82 (m, 6H, 5′‐thiazole H and ArH), 8.04 (d, 2H, 2″‐,
6″‐H, J = 8.4 Hz), 8.80 (dd, 1H, 8‐H, J = 7.5, 2.57 Hz); ms:
(TOF MS ES+) m/z 374 (M+H)+. Anal. Calcd. for
C22H19N3OS: C, 70.75; H, 5.13; N, 11.25; S, 8.59. Found: C,
70.46; H, 5.52; N, 10.91; S, 8.94.
4‐(4‐Chlorophenyl)‐2‐(3‐ethylindeno[1,2‐c]pyrazol‐1(4H)‐yl)
thiazole (6h). The compound 6h was obtained as green needle‐
like crystals (benzene), 49% yield, mp 120–122°C; IR (KBr):
2‐(3‐Methylindeno[1,2‐c]pyrazol‐1(4H)‐yl)‐4‐p‐tolylthiazole
(6b). The compound 6b was obtained as colorless crystals
(benzene), 57% yield, mp 196–198°C; IR (KBr): CN 1542
CN 1537 cm−1 1H‐NMR (CDCl3): δ 1.38 (t, 3H, ethyl‐CH3),
;
2.82 (q, 2H, ethyl‐CH2), 3.64 (s, 2H, 4‐H), 7.22–7.54 (m, 6H,
5′‐thiazole H and ArH), 7.90 (d, 2H, 3″‐, 5″‐H, J = 8.4 Hz) 8.76
(dd, 1H, 8‐H, J = 7.5, 2.70 Hz); ms: (TOF MS ES+) m/z 378.1
(M+H)+, 379.2 (M+2)+, 380.1 (M+3)+, 400.1 (M+Na)+. Anal.
Calcd. for C21H16ClN3S: C, 66.75; H, 4.27; N, 11.12; S, 8.49.
Found: C, 67.07; H, 4.28; N, 10.80; S, 8.79.
cm−1 1H‐NMR (CDCl3): δ 2.42 (s, 3H, CH3), 2.56 (s, 3H,
;
CH3), 3.67 (s, 2H, 4‐H), 7.13–7.53 (m, 6H, 5′‐thiazole H and
ArH), 7.88 (d, 2H, 2″‐, 6″‐H, J = 5.7 Hz), 8.82 (dd, IH, 8‐H,
J = 7.2, 2.50 Hz); ms: (TOF MS ES+) m/z 366.2 (M+Na)+.
Anal. Calcd. for C21H17N3S: C, 73.44; H, 4.99; N, 12.23; S,
9.34. Found: C, 73.19; H, 4.98; N, 11.56; S, 9.58.
4‐(4′‐Methoxyphenyl)‐2‐(3‐methylindeno[1,2‐c]pyrazol‐1
(4H)‐yl) thiazole (6c). The compound 6c was obtained as
colorless crystals (benzene), 55% yield, mp 180–182°C; IR
ANTIMICROBIAL ACTIVITY
(KBr): CN 1537 cm−1
;
1H‐NMR (DMSO‐d6): δ 2.33 (s, 3H,
All the 24 newly synthesized compounds 4a–h, 5a–h,
and 6a–h were screened for their in vitro antimicrobial
activity against five microorganisms, two Gram‐positive
bacteria B. subtilis (MTCC 441) and S. aureus (MTCC
7443) and one Gram‐negative bacteria E. coli (MTCC
42) and two fungi C. albicans (MTCC 183) and A. niger
(MTCC 282) by serial tube dilution technique [33] using
two solid media double strength nutrient broth and
Sabouraud dextrose broth for bacterial and fungal growth,
respectively. The stock solutions (100 μg/mL) of all the
test compounds were prepared by dissolving 1 mg of the
test compound in 10 mL of dimethylsulfoxide. Norfloxacin
and Fluconazole were used as reference against bacteria
and fungi, respectively. The fresh cultures were obtained
by inoculation of respective microorganisms in suitable
medium (double strength nutrient broth in case of bacteria
and Sabouraud dextrose broth in case of fungi) followed by
incubation at 37 1°C. The stock solutions of the test
compounds were serially diluted in test tubes containing
1 mL of sterile medium to get the concentration of
50–3.12 μg/ml and then inoculated with 100 μL of suspen-
sion of respective microorganism in sterile saline. The
inoculated test tubes were incubated at 37 1°C for 24 h
in case of B. subtilis, S. aureus, and E. coli, at 37 1°C
for 48 h in case of C. albicans and at 37 1°C for 120 h
in case of A. niger, and their pMICs (−log of MICs) were
determined. MIC, in microbiology, is the lowest
concentration of an antimicrobial agent that will inhibit
the visible growth of a microorganism after incubation.
The reference compounds Norfloxacin and Fluconazole
were also tested under similar conditions to compare the
results of tested compounds. The data for the antibacterial
and antifungal studies are listed in Table 2.
CH3), 3.65 (s, 2H, 4‐H), 3.86 (s, 3H, OCH3), 7.20–7.79 (m,
6H, 5′‐thiazole H and ArH), 7.93 (d, 2H, 2″‐, 6″‐H, J = 8.4
Hz), 8.74 (dd, 1H, 8‐H, J = 7.5, 2.41 Hz); ms: (TOF MS ES+)
m/z 360.1 (M+H)+. Anal. Calcd. for C21H17N3OS: C, 70.17;
H, 4.77; N, 11.69; S, 8.92. Found: C, 69.82; H, 4.81; N,
12.01; S, 8.63.
4‐(4‐Chlorophenyl)‐2‐(3‐methylindeno[1,2‐c]pyrazol‐1
(4H)‐yl)thiazole (6d). The compound 6d was obtained as colorless
crystals (benzene), 51% yield, mp 174–176°C; IR (KBr): CN 1534
1
cm−1; H‐NMR (DMSO‐d6): δ 2.33 (s, 3H, CH3), 3.65 (s, 2H,
4‐H), 7.34–7.59 (m, 5H, ArH), 7.94 (s, IH, 5′‐thiazole H), 8.01
(d, 2H, 3″‐,5″‐H, J = 7.5 Hz), 8.64 (dd, 1H, 8‐H, J = 7.8, 2.37
Hz); ms: (TOF MS ES+) m/z 364.1 (M+H)+, 365.03 (M+2)+,
366.1 (M+3)+, 386.1 (M+Na)+. Anal. Calcd. for C20H14ClN3S:
C, 66.02; H, 3.88; N, 11.55; S, 8.81. Found: C, 65.73; H, 4.18;
N, 11.21; S, 8.73.
2‐(3‐Ethylindeno[1,2‐c]pyrazol‐1(4H)‐yl)‐4‐phenylthiazole
(6e). The compound 6e was obtained as colorless crystals (benzene),
1
51% yield, mp 174–176°C; IR (KBr): CN 1534 cm−1; H‐NMR
(CDCl3): δ 1.39 (t, 3H, ethyl‐CH3), 2.82 (q, 2H, ethyl‐CH2), 3.66
(s, 2H, 4‐H), 7.29–7.56 (m, 7H, 5′‐thiazole‐H and ArH), 7.99
(d, 2H, 2″‐, 6″‐H, J = 7.8 Hz), 8.83 (dd, 1H, 8‐H, J = 7.5, 2.51
Hz); ms: (TOF MS ES+) m/z 344.2 (M+H)+. Anal. Calcd. for
C21H17N3S: C, 73.44; H, 4.99; N, 12.23; S, 9.34. Found: C,
73.74; H, 4.73; N, 11.97; S, 9.19.
2‐(3‐Ethylindeno[1,2‐c]pyrazol‐1(4H)‐yl)‐4‐p‐tolylthiazole
(6f). The compound 6f was obtained as deep red needles
(benzene), 53% yield, mp 158–160°C; IR (KBr): CN 1544 cm−1
;
1H‐NMR (CDCl3): δ 1.38 (t, 3H, ethyl‐CH3), 2.43 (s, 3H,
CH3), 2.83 (q, 2H, ethyl‐CH2), 3.65 (s, 2H, 4‐H), 7.30 (d,
2H, 3″‐, 5″‐H, J = 8.1 Hz), 7.47–7.82 (m, 4H, 5′‐thiazole‐H
and ArH), 8.03–8.06 (d, 2H, 2″‐, 6″‐H, J = 8.1 Hz), 8.84
(dd, 1H, 8‐H, J = 7.5, 2.50 Hz); ms: (TOF MS ES+) m/z
358.1 (M+H)+, 380.1 (M+Na)+. Anal. Calcd. for C22H19N3S:
C, 73.92; H, 5.36; N, 11.75; S, 8.97. Found: C, 73.88; H,
5.23; N, 12.17; S, 9.12.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis and Antimicrobial Activity of Some 1,3-Disubstituted Indeno[1,2-c]pyrazoles
[18] Maass, G.; Immendoerfer, U.; Koenig, B.; Leser, U.; Mueller,
B.; Goody, R.; Pfatt, B. Antimicrob Agents Chemother 1993, 37, 2612;
(b) Maass, G.; Immendoerfer, U.; Koenig, B.; Leser, U.; Mueller, B.;
Goody, R.; Pfatt, B. Antimicrob Agents Chemother 1993, 37, 2612.
[19] Andreani, A.; Rambaldi, M.; Mascellani, G.; Rugarli, P. Eur J
Med Chem 1987, 22, 19.
Acknowledgements. The authors gratefully acknowledge the
financial support from CSIR New Delhi. They also thank SAIF,
Punjab University, Chandigarh, for providing NMR spectra
of the compounds.
[20] Amin, K. H.; Rahman, A. D. E.; Al‐Erayani, Y. A. Bioorg
Med Chem 2006, 14, 6475.
REFERENCES AND NOTES
[21] Mosher, W. A.; Soeder, R. W. J Heterocycl Chem 1971, 8,
855; (b) Mosher, W. A.; Bechara, I. S. J Heterocycl Chem 1970, 7, 843;
(c) Mosher, W. A.; Bank, T. E. J Heterocycl Chem 1971, 9, 1005; (d)
Mosher, W. A.; Meier, W. E. J Org Chem 1970, 35, 3685; (e) Lemke,
T. L.; Sawhney, K.; Lemke, B. K. J Heterocycl Chem 1982, 19, 363;
(e) Belevich, E. M.; Gudriniece, E.; Paulins, J. Latv PSR Zinat Akad
Vestis Khim Ser 1974, 226; (f) Hamilton, R. W. J Heterocycl Chem
1976, 13, 545.
[22] (a) Priede, J.; Gudriniece, E. Latv PSR Zinat Akad Vestis
Khim Ser 1978, 579; (b) Coombs, R. V.; Houlihan, W. J. U.S. Pat.
3,843,665; Chem Abstr 1975, 82, 57694y; (c) Habeck, D. A.; Houlihan,
W. J. U.S. Pat. 3,932,420; Chem Abstr 1976, 84, 121821m.
[23] (a) Kilgore, L. B.; Ford, J. H.; Wolfe, C. W. Ind Eng Chem
1942, 34, 494; (b) Shapiro, L.; Geiger, K.; Freedman, L. J Org Chem
1960, 25, 1860; (c) Dhawan, S. N.; Dasgupta, S.; Mor, S.; Gupta, S. C.
Indian J Heterocycl Chem 1993, 2, 155.
[24] Sawhney, K. N.; Lemke, T. L. J Org Chem 1983, 48, 4326.
[25] (a) Easmon, J.; Heinisch, G.; Hofman, J.; Langer, T.;
Grunicke, H. H.; Fink, J.; Purstinger, G. Eur J Med Chem 1997, 32,
397; (b) Siddiqui, N.; Arshad, M. F.; Khan, S. A. Acta Pharmaceutica‐
Drug Res 2009, 66, 161.
[26] Braun, R. A.; Mosher, W. A. J Am Chem Soc 1958, 80, 2749.
[27] (a) Gupta, S. C.; Quarishi, M. A.; Dhawan, S. N. Indian J
Chem B 1979, 18, 547; (b) Quarishi, M. A.; Thakur, V. K.; Dhawan, S.
N. Indian J Chem B 1989, 28, 891.
[28] (a) Dhawan, S. N.; Mor, S.; Sharma, K.; Chawla, A. D.; Saini,
A.; Gupta, S. C. Indian J Chem B 1994, 33, 38; (b) Quarishi, M. A.;
Thakur, V. K.; Dhawan, S. N. Indian J Chem B 1989, 28, 891; (c)
Quarishi, M. A.; Dhawan, S. N. J Chem Eng Data 1989, 134; (d)
Hamilton, R. W. J Heterocycl Chem 1976, 13, 545; (e) Mandel, A. N.;
Bhattacharya, S. Indian J Chem B 1984, 23, 736.
[29] Lemke, T. L.; Cramer, M. B.; Shanmugam, P. J Pharm Sci
1978, 67, 1377.
[30] (a) Patra, A.; Misra, S. K. Magn Reson Chem 1991, 29, 749;
(b) Hughes, D. W.; Nalliah, B. C.; Holland, H. L.; Maclean, D. B. Can
J Chem 1977, 55, 3304.
[1] Kumar, S.; Kumar, G.; Kapoor, M.; Surolia, A. Synth
Commun 2006, 36, 215.
[2] Palaska, E.; Aytemir, M.; Uzbay, T.; Erol, D. Eur J Med Chem
2001, 36, 539.
[3] Smith, D.; Forest, A.; Dulin, W. E. J Med Pharm Chem 1965,
8, 350.
[4] (a)Boyd D. B. InTheoretical and Physicochemical Studies on
β‐Lactam Antibiotics in β‐Lactam Antibiotics Chemistry and Biology;
Morin, R. B.;Gorman, M., Eds.;Academic Press:New York, 1982; Vol.
1, pp 437–545; (b)Jungheim, L. N.; Sigmund, S. K.; Jones, N. D.;
Swartzend, J. K. Tetrahedron Lett 1990, 28, 285.
[5] (a) Jungheim, L. N.; Sigmund, S. K.; Fisher, J. W. Tetrahedron
Lett 1987, 28, 285; (b) Jungheim, L. N.; Sigmund, S. K.; Jones, N. D.;
Swartzendruber, J. K. Tetrahedron Lett 1987, 28, 289.
[6] Coombs, R. V.; Houlihan, W. J. U.S. Pat. 3,843,665; Chem
Abstr 1975, 82, 57687b.
[7] (a) Matsuo, Y; Takehara, H; Tanimura, K; Takagi, T.; Nishida,
S. Jpn Kokai Tokkyo Koho JP 62,99,361 ( 1987); Chem Abstr 1987, 107,
198315a; (b) Faidallah, H. M.; Al‐Saadi, M. S.; Rostom, S. A. F.; Fahmy,
H. T. Y. Med Chem Res 2007, 16, 300; (c) Rostom, S. A. F. Bioorg Med
Chem 2006, 14, 6475.
[8] Pasteris, R. J; Muthukrishnan, R. Eur. Pat. EP 203,679 ( 1986);
Chem Abstr 1987, 106, 71132f.
[9] Abdel‐Wahab, B. F.; Abdel‐Aziz, H. A.; Ahmed, E. M. Eur J
Med Chem 2009, 44, 2632.
[10] El‐Sabbagh, O. I.; Baraka, M. M.; Ibrahim, S. M.;
Pannecouque, C.; Andrei, G.; Snoeck, R.; Balzarini, J.; Rashad, A. A.
Eur J Med Chem 2009, 44, 3746.
[11] (a) Dondoni, A.; Marra, A. Chem Rev 2004, 104, 2557; (b)
Jin, Z. Nat Prod Rep 2005, 22, 196.
[12] Kalkhambkar, R. G.; Kulkarni, G. M.; Shivkumar, H.; Rao, N.
R. Eur J Med Chem 2007, 42, 1272.
[13] Ramla, M. M.; Omar, M. A.; El‐Khamry, A. M. M.; El‐Diwan,
H. I. Bioorg Med Chem 2006, 14, 7324.
[14] (a) Ozdemir, A.; Zitouni, G. T.; Kaplancikh, Z. A.; Revial, G.;
Guven, K. Eur J Med Chem 2007, 42, 403; (b) Xin, Z.; Yang‐fang, Z.;
Jia, W.; Wei, J.; Liang, H.;Ping G. Chem Res Chinese U 2006, 22, 459;
(c) Vicini, P.; Geronikaki, A.; Anastasia, K.; Incerti, M.; Zani, F. Bioorg
Med Chem 2006, 14, 3859; (d) Dundar, O. B.; Ozgen, O.; Mentese, A.;
Altanlar, N.; Ath, O.; Kendj, E.; Ertan, R. Bioorg Med Chem 2007, 15,
6012; (e) Cukurovali, A.; Yilmaz, I.; Gur, S.; Kazaz, C. Eur J Med Chem
2006, 41, 201.
[15] (a) Kumar, A.; Rajput, C. S.; Bhati, S. K. Bioorg Med Chem
2007, 15, 3089; (b) Holla, B. S.; Malini, K. V.; Rao, B. S.; Sarojini, B. K.;
Kumari, N. S. Eur J Med Chem 2003, 38, 313.
[16] Pignatello, R.; Mazzone, S.; Panico, A. M.; Mazzone, G.;
Penissi, G.; Castano, R.; Matera, M.; Blandino, G. Eur J Med Chem
1991, 26, 929.
[31] Singh, S. P.; Sehgal, S.; Tarar, L. S. Indian J Chem B 1989, 28,
27.
[32] (a) Thakar, A. S.; Singh, K. K.; Joshi, K. T.; Pancholi, A. M.;
Pandya, K. S. E‐J Chem 2010, 7, 1396; (b) Sonnenschein, R. N.; Johnson,
T. A.; Tenney, K.; Valeriote, F. A.; Crews, P. J Nat Prod 2006, 69, 145.
[33] Pandey, K. S.; Khan, N. Arch Pharm Chem Life Sci 2008, 341,
418.
[34] (a) Rahman, M. M.; Mosaddik, A.; Wahed, M. I. I.; Haque, M.
E. Fitoterapia 2000, 71, 704; (b) Mosaddik, M. A.; Haque, M. E.
Phytother Res 2003, 17, 1155.
[35] (a) Denisova, A. B.; Glukhareva, T. V.; Andronnikova, G. P.;
Mokrushin, V. S.; Dehaen, W.; Luyten, I.; Sosnovskikh, V. Y.; Meervelt,
V.; Bakulev, V. A. J Chem Res 2001, S, 12; (b) Denisova, A. B.;
Glukhareva, T. V.; Andronnikova, G. P.; Mokrushin, V. S.; Dehaen,
W.; Luyten, I.; Sosnovskikh, V. Y.; Meervelt, V.; Bakulev, V. A. J Chem
Res 2001, M, 0133.
[17] Ashtekar, D. R.; Fernandes, F.; Khadse, B. G.; Shirodkar, M. V. A.
Chemotherapy 1987, 33, 22.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet