Synthesis and biological evaluation of chalcones and acetyl pyrazoline derivatives comprising furan nucleus as an antitubercular agents

Article abstract of DOI:10.1007/s00044-011-9857-0

A series of 1-{5-[5-(m,p-dichlorophenyl)furan- 2-yl]-3-aryl-4,5-dihydro-1H- pyrazol-1-yl} ethanone (3a-k) have been synthesized by the condensation of (2E)- 3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-arylprop-2-en-1-one (2a-k) with hydrazine hydrate in glacia

Full text of DOI:10.1007/s00044-011-9857-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3233–3239
DOI 10.1007/s00044-011-9857-0
ORIGINAL RESEARCH
Synthesis and biological evaluation of chalcones and acetyl
pyrazoline derivatives comprising furan nucleus
as an antitubercular agents
•
Dinesh Bhoot Ranjan C. Khunt Hansa H. Parekh
•
Received: 22 June 2011 / Accepted: 28 October 2011 / Published online: 16 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 1-{5-[5-(m,p-dichlorophenyl)furan-
2-yl]-3-aryl-4,5-dihydro-1H-pyrazol-1-yl} ethanone (3a–k)
have been synthesized by the condensation of (2E)-
3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-arylprop-2-en-1-one
(2a–k) with hydrazine hydrate in glacial acetic acid. The
synthesized compounds have been characterized on the basis
of elemental analyses and spectral studies. All the synthe-
sized products have been screened for their antibacterial,
antifungal, and antitubercular activity.
active against many mycobacterium (Kucukguzel et al.,
2002; Kucukguzel and Rollas, 2002; Ali and Yar, 2007).
Terwillige et al. have been concluded that pyrazole
derivatives possess significant anti-HIV activity (Terwilli-
ge et al., 2003). Gunay et al. has been claimed that furan
derivatives possess in vitro antibacterial, antifungal, and
antituberculosis activities (Gunay et al., 1999).
The biodynamic activities of chalcones and pyrazole
derivatives represent one of the most active class of compounds
having a wide spectrum of biological activities lead us to
synthesized some chalcones and pyrazoles derivatives moiety
with hope that they may possess antimicrobial activities.
Keywords Chalcones ꢀ Pyrazoles ꢀ Antimicrobial activity
Introduction
Results and discussion
Tuberculosis, HIV co infection with TB, emergence of
multidrug-resistant TB, and extensively drug-resistant TB
are the major causes of death from infectious diseases
worldwide. Because no new drug has been introduced in
the last several decades, new classes of molecules as anti-
TB drugs are urgently needed. Numerous studies have been
reported on the synthesis of a variety of pyrazole deriva-
tives covering a wide range of bioactivities (Mohammed
et al., 2008). Literature survey reveals that Pyrazole
nucleus shown antitubercular properties (Ali, 2007) and
works as novel potent Mycobacterium tuberculosis PS
inhibitors (Velaparthi et al., 2008). It has been reported that
pyrazole and their derivatives containing the N–N bond are
Chemistry
Several methods have been used for the synthesis of pyr-
azole (Phadtare, 1983; Paul et al., 2001; Mamdouh Hassan
et al., 2001). Here we have reported the synthesis of pyr-
azoline (3a–k) by ring closure of chalcones with hydrazine
hydrate using acetic acid as a solvent. The key intermediate
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-arylprop-2-en-
1-one (2a–k) have been synthesized by the a Claisen–
Schmidt condensation of furfuraldehyde derivative with
aromatic ketones in presence of alkali. The starting
compound 5-(m,p-dichlorophenyl)-2-furaldehyde 1 was
synthesized by the reaction of diazotized solution of m,p-
dichloro aniline and furfural.
D. Bhoot ꢀ R. C. Khunt (&) ꢀ H. H. Parekh
Chemical Research Laboratory, Department of Chemistry,
Saurashtra University, Rajkot 360005, India
e-mail: drrckhunt12@yahoo.com
Stereochemistry
The formation of cis and trans isomer of chalcones (2a–k)
takes place via simple aldol type condensation of furfural
H. H. Parekh
e-mail: hhparekh@yahoo.com
123

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Med Chem Res (2012) 21:3233–3239
with different aromatic ketones in presence of basic cata-
lyst. The cis and trans isomer formation mainly depends on
the steric hindrance group attach with enolate ion (Vas-
hchenko et al., 2007). However, in present case, formyl
group present with heterocyclic ring which create a resis-
tant to attack of enolate ion on carbonyl group of alde-
hydein same plane, which leads to the formation of trans
isomer. The formation of enolate ion takes place by the
abstraction of hydrogen by basic catalyst from a-hydrogen
the development of new antimicrobial agents to overcome
the highly resistant strains of microorganisms. The newly
synthesized compounds 2a–k and 3a–k were tested in vitro
for their antibacterial activity against Bacillus megaterium
ATCC 14518, Staphylococcus aurous ATCC 25923,
Escherichia coli ATCC 25922, Proteus vulgaris
ATCC29905 by the agar well diffusion method (Linday,
1962). DMSO was used as a control solvent and, like
ampicillin, amoxicillin, norfloxacin, penicillin, and gre-
seofulvin as a drug. After 24 h incubation at 37°C, the zone
of inhibition was measured in mm. The results are depicted
in Table 1. Compounds 2a–k and 3a–k were also screened
in vitro for their antifungal activity against Aspergillus
niger ATCC 9029 using the agar plate technique (Collins,
1967). The linear growth of the fungus was obtained by
measuring the diameter of the fungal colony after seven
days. The amount of growth inhibition in each case was
calculated as percentage inhibition. The results showed that
when phenyl group is present as a substituent in case of
1
on methyl ketone. The H NMR spectra of compounds
(2a–k) shows doublets of two protons of vinylic proton
between d 7.56–7.59 and 7.81–7.85, with a coupling con-
stant of J = 15.5 to 15.41 Hz indicating trans stereo-
chemistry at the Chalcones.
Biological activity
Many antimicrobial agents have been introduced into
therapy; however, the field still needs extensive efforts for
Table 1 Antimicrobial & antitubercular screening results of compounds 2a–k and 3a–k
Compound
Zone of inhibition mm
% Inhibition
B. mega
S. aureus
E. coli
P. vulgaris
A. niger
Mtb strain H37 Rv
Ampicillin
22
24
23
25
0
20
22
19
24
0
19
18
20
22
0
17
20
21
23
0
0
0
MIC Rifampin = 0.25 lg/ml
98% inhibition
Amoxicillin
Norfloxacin
0
Assay Alamar
Penicillin
0
Greseofulvin
26
19
17
18
21
14
14
18
19
13
17
19
13
17
19
18
21
17
15
19
20
17
13
2a R = C6H5
20
14
17
21
15
17
12
13
22
19
11
17
14
17
20
21
13
18
12
19
13
16
14
19
12
19
20
12
16
20
13
16
17
20
13
17
12
16
13
16
19
21
14
12
19
16
13
20
14
16
14
12
19
11
12
18
15
17
11
19
12
13
20
12
17
14
15
17
12
16
15
14
11
19
14
17
15
17
15
12
19
18
13
11
14
19
13
14
–
2b R = m-NH2C6H4
2c R = p-NH2C6H4
2d R = p-BrC6H4
2e R = p-ClC6H4
2f R = p-FC6H4
2g R = o-OHC6H4
2h R = p-OCH3C6H4
2i R = p-CH3C6H4
2j R = m-NO2C6H4
2k R = p-NO2C6H4
3a R = C6H5
–
–
–
–
–
–
–
–
–
–
0
3b R = m-NH2C6H4
3c R = p-NH2C6H4
3d R = p-BrC6H4
3e R = p-ClC6H4
3f R = p-FC6H4
3g R = o-OHC6H4
3h R = p-OCH3C6H4
3i R = p-CH3C6H4
3j R = m-NO2C6H4
3k R = p-NO2C6H4
4
74
6
17
1
11
0
0
6
19
123

Med Chem Res (2012) 21:3233–3239
3235
chalcones, it is active against B. megaterium and E. coli
and moderately active against remaining bacterial as well
as fungal strains; when this unsaturated ketone is con-
verted into pyrazoline ring system with the same sub-
stituent’s, Increase in the biological strength for all the
bacterial strains is observed. Presence of methyl sub-
stituent at para position of phenyl ring system significant
increase in activity against bacterial as well as fungal
strains is observed. But with the formation of pyrazoline
ring system shows decrease in activity. For pyrazoline
ring system presence of p-aminophenyl group is moder-
ately active against antitubercular strains while all are
weakly against antitubercular strains. The other com-
pounds showed moderate to low activity. The structure–
activity relationship (SAR) shows that the presence of
substitution at the 4-position (para) of the phenyl sub-
stituent enhanced the antibacterial action of the com-
pounds in case of chalcones series but reverse effect at
pyrazoline ring system.
Experimental
General
All the melting points were determined in an open capillary
tubes and are uncorrected. Thin purity of the synthesized
compounds was tested by thin layer chromatography on
silica gel (acetone:benzene). IR spectra were recorded on
Shimadzu FT-IR-8400 spectrophotometer using KBr disc
1
and H NMR spectra in DMSOd6 and 13CMR spectra in
CdCl3 (Chemical shift in d ppm) on Bruker spectrometer
(300 MHz) using TMS as an internal standard.
Chemistry
5-(m,p-Dichlorophenyl)-2-furaldehyde (1)
A mixture of m,p-dichloroaniline (16.2 g, 100 mol), dil.
HCl (15%, 60 ml), and water (90 ml) was heated to get a
clear solution. The solution was cooled to 0°C and diazo-
tized with NaNO2 solution (30%, 24 ml). The diazonium
salt solution was filtered and to the filtrate, water (50 ml),
and freshly distilled furfural (11.1 ml) and aqueous cupric
chloride (2.5 g in 10 ml of water) were added with stirring.
The stirring was continued for 4 h and kept overnight. The
separated solid was collected by filtration and washed with
cold ethanol, crystallized from a mixture of ethanol-DMF.
yield 80%, m.p. 270°C.
It is worth noting that compounds 2e and 3e exhibited
significant (maximum) antibacterial and antifungal activi-
ties, possibly due to the presence of chloro substitution at
the 4-position (para) of the phenyl substituent, in addition
to the pyrazoline moiety.
Antitubercular activity
All the synthesized compounds were tested in vitro for
their antitubercular activity against M. tuberculosis H37
Rv. The antitubercular evaluation of the compounds were
carried out at Tuberculosis Antimicrobial Acquisition and
Co-ordinating Facility (TAACF), USA. Primary screening
of the compounds for antitubercular activity have been
conducted at 6.25 lg/ml toward M. tuberculosis H37Rv in
BACTEC 12B medium using the BACTEC 460 radio-
metric system. The data were compared with standard drug
Rifampin at 0.25 lg/ml concentration which showed 98%
inhibition (Table 1).
General procedure for the synthesis of (2E)-3-[5-(m,p-
dichlorophenyl)furan-2-yl]-1-arylprop-2-en-1-one (2a–k)
A solution of Arylketone (10 mol) in minimum quantity of
ethanol (5 ml) was added to a mixture of 5-(m,p-dichlo-
rophenyl)-2-furaldehyde (2.41 g, 10 mol) in ethanol
(30 ml) and 40% NaOH was added to make it alkaline. The
reaction mixture was then stirred for 24 h at room tem-
perature. The product was isolated and crystallized from
DMF. Yield 75%, m.p. 210°C. Anal. Found: C, 54.60; H,
2.33%. Calcd for C20H14Cl2O3: C, 54.81; H, 2.51%. (TLC
Solvent system: acetone: benzene, 3:7).
Conclusions
All Chalcones listed in Table 1 were synthesized by the
above mentioned procedure.
In this article, we report the synthesis, spectral studies,
stereochemistry, and antimicrobial and antitubercular
activity of a novel series of novel pyrazoline comprising
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-phenyl-prop-
2-en-1-one (2a) Yield = 68%, m.p. 211–212°C. IR (KBr
cm-1): 1660 (C=O), 1492 (C=C), 1508 (C=C), 783 (C–Cl);
1H NMR (DMSOd6): d 7.20 (d, 1H, fu–H, J = 3.3 Hz), 7.36
(d, 1H, fu–H, J = 3.3 Hz), 7.45 (m, 2H, Ar-H), 7.54 (m, 1H,
Ar-H), 7.56 (d, 1H, Vin–Ha, J = 15.3 Hz), 7.73 (d, 1H,
Ar-Ha, Jab = 8.5 Hz), 7.78 (d, 1H, Vin HB, J = 15.3 Hz),
7.81 (m, 2H, Ar-H), 7.93 (dd, 1H, Ar-Hb, Jba = 8.5 Hz,
Jbc = 2.0 Hz), 8.21 (d, 1H, Ar-Hc, Jcb = 2.0 Hz); 13C
1
furan nucleus. The H NMR studies evidenced the forma-
tion of trans isomers of chalcone and SAR study revealed
a, b unsaturated ketone chain is more active as a sub-
stituent in furan nucleus than pyrazoline ring as substituent.
In summary, we have identified a novel series of pyrazoline
derivatives comprising furan nucleus, which may develop
into the potential class of antimicrobial agents.
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Med Chem Res (2012) 21:3233–3239
NMR (CdCl3): d 106.5, 110.0, 127.0, 128.8, 129.3, 129.9,
130.8, 133.4, 134.6, 150.6, 156.0, 189.0. Anal. Calcd. for
C19H12Cl2O2: C, 66.49; H, 3.52; Cl, 20.66; O, 9.32%.
Found: C, 66.40; H, 3.48; Cl, 20.60; O, 9.28.
(d, 1H, fu–H, J = 3.32 Hz), 7.46 (d, 2H, Ar-H), 7.54 (d,
1H, Vin–Ha, J = 15.2 Hz), 7.73 (d, 1H, Ar-Ha,
Jab = 8.5 Hz), 7.75 (d, 2H, Ar-H), 7.79 (d, 1H, Vin HB,
J = 15.41 Hz), 7.90 (dd, 1H, Ar-Hb, Jba = 8.5 Hz,
Jbc = 2.0 Hz), 8.20 (d, 1H, Ar-Hc, Jcb = 2.0 Hz); 13C
NMR (CdCl3): d 106.4,110.5,127.4, 128.8, 129.4, 130.8,
131.5, 133.4, 133.9, 136.0, 140.1, 150.6, 156.0, 189.6.
Anal. Calcd. for C19H11Cl3O2: C, 60.43; H, 2.94; Cl, 28.16;
O, 8.47. Found: C, 60.38; H, 2.89; Cl, 28.11; O, 8.41.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(m-aminophenyl)-
prop-2-en-1-one (2b) Yield = 71%, m.p. 143–144°C. IR
(KBr cm-1): 3410–3200 (–NH2), 1655 (C=O), 1509
(C=C), 780 (C–Cl); 1H NMR (DMSOd6): d 4.5 (Broad, 2H,
NH2), 7.22 (d, 1H, fu–H, J = 3.32 Hz), 7.38 (d, 1H, fu–H,
J = 3.31 Hz), 6.74–7.20 (m, 4H, Ar-H), 7.57 (d, 1H, Vin–
Ha, J = 15.4 Hz), 7.72 (d, 1H, Ar-Ha, Jab = 8.5 Hz), 7.77
(d, 1H, Vin HB, J = 15.41 Hz), 7.93 (dd, 1H, Ar-Hb,
Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.21 (d, 1H, Ar-Hc,
Jcb = 2.0 Hz); 13C NMR (CdCl3): d 106.7, 110.0, 114.3,
119.9, 122.1, 127.0, 127.5, 128.8, 129.4, 129.8, 130.9,
131.5, 133.4, 156.0, 189.7; Anal. Calcd. for
C19H13Cl2NO2: C, 63.71%; H, 3.66; Cl, 19.79; N, 3.91; O,
8.93. Found: C, 63.66; H, 3.60; Cl, 19.72; N, 3.88; O, 8.85.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-flurophenyl)-
prop-2-en-1-one (2f) Yield = 58%, m.p. 133–135°C. IR
(KBr cm-1): 1656 (C=O), 1508 (C=C), 783 (C–Cl),756
(C–F);1H NMR (DMSOd6):
d 7.21 (d, 1H, fu–H,
J = 3.28 Hz), 7.40 (d, 1H, fu–H, J = 3.28 Hz), 7.46 (m,
2H, Ar-H), 7.55 (d, 1H, Vin–Ha, J = 15.2 Hz), 7.74 (d, 1H,
Ar-Ha, Jab = 8.5 Hz), 7.79 (d, 1H, Vin HB, J = 15.41 Hz),
7.80 (m, 2H, Ar-H), 7.90 (dd, 1H, Ar-Hb, Jba = 8.5 Hz,
Jbc = 2.0 Hz), 8.20 (d, 1H, Ar-Hc, Jcb = 2.0 Hz); 13C
NMR (CdCl3): d 106.2, 110.2, 116.0, 127.4, 128.8, 129.9,
130.8, 131.5, 133.4, 133.9, 150.6, 156.0, 189.8 s. Anal.
Calcd. for C19H11Cl2FO2: C, 63.18; H, 3.07; Cl, 19.63; F,
5.26. Found: C, 63.12; H, 3.16; Cl, 19.58.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-aminophe-
nyl)-prop-2-en-1-one (2c) Yield = 59%, m.p. 170–171°C.
IR (KBr cm-1): 3410–3200 (–NH2), 1654 (C=O), 1508
(C=C), 781 (C–Cl); 1H NMR (DMSOd6): d 5.0 (Broad, 2H,
NH2), 7.20 (d, 1H, fu–H, J = 3.30 Hz), 7.39 (d, 1H, fu–H,
J = 3.31 Hz), 6.5 (d, 2H, Ar-H), 7.56 (d, 1H, Vin–Ha,
J = 15.2 Hz), 7.58 (d, 2H, Ar-H), 7.73 (d, 1H, Ar-Ha,
Jab = 8.5 Hz), 7.75 (d, 1H, Vin HB, J = 15.41 Hz), 7.91
(dd, 1H, Ar-Hb, Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.21 (d, 1H,
Ar-Hc, Jcb = 2.0 Hz); 13C NMR (CdCl3): d 106.5, 111.0,
116.8, 127.9, 129.9, 128.8, 130.7, 131.1, 133.4, 133.9,
154.4, 189.7. Anal. Calcd. for C19H13Cl2NO2: C, 63.71; H,
3.66; Cl, 19.79; N, 3.91; O, 8.93. Found: C, 63.65; H, 3.60;
Cl, 19.72; N, 3.88; O, 8.87.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(o-hydroxyphenyl)-
prop-2-en-1-one (2g) Yield = 68%, m.p. 165–167°C. IR
(KBr cm-1): 3600–3450 (-OH), 1652 (C=O), 1508 (C=C),
781 (C–Cl); 1H NMR (DMSOd6): d 6.92–7.01 (m, 2H, Ar-
H), 7.22 (d, 1H, fu–H, J = 3.26 Hz), 7.37 (m, 1H, Ar-H),
7.42 (d, 1H, fu–H, J = 3.26 Hz), 7.54 (d, 1H, Vin–Ha,
J = 15.2 Hz), 7.625 (m, 1H, Ar-H), 7.75 (d, 1H, Ar-Ha,
Jab = 8.5 Hz), 7.79 (d, 1H, Vin HB, J = 15.41 Hz), 7.90
(dd, 1H, Ar-Hb, Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.20 (d, 1H,
Ar-Hc, Jcb = 2.0 Hz), 8.25 (Broad, 1H, -OH); 13C NMR
(CdCl3): d 106.8, 110.4, 116.4, 127.4, 128.8, 129.9, 130.8,
131.5, 133.4, 133.9, 150.6, 168.7, 189.8. Anal. Calcd. for
C19H12Cl2O3: C, 63.53; H, 3.37; Cl, 19.74; O, 13.36.
Found: C, 63.48; H, 3.31; Cl, 19.68; O, 13.30.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-bromophenyl)-
prop-2-en-1-one (2d) Yield = 63%, m.p. 199–200°C. IR
(KBr cm-1): 1657 (C=O), 1511 (C=C), 783 (C–Cl),750 (C–
Br); 1H NMR (DMSOd6): d 7.21 (d, 1H, fu–H, J = 3.32 Hz),
7.40 (d, 1H, fu–H, J = 3.32 Hz), 7.55 (d, 1H, Vin–Ha,
J = 15.2 Hz), 7.58 (d, 2H, Ar-H), 7.62 (d, 2H, Ar-H), 7.7 (d,
2H, Ar-H), 7.73 (d, 1H, Ar-Ha, Jab = 8.5 Hz), 7.77 (d, 1H,
Vin HB, J = 15.41 Hz), 7.92 (dd, 1H, Ar-Hb, Jba = 8.5 Hz,
Jbc = 2.0 Hz), 8.21(d, 1H, Ar-Hc, Jcb = 2.0 Hz);13C NMR
(CdCl3): d 106.7,110.0,127.4, 128.9, 130.8, 131.5,132.2,
133.4, 136.9, 150.6 156.0, 189.8. Anal. Calcd. for
C19H11BrCl2O2: C, 54.06; H, 2.63; Br, 18.93; Cl, 16.80.
Found: C, 53.96; H, 2.58: Br, 18.89; Cl, 16.77.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-methoxyphenyl)-
prop-2-en-1-one (2h) Yield = 75%, m.p. 209–211°C. IR
(KBr cm-1): 1658 (C=O), 1508 (C=C), 1205(C–O–C), 783
1
(C–Cl); H NMR (DMSOd6): d 3.79 (s, 3H, –OCH3), 6.96
(d, 2H, Ar-H), 7.19 (d, 1H, fu–H, J = 3.31 Hz), 7.38 (d, 1H,
fu–H, J = 3.31 Hz), 7.54 (d, 1H, Vin–Ha, J = 15.2 Hz),
7.62 (d, 2H, Ar-H), 7.73 (d, 1H, Ar-Ha, Jab = 8.5 Hz), 7.77
(d, 1H, Vin HB, J = 15.41 Hz), 7.92 (dd, 1H, Ar-Hb,
Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.21 (d, 1H, Ar-Hc,
Jcb = 2.0 Hz); 13C NMR (CdCl3): d 55.9, 110.0, 106.5,
114.8, 127.4, 128.8, 130.2, 130.9, 133.4, 133.9, 150.6, 156.0,
189.6. Anal. Calcd. for C20H14Cl2O3: C, 64.36; H, 3.78; Cl,
19.00; O, 12.86. Found: C, 64.30; H, 3.74; Cl, 18.96; O,
12.80.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-chlorophenyl)-
prop-2-en-1-one (2e) Yield = 60%, m.p. 155–157°C. IR
1
(KBr cm-1): 1658 (C=O), 1508 (C=C), 783 (C–Cl); H
NMR (DMSOd6): d 7.23 (d, 1H, fu–H, J = 3.30 Hz), 7.42
123

Med Chem Res (2012) 21:3233–3239
3237
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-methylphenyl)-
prop-2-en-1-one (2i) Yield = 73%, m.p. 179–181°C. IR
All pyrazole listed in Table 1 were synthesized by the
above mentioned procedure.
1
(KBr cm-1): 1658 (C=O), 1508 (C=C), 783 (C–Cl); H
NMR (DMSOd6): d 2.41 (s, 3H, –CH3), 7.20 (d, 1H, fu–H,
J = 3.28 Hz), 7.36 (d, 1H, fu–H, J = 3.29 Hz), 7.39 (d,
2H, Ar-He, e’, Jed = 8.0). 7.56 (d, 1H, Vin–Ha,
J = 15.3 Hz), 7.73 (d, 1H, Ar-Ha, Jab = 8.5 Hz), 7.78 (d,
1H, Vin HB, J = 15.3 Hz), 7.93 (dd, 1H, Ar-Hb,
Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.06 (d, 2H, Ar-Hd, d0,
Jde = 8.2 Hz), 8.21 (d, 1H, Ar-Hc, Jcb = 2.0 Hz); 13C
NMR (CdCl3): d 24.3, 106.5, 110.0, 127.0, 128.8, 29.6,
129.9, 131.5, 133.4, 134.9, 144.2, 150.6, 156.2, 189.6.
Anal. Calcd. for C20H14Cl2O2: C, 67.24; H, 3.95; Cl, 19.85;
O, 8.96. Found: C, 67.20; H, 3.89; Cl, 19.78; O, 8.89.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3-phenyl-4,5-dihydro-
1H-pyrazol-1-yl} ethanone (3a) Yield = 59%, m.p.
186–188°C. IR (KBr cm-1): 1670 (C=O), 1605 (C=N),
1
1517 (C=C), 749 (C–Cl); H NMR (DMSOd6): d 2.36 (s,
3H, CO–CH3), 3.51 (dd, 1H, –CHA, JAB = 18,
JAX = 4.83), 3.7 (dd, 1H, –CHB, JBA = 18, JBX = 11.7),
5.60 (dd, 1H, –CHX, JXA = 4.8, JXB = 11.7) 6.48 (d, 1H,
fu–H, J = 3.3), 7.06 (d, H, fu–H, J = 3.3), 7.30 (m, 3H,
Ar-H), 7.57 (dd, 1H, Ar-Hb, Jba = 8.4, Jbc = 1.5), 7.6 (m,
2H, Ar-H), 7.64 (d, 1H, Ar-Ha, Jab = 8.4), 7.85 (d, 1H,
Ar-Hc, Jcb = 1.8); 13C NMR (CdCl3): d 22.8, 38.3, 56.9,
101.0, 127.0, 128.8, 130.7, 131.1, 133.9, 133.4, 168.3.
Anal. Calcd: C21H16Cl2N2O2: C, 63.17; H, 4.04; Cl, 17.76;
N, 7.02; O, 8.01. Found: C, 63.12; H, 3.98; Cl, 17.70; N,
6.98; O, 7.95.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(m-nitrophenyl)-
prop-2-en-1-one (2j) Yield = 70%, m.p. 143–145°C. IR
(KBr cm-1): 1656 (C=O), 1501 (C=C), 1105 (N–O), 783
(C–Cl); 1H NMR (DMSOd6): d 7.21 (d, 1H, fu–H,
J = 3.32 Hz), 7.42 (d, 1H, fu–H, J = 3.32 Hz), 7.55 (d,
1H, Vin–Ha, J = 15.2 Hz), 7.62 (d, 2H, Ar-H), 7.71 (m,
1H, Ar-H), 7.73 (d, 1H, Ar-Ha, Jab = 8.5 Hz), 7.77 (d, 1H,
Vin HB, J = 15.41 Hz), 7.92 (dd, 1H, Ar-Hb,
Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.20 (m, 1H, Ar-H), 8.21 (d,
1H, Ar-Hc, Jcb = 2.0 Hz) 8.47 (m, 1H, Ar-H), 8.74 (d,
1H, Ar-H); 13C NMR (CdCl3): d 106.3, 110.2, 121.6,
127.4, 129.9, 130.8, 133.4, 133.9, 144.0, 150.6, 154.2,
156.0, 189.7. Anal. Calcd. for C19H11Cl2NO4: C, 58.78; H,
2.86; Cl, 18.27; N, 3.61. Found: C, 58.72; H, 2.80; Cl,
18.21; N, 3.55.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(m-aminophenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3b) Yield = 63%,
m.p. 200–202°C. IR (KBr cm-1): 3400–3200 (–NH2),
1
1668 (C=O), 1602 (C=N), 1515 (C=C), 749 (C–Cl); H
NMR (DMSOd6): d 2.36 (s, 3H, CO–CH3), 3.50 (dd, 1H, –
CHA, JAB = 18.10, JAX = 4.84), 3.71 (dd, 1H, -CHB,
JBA = 18, JBX = 11.6), 4.5 (Broad, 2H, –NH2), 5.60 (dd,
1H, –CHX, JXA = 4.8, JXB = 11.7) 6.45 (d, 1H, fu–H,
J = 3.31), 7.05 (d, H, fu–H, J = 3.31), 6.57–7.0 (m, 4H,
Ar-H), 7.58 (dd, 1H, Ar-Hb, Jba = 8.2, Jbc = 1.5), 7.62
(d, 1H, Ar-Ha, Jab = 8.2), 7.84 (d, 1H, Ar-Hc, Jcb = 1.8);
13C NMR (CdCl3): d 22.8, 38.3, 101.0, 107.3, 113.2,
118.6,119.2,127.0 128.8, 150.1, 168.5. Anal. Calcd. for
C21H17Cl2N3O2: C, 63.17; H, 4.04; Cl, 17.76; N, 7.02; O,
8.01. Found: C, 63.12; H, 3.96; Cl, 17.72; N, 7.02;
O, 7.95.
(2E)-3-[5-(m,p-dichlorophenyl)furan-2-yl]-1-(p-nitrophenyl)-
prop-2-en-1-one (2k) Yield = 62%, m.p. 191–193°C. IR
(KBr cm-1): 1650 (C=O), 1500 (C=C), 1101 (N–O), 783
(C–Cl); 1H NMR (DMSOd6): d 7.22 (d, 1H, fu–H,
J = 3.31 Hz), 7.41 (d, 1H, fu–H, J = 3.31 Hz), 7.54 (d,
1H, Vin–Ha, J = 15.2 Hz), 7.73 (d, 1H, Ar-Ha,
Jab = 8.5 Hz), 7.79 (d, 1H, Vin HB, J = 15.41 Hz), 7.90
(dd, 1H, Ar-Hb, Jba = 8.5 Hz, Jbc = 2.0 Hz), 8.07 (d, 2H,
Ar-H), 8.20 (d, 1H, Ar-Hc, Jcb = 2.0 Hz), 8.38 (d, 2H, Ar-
H); 13C NMR (CdCl3): d 106.5, 110.0, 124.8, 126.9, 127.0,
130.8, 133.4, 133.9, 138.8, 150.7, 156.0, 189.7. Anal.
Calcd. for C19H11Cl2NO4: C, 58.78; H, 2.86; Cl, 18.27; N,
3.61. Found: C, 58.71; H, 2.80; Cl, 18.21; N, 3.55.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(p-aminophenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3c) Yield =
72%, m.p. 206–208°C. IR (KBr cm-1): 3415–3310
(–NH2), 1665 (C=O), 1600 (C=N), 1518 (C=C); 740 (C–
1
Cl); H NMR (DMSOd6): d 2.35 (s, 3H, CO–CH3), 3.52
(dd, 1H, –CHA, JAB = 18.20, JAX = 4.84), 3.71 (dd, 1H,
–CHB, JBA = 18.10, JBX = 11.6), 4.8 (Broad, 2H, –NH2)
5.62 (dd, 1H, –CHX, JXA = 4.84, JXB = 11.4) 6.45 (d,
1H, fu–H, J = 3.31), 7.05 (d, H, fu–H, J = 3.31), 6.57 (d,
2H, Ar-H), 7.40 (d, 2H, Ar-H), 7.58 (dd, 1H, Ar-Hb,
Jba = 8.2, Jbc = 1.5), 7.62 (d, 1H, Ar-Ha, Jab = 8.2),
7.84 (d, 1H, Ar-Hc, Jcb = 1.8); 13C NMR (CdCl3): d 22.5,
38.1, 44.6, 101.0, 107.3, 116.4, 127.0, 128.8, 129.6, 130.8,
134.4, 151.8, 168.3. Anal. Calcd. for for C21H17Cl2N3O2:
C, 63.17; H, 4.04; Cl, 17.76; N, 7.02; O, 8.01. Found: C,
63.13; H, 3.98; Cl, 17.74; N, 6.98; O, 7.93.
General procedure for the synthesis of 1-{5-[5-(m,p-dichlo-
rophenyl)furan-2-yl]-3aryl-4,5-dihydro-1H-pyrazol-1-yl}
ethanone (3a–k)
A mixture of 2 (10 mmol) and hydrazine hydrate (2 ml,
40 mmol) in acetic acid (30 ml) was refluxed for 10 h. The
solution was poured onto crushed ice. Product was isolated
and crystallized from ethanol.
123

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Med Chem Res (2012) 21:3233–3239
1
(C=O), 1603 (C=N), 1518 (C=C), 749 (C–Cl); H NMR
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(p-bromophenyl)
Aryl-4,5-dihydro-1H-pyrazol-1-yl} ethanone (3d) Yield =
69%, m.p. 256–258°C. IR (KBr cm-1): 1670 (C=O), 1608
(DMSOd6): d 2.35 (s, 3H, CO–CH3), 3.50 (dd, 1H, –CHA,
JAB = 18.20, JAX = 4.87), 3.70 (dd, 1H, –CHB, JBA =
18.2, JBX = 11.20), 5.61 (dd, 1H, –CHX, JXA = 4.85,
JXB = 11.20) 6. 50 (d, 1H, fu–H, J = 3.31), 6.8 (m, 2H,
Ar-H), 7.07 (d, H, fu–H, J = 3.31) 7.1 (m, 1H, Ar-H), 7.3
(d, 2H, Ar-H), 7.4 (m, 1H, Ar-H), 7.57 (dd, 1H, Ar-Hb,
Jba = 8.2, Jbc = 1.5), 7.65 (d, 1H, Ar-Ha, Jab = 8.2),
7.82 (d, 1H, Ar-Hc, Jcb = 1.8); 13C NMR (CdCl3): d 22.2,
38.0, 44.6, 101.3, 107.3, 116.0, 127.0, 128.8, 129.9, 130.8,
133.9, 150.1, 151.2, 160.8. Anal. Calcd. for C21H16Cl2
N2O3: C, 60.74; H, 3.88; Cl, 17.07; N, 6.75; O, 11.56.
Found: C, 60.69; H, 3.82; Cl, 17.02; N, 6.71; O, 11.50.
1
(C=N), 1518 (C=C), 760 (C–Br), 749 (C–Cl); H NMR
(DMSOd6): d 2.36 (s, 3H, CO–CH3), 3.53 (dd, 1H, –CHA,
JAB = 18, JAX = 4.87), 3.72 (dd, 1H, –CHB, JBA = 18,
JBX = 11.5), 5.60 (dd, 1H, –CHX, JXA = 4.87,
JXB = 11.5) 6. 5 (d, 1H, fu–H, J = 3.31), 7.08 (d, H, fu–
H, J = 3.31),7.52 (m, 4H, Ar-H), 7.58 (dd, 1H, Ar-Hb,
Jba = 8.2, Jbc = 1.5), 7.68 (d, 1H, Ar-Ha, Jab = 8.2),
7.86 (d, 1H, Ar-Hc, Jcb = 1.8); 13C NMR (CdCl3): d 22.8,
38.1, 44.6, 107.3, 116.4, 127.0, 128.8, 129.6, 130.8, 134.4,
133.9, 151.8, 168.3. Anal. Calcd. for C21H15BrCl2N2O2: C,
52.75; H, 3.16; Br, 16.71; Cl, 14.83; N, 5.86; O, 6.69.
Found: C, 52.70; H, 3.11; Br, 16.68; Cl, 14.78; N, 5.80; O,
6.62.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(p-methoxyphenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3h) Yield = 65%,
m.p. 190–192°C. IR (KBr cm-1): 1670 (C=O), 1602
(C=N), 1518 (C=C), 1205 (C–O–C), 749 (C–Cl); 1H NMR
(DMSOd6): d 2.36 (s, 3H, CO–CH3), 3.51 (dd, 1H, –CHA,
JAB = 18, JAX = 4.83), 3.7 (dd, 1H, –CHB, JBA = 18.1,
JBX = 11.7), 3.87 (s, 3H, OCH3), 5.60 (dd, 1H, –CHX,
JXA = 4.8, JXB = 11.7) 6. 49 (d, 1H, fu–H, J = 3. 12),
6.8 (d, 2H, Ar-H), 7.04 (d, H, fu–H, J = 3.12), 7.5 (d, 2H,
Ar-H), 7.57 (dd, 1H, Ar-Hb, Jba = 8.2, Jbc = 1.5), 7.65
(d, 1H, Ar-Ha, Jab = 8.2), 7.82 (d, 1H, Ar-Hc, Jcb = 1.8);
13C NMR (CdCl3): d 22.6, 38.1, 44.5, 55.9, 101.2, 107.2,
114.0, 127.0, 128.8, 129.9, 130.8, 133.9, 150.1, 151.2,
160.8, 168.0. Anal. Calcd. for C22H18Cl2 N2O3: C, 61.55;
H, 4.23; Cl, 16.52; N, 6.53; O, 11.18. Found: C, 61.50; H,
4.18; Cl, 16.49; N, 6.48; O, 11.12.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(p-chlorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3e) Yield =
66%, m.p. 155–157°C. (KBr cm-1): 1661 (C=O), 1605
1
(C=N), 1520 (C=C), 749 (C–Cl); H NMR (DMSOd6): d
2.37 (s, 3H, CO–CH3), 3.51 (dd, 1H, –CHA, JAB = 18.12,
JAX = 4.84), 3.73 (dd, 1H, –CHB, JBA = 18.10, JBX =
11.6), 5.62 (dd, 1H, –CHX, JXA = 4.84, JXB = 11.6) 6. 52
(d, 1H, fu–H, J = 3.31), 7.08 (d, H, fu–H, J = 3.31), 7.3
(d, 2H, Ar-H), 7.58 (dd, 1H, Ar-Hb, Jba = 8.2, Jbc = 1.5),
7.6 (d, 2H, Ar-H), 7.68 (d, 1H, Ar-Ha, Jab = 8.2), 7.86 (d,
1H, Ar-Hc, Jcb = 1.8); 13C NMR (CdCl3): d 22.4, 38.1,
44.5, 101.0, 107.4, 125.4, 127.0, 130.8, 131.8, 150.1,
168.2. Anal. Calcd. for C21H15Cl3N2O2: C, 58.15; H, 3.49;
Cl, 24.52; N, 6.46; O, 7.38. Found: C, 58.11; H, 3.42; Cl,
24.48; N, 6.40; O, 7.32.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(p-methylphenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3i) Yield = 62%,
m.p. 146–148°C. IR (KBr cm-1): 1668 (C=O), 1602
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(p-fluorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3f) Yield = 58%,
m.p. 279–281°C. IR (KBr cm-1): 1663 (C=O), 1605
(C=N), 1525 (C=C), 749 (C–Cl) 680 (C–F); 1H NMR
(DMSOd6): d 2.34 (s, 3H, CO–CH3), 3.51 (dd, 1H, –CHA,
JAB = 18.10, JAX = 4.85), 3.71 (dd, 1H, –CHB, JBA =
18.1, JBX = 11.20), 5.60 (dd, 1H, –CHX, JXA = 4.85,
JXB = 11.20) 6. 48 (d, 1H, fu–H, J = 3.31), 7.0 (m, 2H,
Ar-H), 7.06 (d, H, fu–H, J = 3.31), 7.57 (dd, 1H, Ar-Hb,
Jba = 8.2, Jbc = 1.5), 7.6 (m, 2H, Ar-H) 7.65 (d, 1H, Ar-
Ha, Jab = 8.2), 7.82 (d, 1H, Ar-Hc, Jcb = 1.8); 13C NMR
(CdCl3): d 22.4, 38.0, 44.5, 101.3, 107.4, 127.0, 128.0,
129.0, 130.6, 130.8, 133.9, 150.1,168.3. Anal. Calcd. for
C21H15Cl2 FN2O2: C, 60.45; H, 3.62; Cl, 16.99; F, 4.55; N,
6.71; O, 7.67. Found: C, 60.40; H, 3.58; Cl, 16.92; F, 4.50;
N, 6.68; O, 7.62.
1
(C=N), 1515 (C=C), 749 (C–Cl); H NMR (DMSOd6): d
2.29(s, 3H, –CH3), 2.36 (s, 3H, CO–CH3), 3.50 (dd, 1H,
–CHA, JAB = 18, JAX = 4.8), 3.75 (dd, 1H, –CHB,
JBA = 18, JBX = 11.7), 5.67 (dd, 1H, –CHX, JXA = 4.8,
JXB = 11.7) 6. 46 (d, 1H, fu–H, J = 3. 33), 7.06 (d, H,
fu–H, J = 3.33), 7.3 (d, 2H, Ar-H), 7.57 (dd, 1H, Ar-Hb,
Jba = 8.2, Jbc = 1.5), 7.64 (d, 1H, Ar-Ha, Jab = 8.2),
7.72 (d, 2H, Ar-H), 7.85 (d, 1H, Ar-Hc, Jcb = 1.8); 13C
NMR (CdCl3): d 22.7, 24.3, 38.2, 44.5, 101.0, 107.3, 127.0,
128.8, 129.2, 130.8, 133.4, 140.7, 150.1,168.3. Anal.
Calcd. for C22H18Cl2 N2O2: C, 63.93; H, 4.39; Cl, 17.16;
N, 6.78; O, 7.74. Found: C, 63.89; H, 4.32; Cl, 17.11; N,
6.72; O, 7.68.
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(m-nitrophenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3j) Yield =
70%, m.p. 199–201°C. IR (KBr cm-1): 1665 (C=O), 1609
1-{5-[5-(m,p-Dichlorophenyl)furan-2-yl]-3(o-hydroxyphenyl)-
4,5-dihydro-1H-pyrazol-1-yl} ethanone (3g) Yield = 71%,
m.p. 240–242°C. IR (KBr cm-1): 3600–3400 (–OH), 1661
1
(C=N), 1518 (C=C), 1105 (–N–O), 744 (C–Cl); H NMR
(DMSOd6): d 2.35 (s, 3H, CO–CH3), 3.52 (dd, 1H, –CHA,
123

Med Chem Res (2012) 21:3233–3239
3239
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JAB = 18.1, JAX = 4.81), 3.74 (dd, 1H, –CHB, JBA =
18.1, JBX = 11.7), 5.67 (dd, 1H, –CHX, JXA = 4.91,
JXB = 11.7) 6. 47 (d, 1H, fu–H, J = 3. 33), 7.04 (d, H, fu–
H, J = 3.33), 7.58 (dd, 1H, Ar-Hb, Jba = 8.2, Jbc = 1.5),
7.6 (m, 1H, Ar-H), 7.64 (d, 1H, Ar-Ha, Jab = 8.2), 7.72 (d,
2H, Ar-H), 7.85 (d, 1H, Ar-Hc, Jcb = 1.8), 8.0–8.6 (m,
3H, Ar-H); 13C NMR (CdCl3): d 22.7, 38.2, 44.6, 101.0,
107.3, 127.0, 128.8, 129.2, 130.8, 133.4, 140.7,
150.1,168.3. Anal. Calcd. for C21H15Cl2 N3O4: C, 56.77;
H, 3.40; Cl, 15.96; N, 9.46; O, 14.41. Found: C, 56.72; H,
3.35; Cl, 15.91; N, 9.41; O, 14.37.
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4,5-dihydro-1H-pyrazol-1-yl} ethanone (3k) Yield = 68%,
m.p. 140–142°C. IR (KBr cm-1): 1669 (C=O), 1607
1
(C=N), 1510 (C=C), 1110 (N–O), 743 (C–Cl); H NMR
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Mascagni P, Coates A, Wood S, Goulding C, Apostol M,
Anderson D, Gill H, Eisenberg D, Taneja B, Mande S, Pohl E,
Lamzin V, Tucker P, Wilmanns M, Colovos C, Meyer-Klaucke
W, Munro A, McLean K, Marshall K, Leys D, Yang J, Yoon H,
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protocol for Claisen–Schmidt condensation of Hindered cyclic
ketones with aromatic aldehyde. Synthesis: 2125–2134
(DMSOd6): d d 2.37 (s, 3H, CO–CH3), 3.52 (dd, 1H,
–CHA, JAB = 18.02, JAX = 4.82), 3.76 (dd, 1H, –CHB,
JBA = 18.02, JBX = 11.8), 5.68 (dd, 1H, –CHX,
JXA = 4.92, JXB = 11.8) 6. 45 (d, 1H, fu–H, J = 3. 33),
7.04 (d, H, fu–H, J = 3.33), 7.58 (dd, 1H, Ar-Hb,
Jba = 8.2, Jbc = 1.5), 7.64 (d, 1H, Ar-Ha, Jab = 8.2),
7.85 (d, 1H, Ar-Hc, Jcb = 1.8) 7.9 (d, 2H, Ar-H), 8.2 (d,
2H, Ar-H); 13C NMR (CdCl3): d 22.8, 38.2, 44.5, 101.1,
107.3, 127.0, 123.4, 128.8, 129.8, 133.4, 133.9, 150.7,
151.0, 168.7. Anal. Calcd. for C21H15Cl2 N3O4: C, 56.77;
H, 3.40; Cl, 15.96; N, 9.46; O, 14.41. Found: C, 56.74; H,
3.34; Cl, 15.90; N, 9.39; O, 14.35.
Acknowledgments The authors are thankful to the Professor and
Head, Department of Chemistry, Saurashtra University, Rajkot for
providing research facilities and Department of Science and Tech-
nology, New Delhi for providing Major Research Project (Sanction
No. 02-/2008). Authors are also thankful to TAFFC, Southern
research Centre, Alabama for antitubercular screening. Authors are
also thankful to National Facility and Drug Discovery, Rajkot for
instrumental support.
Velaparthi
S et al (2008) -Tert-butyl-n-pyrazol-4-yl-4,5,6,7-tra-
hydrobenzo[d]isoxazole-3-carboxamide derivatives as novel
potent inhibitors of Mycobacterium tuberculosis pantothenate
synthetase: initiating a quest for new antitubercular drugs. J Med
Chem 51(7):1999–2002
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