A facile and efficient synthesis of 2-(5-(4-substitutedphenyl)-4, 5-dihydro-3-phenylpyrazol-1-yl)-6-substitutedbenzothiazoles and their biological studies

Article abstract of DOI:10.1002/jhet.1618

A series of new 1-substituted 3, 5-diarylpyrazolines (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25) were synthesized in good yield by both conventional and microwave-assisted synthesis from α, β- unsaturated ketones (6, 7, 8, 9) in n-butanol and benzothiazole hydrazines (2, 3, 4, 5). All the new compounds were characterized by IR, NMR, and mass spectral data. The synthesized compounds (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25) were evaluated for antibacterial and anthelmintic activities. The compounds showed potent anthelmintic activity against earthworm species (Eudrilus eugeniae) and moderate antibacterial activity against bacterial strains such as Gram positive bacteria, Enterococcus faecalis, Staphylococcus aureus, and Bacillus subtilis, and Gram negative bacteria, Escherichia coli and Proteus mirabilis.

Full text of DOI:10.1002/jhet.1618

March 2014
A Facile and Efficient Synthesis of 2-(5-(4-Substitutedphenyl)-4,
5-dihydro-3-phenylpyrazol-1-yl)-6-Substitutedbenzothiazoles and
Their Biological Studies
459
a
a
b
*
D. Munirajasekhar, M. Himaja, and Sunil V. Mali
aSchool of Advanced Sciences, VIT University, Vellore, 632 014, Tamil Nadu, India
bMedicinal Chemistry Division, Piramal Healthcare Ltd, Mumbai, India
*
E-mail: dr_himaja@yahoo.com
Received October 25, 2011
DOI 10.1002/jhet.1618
Published online 20 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
A series of new 1-substituted 3, 5-diarylpyrazolines (10–25) were synthesized in good yield by both
conventional and microwave-assisted synthesis from a, b- unsaturated ketones (6–9) in n-butanol and
benzothiazole hydrazines (2–5). All the new compounds were characterized by IR, NMR, and mass spectral data.
The synthesized compounds (10–25) were evaluated for antibacterial and anthelmintic activities. The compounds
showed potent anthelmintic activity against earthworm species (Eudrilus eugeniae) and moderate antibacterial
activity against bacterial strains such as Gram positive bacteria, Enterococcus faecalis, Staphylococcus aureus,
and Bacillus subtilis, and Gram negative bacteria, Escherichia coli and Proteus mirabilis.
J. Heterocyclic Chem., 51, 459 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
Benzothiazoles have special significance in the field of
medicine because of their remarkable pharmacological
activities [1–5]. Recently, there have been interesting
developments in the synthesis of novel benzothiazole
derivatives as therapeutic agents, such as antitumor [6–11],
antitubercular [12], antimalarial [13], anticonvulsant [14],
anthelmintic [15], analgesic [16], anti-inflammatory [17], and
antidiabetic [18] activities. Substituted 2-arylbenzothiazoles
emerged as important pharmacophores in noninvasive
diagnosis of Alzheimer’s disease. Recently, 11C labeled-
2-aryl-benzothiazoles have been used as potent amyloid-
binding diagnostic agent in neurodegenerative disease
[19,20] and also as selective fatty acid amide hydrolase
inhibitors [21].
Pyrazolines were reported to be useful constituents in
antitumor [22], immunosuppressive [23], antibacterial [24],
antitubercular [25], anti-inflammatory [26], anticancer [27],
antidiabetic [28], and antidepressant [29] activities. Pyrazo-
line derivatives were also used as dyestuffs, analytical
reagents, and in agrochemicals [30].
Chemistry.
Synthesis of compounds 1–5. The precursor 2-amino-6-
substituted benzothiazole (1a–d) was prepared from aniline
by modifying the procedure [31] for MW-assisted synthesis.
The reaction could be completed within 6 min at 455 Watts.
The compounds 1a–d were treated with hydrazine hydrate in
the presence of ethylene glycol to obtain the corresponding
6-substituted-2-hydrazinobenzothiazoles (2–5) as shown in
Scheme 1. Chalcones (6–9) were prepared by MW-assisted
Claisen–Schmidt reaction using acetophenone and substituted
aldehydes (Scheme 2). The reaction time was reduced to
2 min at 245 Watts as compared with the conventional
procedure [32]. All the products (2–5) were characterized by
1
FTIR, H NMR, and mass spectral analysis. FTIR spectra
of compound 2 exhibited absorptions at 3320 cmÀ1 for NH2
stretching, 3100 cmÀ1 for NH stretching, 1627 cmÀ1 for
C═N stretching, 1447 cmÀ1 for C-N stretching, and
1218 cmÀ1 for C-S stretching. The 1H NMR of compound 2
showed a singlet at d 8.857 for NH proton and another
singlet at d 4.948 for NH2 protons. Aromatic protons are
observed as multiplet at d 6.974–7.452. The structure was
further confirmed by mass spectral analysis. It gave a
molecular ion peak at m/z 180.1 corresponding to molecular
A series of benzothiazol-pyrazoline compounds were
designed, which were expected to exhibit potent biological
activities owing to their synergistic effect. The present
article describes a convenient MW-assisted synthesis
and characterization of a series of new benzothiazol-
pyrazolines and evaluation of their antibacterial and anthel-
mintic activities.
formula C8H9N3S (Scheme 1). Similarly compounds 3–5
were also characterized on the basis of spectral data.
Synthesis of compounds 10–25. Preliminary studies on
the reactions of various hydrazine-benzothiazoles (2–5)
© 2013 HeteroCorporation

460
D. Munirajasekhar, M. Himaja, and S. V. Mali
Vol 51
Scheme 1. Reaction sequence for the synthesis of hydrazine benzothiazoles (2–5). Reagents and conditions: (a) KSCN/Br2, CH3COOH, (b) Liq.NH3,
H2O, (c) N2H4.H2O, ethylene glycol.
Scheme 2. Reaction sequence for the synthesis of chalcones (6–9).
with chalcones (6–9) revealed that the rate of formation of
benzothiazole pyrazolines (10–25) depended on the nature
of the solvent (Scheme 3). Better yields were obtained by
refluxing with n-butanol for 9 h. The reaction time was
further reduced to 35–50 min when the reaction mixture
was irradiated with microwaves at 560 watts using
butanol as solvent. Table 1 shows the optimized
experimental conditions for compound 10.
reaction was monitored by IR spectra, and the disappearance
of strong intense carbonyl peak 1670cmÀ1 related to
chalcones indicated the completion of the reaction. IR
spectra of compound 10 exhibited absorption peaks at
3024 cmÀ1 for aromatic stretching, 2918 cmÀ1 for C-H
stretching in methyl group, 1627cmÀ1 for C═N stretching
in benzothiazole, 1594 cmÀ1 for C═C stretching, 1533 cmÀ1
for C═N stretching in pyrazoline ring, 1454 cmÀ1 for
C-N stretching, and 1237 cmÀ1 for C-S stretching. The
other functional groups of compounds 10–25 appeared
as absorption peaks at 2900 cmÀ1 for C-H stretching
in OCH3 group, 1400 cmÀ1 for C-F stretching, and
The purity of all the compounds was monitored by thin
layer chromatography. The physical data of the synthesized
compounds are given in Table 2.
The structure of the compounds 10–25 was confirmed by
FTIR, 1H NMR, 13C NMR, and HRMS analysis. The
700–750 cmÀ1 for C-Cl stretching. Although in the H
1
Table 1
Synthesis of 2-(4,5-dihydro-3,5-diphenylpyrazol-1-yl)-6-methylbenzo[d]thiazole (10) at different reaction conditions.
Conventional method
Microwave method
Entry
Solvent
Ethanol
Acetic acid
Pyridine
Time (h)
Yield (%)
Time (min)
Yield (%)
1
2
3
4
20
14
16
14
42.4
56.1
32.3
86.7
50
45
50
35
51.2
59.4
34.6
88.4
n-Butanol
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A Facile and Efficient Synthesis of 2-(5-(4-Substitutedphenyl)-4, 5-dihydro-3-
461
March 2014
phenylpyrazol-1-yl)-6-Substitutedbenzothiazoles and Their Biological Studies
Table 2
The physical data of the synthesized compounds (10–25).
Compound
R1
R2
Molecular formula (MW)
mp (ꢀC)
Yield (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
Cl
Cl
Cl
Cl
F
H
C23H19N3S (369.48)
C24H21N3OS (399.50)
C24H21N3S (383.50)
158–160
131–132
146–148
210–212
162–164
126–128
154–156
164–166
165–167
156–158
174–176
230–232
170–172
162–164
156–158
200–202
88.4
87.1
84.3
85.7
79.6
77.4
76.7
71.8
73.2
76.4
84.8
89.3
91.2
89.8
90.7
91.8
OCH3
CH3
Cl
C23H18ClN3S (403.92)
C23H19N3OS (385.48)
C24H21N3O2S (415.50)
C24H21N3OS (399.50)
C23H18ClN3OS (419.92)
C22H16ClN3S (389.90)
C23H18ClN3OS (419.92)
C23H18ClN3S (403.92)
C22H15Cl2N3S (424.34)
C22H16FN3S (373.44)
C23H18FN3OS (403.47)
C23H18FN3S (387.47)
C22H15ClFN3S (407.89)
H
OCH3
CH3
Cl
H
OCH3
CH3
Cl
H
F
F
F
OCH3
CH3
Cl
NMR spectra of the compounds 10–25, the protons at-
tached to the C-4 and C-5 carbon atoms of the five-mem-
bered ring (Scheme 2) gave an ABX spin system.
Compounds 10–25 exhibited double doublets for each -
CH2 proton between d 3.23–3.64 and d 3.88–4.00 and
double doublet between d 5.25–6.22 for -CH proton.
These chemical shifts proved the formation of pyrazoline
moiety [33,34]. The 13C NMR spectrum of compound
10 showed signals at d 21.5, 44.0 (C-4 position in pyrazo-
line ring), 64.0 (C-4 position in pyrazoline ring), 119.9,
121.1, 126.3, 126.8, 127.1, 128.1, 129.0, 129.2, 130.34,
131.6, 131.9, 141.6, 150.7, 152.6 (C═N of pyrazoline
ring), and 163.1 (C═N of benzothiazole ring). The struc-
ture was further confirmed by its HRMS spectral analysis.
HRMS of the compound was in good agreement with
the theoretical values. Similarly, compounds 11–25 were
characterized by spectral analysis. All the synthesized
compounds 10–25 were evaluated for their antibacterial
and anthelmintic activities.
Biological studies
Antibacterial activity.
The title compounds that were
screened in vitro for their antibacterial activity using the
well-diffusion method [35,36] against a variety of bacterial
strains such as Gram positive bacteria [Bacillus subtilis
(ATCC-6633), Enterococcus faecalis (ATCC-700802), and
Staphylococcus aureus (ATCC-6538)] and Gram negative
bacteria [Escherichia coli (ATCC-25922) and Proteus
mirabilis (ATCC-14153)] were tested. Each test compound
Scheme 3. Reaction sequence for the synthesis of 2-(5-(substitutedphenyl)-4,5-dihydro-3-phenylpyrazol-1-yl)-6-substitutedbenzothiazoles (10–25).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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D. Munirajasekhar, M. Himaja, and S. V. Mali
Vol 51
(5 mg) was dissolved in 1 mL of dimethylformamide
(5000 mg/mL) that was used as a sample solution; the
sample size for all the compounds was fixed as 0.1 mL.
The solutions of each test compound (0.1 mL) were
added into wells in petri dishes and were subsequently
incubated at 37ꢀC. Ciprofloxacin and Gentamicin were
used as reference drugs, and dimethylformamide was used
as control. Zone of inhibition was produced by each
compound that was measured in mm. The results are
shown in Table 3.
CONCLUSION
A novel series of benzothiazole derivatives of 2-pyrazolines
(10–25) were synthesized using MW-assisted technique in
good yields and drastically reduced time. All the compounds
showed moderate to low antibacterial activity against various
strains. However, the compounds showed potent anthelmintic
activity against E. eugeniea species, especially compounds
containing fluoro-/chloro-substituent on C6 of benzothiazole
ring.
Anthelmintic activity.
Newly synthesized compounds
were subjected to anthelmintic activity studies against
earthworm species (Eudrilus eugeniea) at a concentration of
2 mg/mL using Garg’s method [37]. Tween 80 (15%
solution) in distilled water was used as a control, and
Mebendazole was used as a standard drug. Suspension of the
samples was prepared by triturating the synthesized
compounds (100 mg) with tween 80 (15% solution), and the
resulting mixtures were stirred for 30 min. The suspensions
were diluted to contain 0.2% (w/v) of the test samples. In a
similar way, a suspension of the reference drug Mebendazole
was prepared with the same concentration. Three sets of
the five earthworms of almost similar sizes (2 in. in
length) were placed in 100 mL beaker containing 50 mL
of suspension of the test sample. Another set of five
earthworms was kept as a control in 50 mL of suspension
of distilled water in tween 80 (15% solution). The
paralyzing and death times were noted and calculated for
triplicate sets. The death time was ascertained by placing
the earthworms in warm water (50ꢀC) that stimulated the
movement, if the worm was alive. The anthelmintic
study results are tabulated in Table 4.
EXPERIMENTAL
General procedures. All the melting points were determined
by open capillary tube and were uncorrected. Microwave-assisted
synthesis was carried out in a laboratory microwave oven
(catalyst systems, model: CATA-R). Purity of the synthesized
compounds was checked by TLC and column using chloroform
and ethyl acetate (90/10 V/V). The IR spectra were recorded on
Avatar 330 FTIR spectrometer equipped with DTGS detector.
The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Bruker Avance-111 300 MHz spectrometer in
CDCl3 or DMSO using TMS as internal standard, and the
chemical shifts are expressed in d ppm. MS spectra and HRMS
were recorded by JEOL AccuTOFTM mass spectrometer.
Microwave-assisted synthesis of 2-hydrazino-benzothiazoles
2–5. Conc. hydrochloric acid (2 mL) was added dropwise with
stirring to hydrazine hydrate (40 mmol, 1.94 mL) at 5ꢀC, followed
by ethylene glycol (5 mL). To this, substituted benzothiazol-amine
(10 mmol) was added in portions. The reaction mixture was
irradiated with microwaves for 5–6 min at 455 W (65% of
microwave power). Progress of the reaction was checked by TLC.
Fine crystalline solid separated out on cooling the reaction
mixture, which was filtered, washed with water, and recrystallized
from ethanol.
Table 3
Antibacterial activity of the compounds (10–25).
Escherichia coli
Enterococcus faecalis
Bacillus subtilis
Staphylococcus aureus Proteus mirabilis
Compound
R1
R2
(ATCC-25922)
(ATCC-700802)
(ATCC-6633)
(ATCC-6538)
(ATCC-6538)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
CH3
CH3
CH3
CH3
OCH3
OCH3 OCH3
OCH3 CH3
OCH3 Cl
Cl
Cl
Cl
Cl
F
H
15
19
17
21
—
—
12
9
19
—
21
—
—
9
16
—
—
19
—
6
—
7
11
—
8
—
11
11
8
—
22
16
—
17
—
21
—
—
—
—
11
—
11
13
16
15
—
—
24
18
—
18
17
—
—
—
—
—
9
—
10
11
—
13
17
19
24
13
11
14
—
17
—
11
—
—
14
—
17
14
—
8
OCH3
CH3
Cl
H
H
OCH3
CH3
Cl
H
F
F
F
OCH3
CH3
Cl
8
9
24
14
6
—
16
12
Ciprofloxacin
Gentamicin
Journal of Heterocyclic Chemistry
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A Facile and Efficient Synthesis of 2-(5-(4-Substitutedphenyl)-4, 5-dihydro-3-
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March 2014
phenylpyrazol-1-yl)-6-Substitutedbenzothiazoles and Their Biological Studies
Table 4
mixture was neutralized with diluted HCl, washed with water,
and was recrystallized from ethanol. All the products were
confirmed by comparing their melting points with literature
melting points [32].
Anthelmintic activity of the compounds (10–25).
Eudrilus eugeniea
General method for the preparation of benzothiazole-2-
pyrazolines 10–25
Mean
paralyzing
time (min)
Mean death
time (min)
Method A: conventional method. A mixture of 2-hydrazino-
benzothiazole (2–5, 5 mmol), the appropriate chalcone (6–9,
5 mmol), and n-butanol (20 mL) was refluxed for 12–18h. The
reaction mixture was allowed to stand for 8–9 h until a precipitate
was formed. The solvent was decanted, and the precipitate was
washed with petroleum ether, and it was purified by column
chromatography (chloroform/ethyl acetate 21:4), and it was
recrystallized from the ethanol to obtain pure benzothiazol-
pyrazoline compounds (10–25).
Method B: microwave method. A mixture of 2-hydrazino-
benzothiazole (2–5, 5 mmol), the appropriate chalcone (6–9,
5 mmol), and n-butanol (10 mL) was placed in the microwave
oven and was irradiated at 560 W (80% of microwave power)
for 40–45 min. The progress of the reaction was checked by
TLC. A solid product was obtained, which was washed with
petroleum ether and was purified by column chromatography
(chloroform/ethyl acetate 21: 4), and it was recrystallized from
the ethanol to obtain pure benzothiazole pyrazoline compounds
(10–25).
Compound
R1
R2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
CH3
CH3
CH3
CH3
OCH3
OCH3 OCH3
OCH3 CH3
OCH3 Cl
Cl
Cl
Cl
Cl
F
H
12.04 Æ 0.24
9.56 Æ 0.47
10.24 Æ 0.23
12.36 Æ 0.52
9.16 Æ 0.45
10.14 Æ 0.41
9.46 Æ 0.51
8.46 Æ 0.23
9.52 Æ 0.51
16.17 Æ 0.21
9.32 Æ 0.34
11.32 Æ 0.24
9.16 Æ 0.42
9.34 Æ 0.14
8.14 Æ 0.31
8.56 Æ 0.34
7.40 Æ 0.43
13.20 Æ 0.37
10.14 Æ 0.32
11.12 Æ 0.28
13.12 Æ 0.47
10.54 Æ 0.38
11.46 Æ 0.39
10.17 Æ 0.37
9.52 Æ 0.28
11.34 Æ 0.32
18.34 Æ 0.37
11.34 Æ 0.23
12.14 Æ 0.56
9.54 Æ 0.21
10.17 Æ 0.39
8.51 Æ 0.23
9.24 Æ 0.37
8.54 Æ 0.12
OCH3
CH3
Cl
H
H
OCH3
CH3
Cl
H
F
F
F
OCH3
CH3
Cl
Mebendazole
2-(4,5-Dihydro-3,5-diphenylpyrazol-1-yl)-6-methylbenzo[d]
thiazole (10). Red crystals (yield 88.4%), mp 158–160ꢀC; IR
v (KBr): 3024, 2918, 1601, 1539, 1454, 1383, 1237, 1123,
1-(6-Methylbenzo[d]thiazol-2-yl) hydrazine (2). Red color
needles, (yield 99.2%), mp 198–200ꢀC; IR v (KBr): 3320,
3200, 3063, 2961, 1650, 1303, 1468, 1256, 976, 814,
1026, 832, 757 cmÀ1 1H NMR (300 MHz) (CDCl3): d 2.394
;
(s, 3H, Me), 3.31 (dd, 1H, J1 = 5.4, J2 = 12.0 Hz, 4-Htrans),
3.94 (dd, 1H, J1 = 12.30, J2 = 17.10 Hz, 4-Hcis), 5.81 (dd, 1H,
J1 = 5.10, J2 = 12.0 Hz, 5-H), 7.04–7.79 (m, 13arom. H); 13C
NMR (75 MHz) (CDCl3): d 21.5, 44.0, 64.0, 119.9, 121.1,
126.3, 126.8, 127.1, 128.1, 129.0, 129.2, 130.34, 131.6,
131.9, 141.6, 150.7, 152.6 (C═N of pyrazoline ring), 163.1
(C═N of benzothiazole ring); HRMS Calcd for C23H19N3S
369.4821 found 369.4820. Anal. Calcd for C23H19N3S:
C, 74.77; H, 5.18; N, 11.37%. Found: C, 74.71; H, 5.14;
N, 11.32%.
1
747 cmÀ1; H NMR (300 MHz) (DMSO): d 2.289 (s, 3H, Me),
4.948 (s, 2H, NH2), 6.974–7.452 (m, 3H, Ar-H), 8.857 (s, 1H,
NH); MS: ES + 180.1 (M + 1). Anal. Calcd for C8H9N3S: C,
53.61; H, 5.06; N, 23.44%. Found: C, 53.72; H, 5.17; N, 23.87%.
1-(6-Methoxybenzo[d]thiazol-2-yl) hydrazine (3).
color sponge, (yield 97.3%), mp 192–194ꢀC; IR v (KBr): 3350,
3120, 2862, 1627, 1471, 1326, 1260, 970, 819, 798 cmÀ1 1H
Red
;
NMR (300 MHz) (CDCl3): d 3.8419 (s, 3H, OCH3), 4.2205 (s,
2H, NH2), 6.9045–7.404 (m, 3H, Ar-H), 7.4696 (s, 1H, NH);
MS: ES + 196.1 (M + 1). Anal. Calcd for C8H9N3OS: C, 49.21;
H, 4.65; N, 21.52%. Found: C, 49.63; H, 4.83; N, 22.81%.
2-(4,5-Dihydro-5-(4-methoxyphenyl)-3-phenylpyrazol-1-yl)-
6-methylbenzo[d]thiazole (11).
(yield 87.1%), mp 131–132ꢀC; IR v (KBr): 2917, 1606,
1572, 1539, 1457, 1243, 1176, 1131, 1030, 826 cmÀ1 1H
NMR (300 MHz) (CDCl3): 2.376 (s, 3H, Me), 3.28
Light yellow color powder
1-(6-Chlorobenzo[d]thiazol-2-yl) hydrazine (4).
color needles, (yield 98.1%), mp 196–198ꢀC; IR v (KBr): 3320,
3199, 3061, 1649, 1447, 1267, 976, 705, 766 cmÀ1 1H NMR
White
;
;
d
(300 MHz) (DMSO): d 5.090 (s, 2H, NH2), 7.202–7.295 (m,
3H, Ar-H), 9.155 (s, 1H, NH); LC-MS: m/z 200.2 (M + 1).
Anal. Calcd for C7H6ClN3S: C, 42.11; H, 3.03; N, 21.05%.
Found: C, 42.37; H, 3.23; N, 21.17%.
(dd, 1H, J1 = 5.1, J2 = 12.3 Hz, 4-Htrans), 3.754 (s, 3H, OCH3 ),
3.9 (dd, 1H, J1 = 12.0, J2 = 17.4 Hz, 4-Hcis), 5.74 (dd, 1H,
J1 = 5.1, J2 = 11.7 Hz, 5-H), 6.82–7.78 ( m, 12arom. H); 13C
NMR (75 MHz) (CDCl3): d 21.6, 44.0, 55.6, 63.6, 114.5,
120.0, 121.1, 126.8, 127.1, 127.6, 129.0, 130.2, 131.9, 133.8,
150.8, 152.5 (C═N of pyrazoline ring), 159.4, 163.0 (C═N of
benzothiazole ring); HRMS Calcd for C24H21N3OS 399.5080
found 399.5079. Anal. Calcd for C24H21N3OS: C, 72.15; H,
5.30; N, 10.52%. Found: C, 72.13; H, 5.27; N, 10.49%.
1-(6-Fluorobenzo[d]thiazol-2-yl) hydrazine (5).
color needles, (yield 97.4%), mp 204–206ꢀC; IR v (KBr): 3321,
3202, 3072, 2966, 1650, 1460, 1264, 979, 817, 750 cmÀ1 1H
White
;
NMR (300 MHz) (DMSO): d 5.026 (s, 2H, NH2), 6.974–7.598
(m, 3H, Ar-H), 9.003(s, 1H, NH); MS: ES + 184.0 (M + 1).
Anal. Calcd for C7H6FN3S: C, 45.89; H, 3.30; N, 22.94%.
Found: C, 43.14; H, 3.57; N, 23.07%.
2-(4,5-Dihydro-3-phenyl-5-p-tolylpyrazol-1-yl)-6-methylbenzo
[d]thiazole (12). Light orange color powder, (yield 84.3%), mp
146–148ꢀC; IR v (KBr): 2921, 1606, 1571, 1539, 1456, 1277,
Microwave-assisted method for the preparation of
chalcones.
Substituted aldehyde (5 mmol) and acetophenone
1237, 1137, 839 cmÀ1 1H NMR (300 MHz) (CDCl3): d 2.294
;
(s, 3H, Me), 2.375 (s, 3H, Me), 3.28 (dd, 1H, J1 =5.1,
J2 = 12.3 Hz, 4-Htrans), 3.91 (dd, 1H, J1 = 12.0, J2 = 17.4 Hz, 4-Hcis),
5.76 (dd, 1H, J1 =5.4, J2 = 11.7 Hz, 5-H), 7.03–7.77 (m, 12arom.
H); 13C NMR (75 MHz) (CDCl3): d 21.5, 21.6, 44.0, 63.8, 120.0,
121.1, 126.2, 126.8, 127.1, 129.0, 129.9, 130.2, 131.7, 131.9,
(5 mmol) were placed in a beaker, and 2 mL of ethanol and
2 mL of 40% KOH solution were added to the mixture. The
reaction mixture was placed in the microwave oven and was
irradiated at 245 W (35% microwave power) for 2–3 min.
Progress of the reaction was checked by TLC. The reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

464
D. Munirajasekhar, M. Himaja, and S. V. Mali
Vol 51
132.1, 137.7, 138.7, 150.8, 152.5 (C═N of pyrazoline ring), 163.0,
(C═N of benzothiazole ring); HRMS Calcd for C24H21N3S
383.5086 found 383.5083. Anal. Calcd for C24H21N3S: C, 75.16;
H, 5.52; N, 10.96%. Found: C, 75.28; H, 5.59; N, 10.98%.
2-(5-(4-Chlorophenyl)-4,5-dihydro-3-phenylpyrazol-1-yl)-6-
methylbenzo[d]thiazole(13). Red color crystals, (yield 85.7%),
mp 210–212ꢀC; IR v (KBr): 2917, 1605, 1573, 1540, 1487, 1405,
1327, 1277, 1241, 1138, 1083, 1007, 892cmÀ1 1H NMR
(300 MHz) (CDCl3): d 2.380 (s, 3H, Me), 3.25 (dd, 1H, J1 =5.4,
J2 = 12.0 Hz, 4-Htrans), 3.92 (dd, 1H, J1 =12.0, J2 = 17.4 Hz, 4-Hcis),
105.5, 113.8, 120.8, 126.8, 127.9, 129.1, 129.4, 130.4, 131.4, 133.1,
133.8, 140.2, 147.0, 152.2 (C═N of pyrazoline ring), 155.8,
162.0 (C═N of benzothiazole ring); HRMS Calcd for
C23H18ClN3OS 419.9265 found 419.9264. Anal. Calcd for
C23H18ClN3OS: C, 65.78; H, 4.32; N, 10.01%. Found: C,
65.80; H, 4.34; N, 10.08%.
6-Chloro-2-(4,5-dihydro-3,5-diphenylpyrazol-1-yl)benzo[d]
thiazole (18). Red color powder, (yield 73.2%), mp 165–167ꢀC;
IR v (KBr): 3056, 2929, 1600, 1537, 1493, 1437, 1327, 1271, 1132,
1085, 1029, 861 cmÀ1 1H NMR (300MHz) (CDCl3): d 3.34
.
5.75 (dd, 1H, J1 =5.4, J2 = 12.0 Hz, 5-H), 7.04–7.76 (m, 12arom.
(dd, 1H, J1 = 5.4, J2 = 17.7 Hz, 4-Htrans), 3.95 (dd, 1H, J1 = 11.7,
J2 = 17.7 Hz, 4-Hcis), 5.78 (dd, 1H, J1 = 5.1, J2 = 11.2 Hz, 5-H),
7.718–7.795 (m, 13arom. H); 13C NMR (75 MHz) (CDCl3):
d 43.8, 63.7, 120.4, 120.7, 125.9, 126.0, 126.5, 12.0, 127.9,
128.7, 128.9, 130.2, 131.0, 133.0, 141.0, 151.2, 153.0 (C═N of
pyrazoline ring), 163.4 (C═N of benzothiazole ring); HRMS
Calcd for C22H16ClN3S 389.9005 found 389.9002. Anal. Calcd
for C22H16ClN3S: C, 67.77; H, 4.14; N, 10.78%. Found: C,
67.83; H, 4.19; N, 10.84%.
6-Chloro-2-(4,5-dihydro-5-(4-methoxyphenyl)-3-phenylpyrazol-
1-yl)benzo[d]thiazole (19). White color powder, yield (76.4%),
mp 156–158ꢀC; IR v (KBr): 2920, 1600, 1534, 1438, 1327, 1286,
1240, 1170, 1124, 1029, 910 cmÀ1. 1H NMR (300MHz) (CDCl3):
d 3.31 (dd, 1H, J1 =5.4, J2 = 17.7 Hz, 4-Htrans), 3.778 (3H, s,
OMe), 3.93 (dd, 1H, J1 =11.7, J2 = 17.4 Hz, 4-Hcis), 5.73 (dd, 1H,
J1 =5.4, J2 = 11.7 Hz, 5-H), 6.8497–7.798 (m, 12arom. H); HRMS
Calcd for C23H18ClN3OS 419.9265 found 419.9237. Anal. Calcd
for C23H18ClN3OS: C, 65.78; H, 4.32; N, 10.01%. Found: C,
65.92; H, 4.49; N, 10.28%.
13
H);
C NMR (75 MHz) (CDCl3 +DMSO): d 21.5, 43.8, 63.3,
119.9, 121.1, 126.7, 127.1, 127.8, 129.0, 129.3, 130.4, 131.2,
132.0, 133.7, 140.2, 152.5 (C═N of pyrazoline ring), 163.1 (C═N
of benzothiazole ring); HRMS Calcd for C23H18ClN3S 403.9271
found 403.9270. Anal. Calcd for C23H18ClN3S: C, 68.39; H, 4.49;
N, 10.40%. Found: C, 68.74; H, 4.56; N, 10.67%.
2-(4,5-Dihydro-3,5-diphenylpyrazol-1-yl)-6-methoxybenzo[d]
thiazole (14).
162–164ꢀC; IR v (KBr): 3053, 2920, 2826, 1604, 1537, 1459,
1322, 1265, 1209, 1132, 1064, 1026, 900cmÀ1 1H NMR
Dark yellow color powder, (yield 79.6%), mp
;
(300MHz) (CDCl3): d 3.27 (dd, 1H, J1 = 5.7, J2 = 12Hz, 4-Htrans),
3.824 (s, 3H, OCH3 ), 3.92 (dd, 1H, J1 = 12, J2 = 17.4 Hz, 4-Hcis),
5.77 (dd, 1H, J1 = 5.4, J2 = 12Hz, 5-H), 6.82–7.76 (m, 12arom.
H); 13C NMR (75 MHz) (CDCl3): d 44.0, 56.2, 64.1, 105.4,
113.7, 120.8, 126.3, 126.7, 128.1, 129.0, 130.2, 131.6, 133.1,
141.7, 147.1, 152.3 (C═N of pyrazoline ring), 155.7, 162.1
(C═N of benzothiazole ring); HRMS Calcd for C23H19N3OS
385.4815 found 385.4812. Anal. Calcd for C23H19N3OS: C,
71.66; H, 4.97; N, 10.90%. Found: C, 71.88; H, 5.23; N, 10.96%.
2-(4,5-Dihydro-5-(4-methoxyphenyl)-3-phenylpyrazol-1-yl)-
6-methoxybenzo[d]thiazole (15). Green color powder, (yield
77.4%), mp 126–128ꢀC; IR v (KBr): 3051, 2924, 2823, 1605,
6-Chloro-2-(4,5-dihydro-3-phenyl-5-p-tolylpyrazol-1-yl)benzo
[d]thiazole(20).
174–176ꢀC; IR v (KBr): 3051, 2921, 1597, 1535, 1495, 1435,
1327, 1269, 1225, 1128, 1086, 1033, 859 cmÀ1 1H NMR
Orange color powder, (yield 84.8%), mp
;
1
1536, 1460, 1382, 1328, 1259, 1173, 1108, 1026, 963 cmÀ1; H
(300 MHz) (CDCl3): d 2.337 (s, 3H, Me), 3.33 (dd, 1H, J1 = 5.0,
J2 = 12.5 Hz, 4-Htrans), 3.95 (dd, 1H, J1 = 11.5, J2 = 17.5 Hz, 4-
Hcis), 5.76 (dd, 1H, J1 = 5.5, J2 = 12.0 Hz, 5-H), 7.15–7.803
(m, 12arom. H); HRMS Calcd for C23H18ClN3S 403.9271
found 403.9271. Anal. Calcd for C23H18ClN3S: C, 68.39; H,
4.49; N, 10.40%. Found: C, 68.46; H, 4.54; N, 10.45%.
NMR (300 MHz) (CDCl3): d 3.27 (dd, 1H, J1 = 3.9, J2 = 9.6 Hz,
4-Htrans), 3.719 (s, 3H, OCH3), 4.04 (dd, 1H, J1 = 9.0,
J2 = 13.5 Hz, 4-Hcis), 5.72 (dd, 1H, J1 = 3.9, J2 = 9.0 Hz, 5-H),
6.84–7.80 (m, 12arom. H); 13C NMR (75 MHz) (CDCl3):
d 44.0, 55.6, 56.2, 63.6, 105.4, 113.7, 114.5, 120.8, 126.7,
127.7, 129.0, 130.2, 131.7, 133.1, 133.8, 147.2, 152.3 (C═N
of pyrazoline ring), 155.7, 159.4, 162.1 (C═N of benzothiazole
ring); HRMS Calcd for C24H21N3O2S 415.5074 found
415.5073. Anal. Calcd for C23H19N3OS: C, 69.37; H, 5.09; N,
10.11%. Found: C, 69.45; H, 5.29; N, 10.68%.
6-Chloro-2-(5-(4-chlorophenyl)-4,5-dihydro-3-phenylpyrazol-
1-yl)benzo[d]thiazole(21). White color powder, (yield 89.3%),
mp 230–232ꢀC; IR v (KBr): 3039, 2917, 1598, 1536, 1485,
1
1436, 1405, 1327, 1270, 1245, 1133, 1088, 1029, 992 cmÀ1; H
NMR (300 MHz) (CDCl3): d 3.29(dd, 1H, J1 = 5.7, J2 = 14.1 Hz,
4-Htrans), 3.95 (dd, 1H, J1 = 12.3, J2 = 17.1 Hz, 4-Hcis), 5.75
(dd, 1H, J1 = 5.1, J2 = 12.3 Hz, 5-H), 6.918–7.757 (m,12arom.
H); HRMS Calcd for C22H15Cl2N3S 424.3456 found 424.355.
Anal. Calcd for C22H15Cl2N3S: C, 62.27; H, 3.56; N, 9.90%.
Found: C, 62.39; H, 3.68; N, 9.98%.
2-(4,5-Dihydro-3-phenyl-5-p-tolylpyrazol-1-yl)-6-methoxybenzo
[d]thiazole (16).
Green color sponge, yield (76.7%), mp
154–156ꢀC; IR v (KBr): 2913, 1607, 1540, 1463, 1384, 1329,
1271, 1206, 1115, 1056, 1021, 842cmÀ1; H NMR (300MHz)
1
(CDCl3): d 2.29 (s, 3H, CH3), 3.27 (dd, 1H, J1 = 5.4, J2 = 17.4Hz,
4-Htrans), 3.808 (3H, s, OMe), 3.90 (dd, 1H, J1 = 12, J2 = 17.4 Hz,
4-Hcis), 5.73 (dd, 1H, J1 = 5.4, J2 = 12Hz, 5-H), 6.81–7.76
(m, 12arom. H); HRMS Calcd for C24H21N3OS 399.5080 found
399.5080. Anal. Calcd for C24H21N3OS: C, 72.15; H, 5.30; N,
10.52%. Found: C, 72.37; H, 5.52; N, 10.74%.
6-Fluoro-2-(4,5-dihydro-3,5-diphenylpyrazol-1-yl)benzo[d]
thiazole(22). White color sponge, yield (91.2%), mp 170–172ꢀC;
IR v (KBr): 2920, 1606, 1548, 1491, 1452, 1323, 1296, 1245, 1191,
1128, 1031, 847cmÀ1 1H NMR (300 MHz) (CDCl3): d 3.33
;
(dd, 1H , J1 = 5.4, J2 = 72.9Hz, 4-Htrans), 3.96 (dd, 1H, J1 = 12.0,
J2 = 17.4Hz, 4-Hcis), 5.78 (dd, 1H, J1 = 5.4, J2 = 12.0Hz, 5-H),
6.932–7.793 (m, 13arom. H); 13C NMR (75 MHz) (CDCl3):
d 44.1, 64.0, 107.6, 107.9, 113.4, 113.8, 120.7, 120.9, 126.3,
126.8, 128.2, 129.1, 129.3, 130.5, 131.4, 132.9, 141.5, 149.3,
153.0 (C═N of pyrazoline ring), 157.2, 160.3, 163.2 (C═N of
benzothiazole ring); HRMS Calcd for C22H16FN3S 373.4459
found 373.4718. Anal. Calcd for C22H16FN3S: C, 70.76; H,
4.32; N, 11.25%. Found: C, 70.85; H, 4.47; N, 11.33%.
2-(5-(4-Chlorophenyl)-4, 5-dihydro-3-phenylpyrazol-1-yl)-6-
methoxybenzo[d]thiazole (17).
Yellow color powder, (yield
71.8%), mp 164–166ꢀC; IR v (KBr): 2925, 1609, 1576, 1545,
1462, 1328, 1267, 1208, 1137, 1070, 1012, 838 cmÀ1. H NMR
1
(300 MHz) (CDCl3): d 3.27 (dd, 1H, J1 =5.7, J2 = 17.4 Hz, 4-Htrans),
3.825 (s, 3H, OMe), 3.94 (dd, 1H, J1 = 12.0, J2 = 17.7 Hz, 4-Hcis),
5.74 (dd, 1H, J1 = 5.7, J2 = 11.7 Hz, 5-H), 6.84–7.78
(m, 12arom. H); 13C NMR (75 MHz) (CDCl3): d 43.9, 56.2, 63.5,
Journal of Heterocyclic Chemistry
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465
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phenylpyrazol-1-yl)-6-Substitutedbenzothiazoles and Their Biological Studies
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6-Fluoro-2-(4,5-dihydro-5-(4-methoxyphenyl)-3-phenylpyrazol-
1-yl)benzo[d]thiazole(23).
89.8%), mp 162–164ꢀC; IR v (KBr): 3066, 2923, 1609, 1546,
1507, 1454, 1383, 1295, 1244, 1173, 1111, 1030, 849, 808 cmÀ1
1H NMR (300 MHz) (CDCl3):
3.31 (dd, 1H, J1 =6.9,
Light orange color powder, (yield
.
d
J2 = 30.3 Hz, 4-Htrans), 3.778 (s, 3H, OMe), 3.92 (dd, 1H, J1 =12.0,
J2 = 17.4 Hz, 4-Hcis), 5.73 (dd, 1H, J1 =5.1, J2 = 12.0 Hz, 5-H),
6.851–7.796 (12arom. H); 13C NMR (75 MHz) (CDCl3): d 44.1,
55.6, 63.6, 107.6, 107.9, 113.4, 113.7, 114.6, 120.7, 120.8, 126.8,
127.7, 129.1, 130.4, 131.5, 132.8, 132.9, 133.6, 149.4, 153.0
(C═N of pyrazoline ring), 157.2, 159.5, 160.3, 163.2 (C═N of
benzothiazole ring); HRMS Calcd for C23H18FN3OS 403.4719
found 403.4719. Anal. Calcd for C23H18FN3OS: C, 68.47; H, 4.50;
N, 10.41%. Found: C, 68.56; H, 4.54; N, 10.47%.
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6-Fluoro-2-(4,5-dihydro-3-phenyl-5-p-tolylpyrazol-1-yl)benzo
[d]thiazole(24). Orange color powder, (yield 90.7%), mp 156–
158ꢀC; IR v (KBr): 3055, 2919, 1606, 1548, 1499, 1450, 1328,
[17] Gurupadayya, B. M.; Gopal, M.; Padmashali, B.; Vaidya, V. P.
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Schwaiger, M.; Drzega, A.; Wester, H. J. J Med Chem 2007, 50, 1087.
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M. L.; Klunk, W. E. J Med Chem 2003, 46, 2740.
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1
1276, 1239, 1185, 1128, 1031, 967cmÀ1; H NMR (300MHz)
(CDCl3): d 2.326 (s, 3H, Me), 3.31 (dd, 1H, J1 = 5.4, J2 = 17.4 Hz,
4-Htrans), 3.93 (dd, 1H, J1 = 12.0, J2 = 17.4Hz, 4-Hcis), 5.74
(dd, 1H, J1 = 5.4, J2 = 11.7Hz, 5-H), 6.931–7.791 (m, 12arom. H);
HRMS Calcd for C23H18FN3S 387.4725 found 387.4725. Anal.
Calcd for C23H18FN3S: C, 71.29; H, 4.68; N, 10.84%. Found: C,
71.33; H, 4.71; N, 11.08%.
2-(5-(4-Chlorophenyl)-4,5-dihydro-3-phenylpyrazol-1-yl)-6-
fluorobenzo[d]thiazole(25).
Light orange color powder,
(yield 91.8%), mp 200–202ꢀC; IR v (KBr): 3068, 2918, 1607,
1551, 1488, 1453, 1408, 1329, 1270, 1243, 1189, 1134, 1083,
1008, 852 cmÀ1
;
1H NMR (300 MHz) (CDCl3): d 3.30
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D.; Chimenti, P.; Ferlini, C.; Scambia, G. Bioorg Med Chem Lett 2005,
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(dd, 1H, J1 = 3.6, J2 = 10.5 Hz, 4-Htrans), 3.98 (dd, 1H, J1 = 7.2,
J2 = 10.5 Hz, 4-Hcis), 5.76 (dd, 1H, J1 = 3.3, J2 = 7.2 Hz, 5-H),
6.979–7.797 (m, 13arom. H); HRMS Calcd for
C22H15ClFN3S 407.8910 found 407.8909. Anal. Calcd for
C22H15ClFN3S: C, 64.78; H, 3.71; N, 10.30%. Found: C,
64.92; H, 3.87; N, 10.34%.
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Acknowledgments. The authors are highly thankful to VIT
University, Vellore, for the financial support and facilities.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet