Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives

Article abstract of DOI:10.1002/jhet.2786

A novel series of imidazolone fused pyrazolo[1,5-a]pyrimidine derivatives has been designed and synthesized using a convergent approach, and the structures of these compounds were confirmed by ¹H NMR, ¹³C NMR, ESI-MS, and IR analyses. These new compounds were tested for their in vitro antiproliferative activity using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Out of the 20 derivatives prepared in the current study, compounds 8h, 8n, and 8r exhibited good anticancer activities tested against HeLa cells and HepG₂ cells. However, the in vitro anticancer activity of compound 8r against HeLa, HepG₂, and MCF-7 cell lines is superior to the marketed drugs Paclitaxel and SAHA.

Full text of DOI:10.1002/jhet.2786

Month 2016 Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel
Series of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
a
b
a
a
c
Ajeesh Kumar A.K., * Yadav D. Bodke, Ashwath N. Gowda, Ganesh Sambasivam, and Kishore G. Bhat
a
Anthem Biosciences Pvt. Ltd., #49 Bommasandra Industrial Area, Bangalore 560 099, Karnataka, India
b
Department of PG Studies and Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu University,
Shankaraghatta, Shimoga, Karnataka 577 451, India
Department of Microbiology, Maratha Mandal’s NGH Institute of Dental Sciences & Research Centre, Belgaum,
c
Karnataka 590 010, India
E-mail: ajuedat@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received July 21, 2016
DOI 10.1002/jhet.2786
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of imidazolone fused pyrazolo[1,5-a]pyrimidine derivatives has been designed and synthe-
1
13
sized using a convergent approach, and the structures of these compounds were confirmed by H NMR,
C
NMR, ESI-MS, and IR analyses. These new compounds were tested for their in vitro antiproliferative
activity using an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Out of the
2
0 derivatives prepared in the current study, compounds 8h, 8n, and 8r exhibited good anticancer activities
tested against HeLa cells and HepG cells. However, the in vitro anticancer activity of compound 8r against
2
2
HeLa, HepG , and MCF-7 cell lines is superior to the marketed drugs Paclitaxel and SAHA.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
depressant [8], antihypertensive [9], antileishmanial [10],
and antimicrobial activities [11].
Pyrazolo[1,5-a]pyrimidines and related heterocyclic
compounds can be found in a wide range of interesting
compounds with applications in numerous fields, including
medicine and agriculture [1–3]. Pyrazolo[1,5-a]pyrimidine
derivatives have been reported to possess a diverse range
of pharmacological activities, as well as being able to
mimic the structural characteristic of biogenic purines,
making them potential drug candidates [4,5]. Pyrazolo[1,5-
a]pyrimidines are also bioisosteres for triazolothie
Substituted imidazolones have been reported to exhibit
a wide range of interesting pharmacological activities
[12–14], making those excellent substrates for diversity
oriented synthesis. Amongst the many substituted
imidazolones reported in the literature, several have been
used as intermediates for the preparation of polymers and
agrochemicals, while others have been used as biotin
antagonists in biological systems that are capable of
inhibiting the growth of malignant tumors [15,16].
nopyrimidines,
imidazoquinazolines,
pyrimido
Furthermore,
compounds
containing
imidazolone
quinazolines, and imidazoquinolinones, all of which have
shown reported to exhibit good anticancer activity.
Furthermore, pyrazolo[1,5-a]pyrimidines have been
reported to show tuberculostatic [6], neuroleptic [7], CNS
chromophores have been reported to possess a broad range
of biological properties, including anticancer, cardio, anti-
inflammatory, and angiotensin II receptor antagonistic
activities [17]. Trisubstituted imidazolones induce a high
©
2016 Wiley Periodicals, Inc.

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
level of apoptosis in human leukemia cells, as well as
exhibiting pronounced cytotoxicity [18,19]. Furthermore,
trisubstituted imidazolones possess antipyretic and
analgesic properties [20]. Based on their pharmacological
importance, significant research efforts have been directed
towards the development of synthetic strategies for the
preparation of imidazolones using solution and solid phase
techniques.
consecutive sequences via a divergent approach. The first
of these three sequences involved the synthesis of a 5,7-
Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide
derivative, as shown in Scheme 1. Ethyl 5-amino-1H-
pyrazole-4-carboxylate (2) was previously synthesized via
a two-step protocol [29,30]. However, we have developed
a one-pot process for the preparation of this material by
reacting commercially available ethyl cyanoacetate (1)
with dimethylformamide dimethyl acetal and hydrazine
hydrate in acetic acid under gentle heating with
dimethylformamide as a solvent. The subsequent reaction
of compound 2 with acetylacetone in acetic acid at 82°C
gave ethyl 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-
carboxylate (3) in good yield [31]. The treatment of ester 3
with hydrazine hydrate in ethanol at 72°C for 7h gave the
5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide
derivative 4 [32].
The second sequence in the synthesis of the imidazolone
fused pyrazolo[1,5-a]pyrimidine derivatives involved the
synthesis of a series of aryl substituted oxazolones in two
steps, as shown in Scheme 2. The hippuric acid
derivatives 6a–e was obtained by the treatment of the
corresponding acid chlorides 5a–e with glycine in the
presence of an aqueous sodium hydroxide solution at
room temperature [33,34]. The hippuric acid derivatives
6a–e were subsequently treated with a variety of different
substituted aldehydes in the presence of acetic anhydride
and sodium acetate at 80°C, in accordance with the
previously reported Erlenmeyer–Plochl reaction, to give
the corresponding oxazolones 7a–t [27,35].
Imidazolone derivatives are usually prepared from the
corresponding oxazolones [21]. Oxazolones themselves
have been used as important synthons for the synthesis of
several organic molecules, including amino acids, dyes,
and drugs [22–24], as well as many biologically active
drug compounds, including analgesic, anti-inflammatory,
anti-depressant, anticancer, anti-microbial, anti-diabetic,
and anti-obesity agents [25–27]. The chemistry of 5-(4)-
oxazolones has been reviewed in detail by Carter [28].
Islam et al. [21] reported their work towards the synthesis
of imidazolones via the reaction of the corresponding
oxazolones with an appropriate primary amine under a
variety of different experimental conditions. Amongst the
many compounds synthesized in this way, imidazolone
rings containing a pyrazolo[1,5-a]pyrimidine moiety have
been identified as attractive scaffolds for the development
of anticancer agents because of their strong hydrogen bond
donor and acceptor abilities, which could form strong
interactions to the active sites of their target proteins. To
the best of our knowledge, there have been no reports in
the literature pertaining to the biological activities of
imidazolone fused pyrazolo[1,5-a]pyrimidine derivatives.
Inspired by these findings, we report herein our recent
work towards the synthesis and evaluation of the
anticancer properties of a series of imidazolone fused
pyrazolo[1,5-a]pyrimidine derivatives. The design strategy
used for the preparation of these compounds is shown in
Figure 1 using compound 8r as a representative example.
The third sequence in the synthesis of the target
compounds involved the synthesis of imidazolones 8a–t,
as shown in Scheme 3. Our initial trial reactions were
based on reports from the literature and involved (i) the
use of a copper catalyst at elevated temperatures [36], (ii)
the fusing of both intermediates at elevated temperatures
[37], (iii) the heating of the reaction mixture with
pyridine at 115°C for 6h [38], and (iv) the heating of the
reaction mixture with DMF at 115°C [39] to allow for
the coupling of intermediate 4 with the oxazolones 7.
However, all of these efforts resulted in a low conversion
to the required product. Pleasingly, the reaction gave the
desired product in a much higher yield when it was
conducted in acetic acid at reflux [40]. Thus, the final
target compounds 8a–t were synthesized in good yields
by the reaction of intermediates 4 with oxazolones 7a–t
in refluxing acetic acid for a minimum of 6 h.
RESULTS AND DISCUSSION
Chemistry.
The imidazolone fused pyrazolo[1,5-a]
pyrimidine derivatives were synthesized over three
The structure of ethyl 5-amino-1H-pyrazole-4-
carboxylate (2) was confirmed by a series of spectral
studies. Fourier transform infrared (FTIR) analysis showed
ꢀ
1
a broad peak at 3193.8 cm , which was attributed to the
stretching of the ꢀNH of the pyrazole ring. Two other
ꢀ
1
peaks were also observed at 1615.9 and 1337.6 cm
,
Figure 1. Chemical structure of compound 8r which showed good anti-
proliferative activity.
which were attributed to N–H bending and C–N stretching
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
Scheme 1. Synthetic route to synthesize compound 4.
Scheme 2. Synthetic route to synthesize compounds (7a–t).
Scheme 3. Synthetic route to synthesize compounds (8a–t).
1
vibrations, respectively. The H NMR spectrum of 2
contained a singlet with a chemical shift of 7.45 ppm,
which was consistent with the proton of the pyrazole ring.
A broad singlet was also observed with a chemical shift of
contained a signal at 162.13 ppm, which was consistent
with the bridging carbon of the pyrazole pyrimidine ring.
LC-MS analysis of compound 3 gave a molecular ion peak
with an m/z value of 220.7 for [M + H], which was
consistent with the molecular formula C H N O . The
1
1.84 ppm, which was consistent with the ꢀNH proton of
1
1 13 3 2
13
1
the pyrazole ring. The C NMR spectrum of 2 contained
three signals at 94.00, 139.93, and 151.86 ppm, which
were consistent with the aromatic carbons of the pyrazole
ring. The structure of compound 2 was further confirmed
by mass spectrometry, which gave a molecular ion peak
with an m/z value of 156.7 for [M +H], which was
consistent the molecular formula C H N O . The structure
structure of compound 4 was determined by IR, H NMR,
1
3
C NMR, and LC-MS analyses. The IR spectrum showed
ꢀ
1
peaks at 3054.8 and 2920.8 cm , which were attributed to
the ꢀNH stretching vibrations of the amine and amide
1
functionalities of the hydrazide group. The H NMR
spectrum of compound 4 contained a broad singlet with a
chemical shift of 8.89 ppm, which was consistent with the
6
9 3 2
1
13
1
of compound 3 was confirmed by IR, H NMR, C NMR,
and LC-MS analyses. The FTIR spectrum of 3 contained a
broad band at 3193.8 cm , which was attributed to the
NH stretching vibration of the pyrazole ring. Two other
peaks were observed at 1615.9 and 1337.6 cm for the N–
H bending and C–N stretching vibrations, respectively.
The H NMR spectrum of compound 3 contained a singlet
amide proton. The H NMR spectrum also contained
doublet with a chemical shift of 4.50 ppm, which was
consistent with the amine group of the carbohydrazide.
The structure of compound 4 was further confirmed by
mass spectrometry, which gave a molecular ion peak with
an m/z value of 206.6 for [M+ H], which was consistent
ꢀ
1
ꢀ
ꢀ
1
1
13
with the molecular formula C H N O. The C NMR
9
11 5
with a chemical shift of 7.12ppm, which was consistent
with the proton of the pyrimidine ring, and a singlet with a
chemical shift of 8.53 ppm, which was consistent with the
spectrum of compound 4 contained a signal at 162.34 ppm,
which was consistent with the carbonyl group of the
13
hydrazide moiety. The C NMR spectrum also contained
a peak at 161.97 ppm, which was consistent with the
1
3
proton of the pyrazole ring. The C NMR spectrum of 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
presence of the fused carbon in the pyrazolo[1,5-a]
pyrimidine ring.
The structures of compounds 7a–t were confirmed by
spectroscopic analysis. The IR spectra of compounds 7a–t
contained only one peak for the stretching vibration of a
C¼O group, while the hippuric acid molecules from which
they were prepared contained two carbonyl stretching
The formation of acid derivatives 6a–e from the
corresponding acid chlorides 5a–e was confirmed by
1
spectroscopic analysis. The H NMR spectra of these
1
compounds all contained a doublet signal in the range of
vibrations. The H NMR spectra of compounds 7a–t all
3
.90–3.99 ppm, which suggested that these compounds
contained a singlet in the range of 7.17–7.6 ppm, which
was attributed to the proton on the exocyclic olefin group
of their oxazolone ring. The structures of these compounds
contained an ꢀNH –CH -moiety in their structure. The
2
LC-MS analysis of these compounds gave mass ions that
were consistent with their molecular formulae. The IR
spectra of compounds 6a–e revealed the presence of two
stretching vibrations for their carbonyl C¼O groups. The
13
were further confirmed by LC-MS analysis. The C NMR
spectra of these compounds showed two signals in the
range of 130–135 ppm, which were consistent with the
exocyclic carbons of the benzylidine portion of their
13
C NMR spectra of all of these compounds contained a
13
signal in the range of 41.6–41.8 ppm, which was
oxazolone ring. The C NMR spectra also contained a
signal in the range of 163–165ppm, which was consistent
the bridging carbon between oxygen and the nitrogen atoms
(i.e.,ꢀO–C¼N) of the oxazolone ring. The physicochemical
characteristics of these newly synthesized oxazolone
compounds are shown in Table 1.
consistent with the formation of an ꢀNH–CH -moiety in
2
1
3
their structure. Furthermore, the C NMR spectra of all
of these compounds contained two signals in the range of
1
66–172ppm, which were consistent with the presence of
two carbonyl groups.
Table 1
Physicochemical characteristics of compounds (7a–t).
a
Compound
R1
R2
MF/M. Wt
Yield (%)
80
MP (°C)
7a
C
17
H12FNO
3
/297.28
204.2–205.1
172.0–173.6
7b
C19H17NO3/307.35
76
7c
7d
7e
C
18
H
15NO
4
/309.31
78
71
200.7–201.8
174.8–175.4
17 2 3
C H10ClF NO /349.71
C
17
H
11BrFNO
3
/376.17
70
81
203.8–204.6
208.7–210.1
7f
C
17
H
9
3 2
ClF NO
/351.70
7g
C
19
H
14
F
3
NO
4
/377.31
78
212.1–213.0
(
Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
Table 1
(Continued)
a
Compound
R1
R2
MF/M. Wt
Yield (%)
75
MP (°C)
7h
C
17
H
9
ClF
3
NO
2
/351.70
129.3–130.3
7i
C
17
H
12FNO
2
/281.28
76
73
166.8–168.1
151.3–152.3
7
7
j
C
17
H12ClNO
2
/297.73
k
C
19
H
17NO
2
/291.34
77
72
157.1–157.8
161.8–163.4
7
7
l
17 2
C H11BrFNO /360.17
m
C
19
H
13
F
4
NO
2
/363.30
81
83
156.2–157.6
199.8–201.6
7n
20 16 3 4
C H F NO S/423.40
7o
C
18
H
14ClNO
2
/311.76
80
76
156.2–157.7
209.9–211.6
7p
C20H19NO4/337.36
C19H13F4O4/395.30
7
q
r
80
79
158.1–159.6
198.2–199.8
7
C20H16F3O6S/455.40
C18H14ClO4/343.76
C20H19NO6/369.36
7
s
t
78
81
153.4–154.8
185.9–187.3
7
a
Melting point of compounds at their decomposition.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
The structures of compounds 8a–t were confirmed
attributed to the carbonyl group of the carbohydrazide
moiety attached to the pyrazolo[1,5-a]pyrimidine core.
The structure of compound 8a was further confirmed
by LC-MS analysis, which gave a molecular ion peak
with an m/z value of 485.4 [M + H], which was
consistent with the molecular formula of compound 8a
(i.e., C H FN O ). The spectral data generated in the
current study were in good agreement with the
proposed structures of all of the novel molecules
synthesized in this series. The physicochemical
characteristics of the newly synthesized imidazolone
fused pyrazolo[1,5-a]pyrimidine compounds are shown in
Table 2.
1
13
based on their IR, H NMR, C NMR, and LC-MS
analyses. The IR spectrum of 8a contained two peaks
that were consistent with the presence of two carbonyl
ꢀ
1
groups. The first of these bands appeared at 1676 cm
and was attributed to the carbonyl group of the newly
formed imidazolone ring, while the second peak at
26
21
6 3
ꢀ
1
1
726.7 cm
was attributed to the C¼O group of the
carbohydrazide attached to the pyrazolo[1,5-a]
pyrimidine. The H NMR spectrum of 8a contained a
1
singlet with a chemical shift of 10.69ppm, which was
1
3
attributed to the amide-NH proton. The
spectrum of 8a contained a signal at 163.15 ppm, which
was consistent with the presence of carbonyl
C NMR
a
Anticancer Evaluation.
All of the compounds
functional group in the newly formed imidazolone ring.
A signal was also observed at 168.88 ppm, which was
prepared in the current study were screened for their
in vitro anticancer activity against HeLa cells, which
Table 2
Physicochemical characteristics of compounds (8a–t).
a
Compound
R1
R2
MF/M. Wt
Yield (%)
81
MP (°C)
8a
C
26
H
6
21FN O
3
/484.49
146.7–148.1
138.2–139.4
8b
C
28
H
H
26
N
6
O
3
/494.56
/496.53
78
8c
C
27
24
N
6
O
4
76
83
79
138.9–140.2
188.7–190.2
172.1–173.7
8
d
e
C
26 2 6 3
H19ClF N O /563.39
8
C
26 6 3
H20BrFN O /563.39
8
8
f
C
26
H
18ClF
3
N
6
O
2
/538.92
74
77
276.8–278.7
265.9–267.7
g
C
28
H
23
F
3
N
6
O
4
/564.53
(
Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
Table 2
(Continued)
a
Compound
R1
R2
MF/M. Wt
Yield (%)
82
MP (°C)
8h
C
26
H
18ClF
3
N
6
O
2
/538.92
203.8–204.6
180.3–182.7
211.5–212.9
8
8
8
i
C
26
H
6
21FN O
2
/468.49
80
85
j
26 6 2
C H21ClN O /484.95
k
C
28
H
26
N
6
O
2
/478.56
78
74
195.7–197.2
254.4–255.5
8l
26 6 2
C H20BrFN O /547.39
8m
C
28
22
H F
4
N
6
O
2
/550.52
78
221.8–222.8
8n
C
29
H
25
F
3
N
6
O
4
S/610.62
80
82
270.1–271.4
188.9–190.6
8
8
o
27 6 2
C H23ClN O /498.98
p
C
29
H
28
N
6
O
4
/524.58
83
196.8–198.1
8
8
8
8
q
r
s
C
28
H
22
F
4
N
6
O
4
/582.52
81
82
84
198.1–199.8
247.2–249.0
201.8–203.5
29 25 3 6 6
C H F N O S/642.62
27 6 4
C H23ClN O /530.98
t
C
29
H
28
N
6
O
6
/556.58
83
216.8–218.0
a
Melting point of compounds at their decomposition
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
were used as a representative human cervical cancer cell
Table 3
line, HepG2 cells, which were used as human liver
cancer line, and MCF-7 cells, which were used as a
representative human breast carcinoma cancer cell line.
These cell lines were obtained from American Type
Culture Collection. Paclitaxel and SAHA were used as
reference standards. The anticancer activities of the
compounds are listed in Table 3. These data showed that
some of the compounds exhibited good inhibitory
activity towards the growth of HeLa, HePG2, and
MCF-7 cell lines.
In particular, compounds 8f, 8g, 8h, 8m, 8n, 8q, and 8r
showed good anti-proliferative activities against HeLa
cells. Furthermore, compounds 8h, 8m, 8n, 8q, and 8r
exhibited superior anticancer activity than the marketed
anticancer drugs Paclitaxel and SAHA. In contrast, all of
the other compounds synthesized in this study showed
lower levels of anticancer activity than Paclitaxel and
SAHA.
In general, compounds 8h, 8k, 8m, 8n, 8p, 8q, and 8r
showed good anti-proliferative activities against HePG2
cells. Furthermore, compounds 8h, 8n, and 8r exhibited
superior anticancer activity than the marketed anticancer
drugs Paclitaxel and SAHA. But all of the other
compounds synthesized in this study showed lower levels
of anticancer activity than Paclitaxel and SAHA in this
cell line.
Finally, compounds 8i and 8r showed good anti-
proliferative activities against MCF-7 cell line. In
addition to that, these compounds 8i and 8r exhibited
superior anticancer activity than the marketed anticancer
drugs Paclitaxel and SAHA. In contrast, all of the other
compounds synthesized in this study showed lower levels
of anticancer activity than Paclitaxel and SAHA in the
case of MCF-7 cell line.
Anticancer activity of compounds 8a to 8t.
Percentage growth inhibition in different cell lines
Compound
Concn.(μg)
HeLa
HepG2
MCF-7
8a
10
20
30
10
17.4014
19.0985
27.1445
11.6009
15.3025
39.1304
5.6844
10.3203
20.6816
9.3967
7.7806
10.8497
19.6891
3.5714
4.4554
12.1099
18.4576
3.3415
8b
2
3
0
0
7.3202
9.1136
22.7979
ꢀ2.1683
ꢀ0.5228
9.4559
21.7446
0.61881
6.6167
13.78
7.797
10.2372
14.665
3.3415
8.3645
11.378
8c
10
2
3
0
0
8
8
8
8
d
e
f
10
2.1683
2
30
10
2
3
0
14.4721
19.9765
6.9605
6.287
7.638
4.0522
10.2332
ꢀ2.2959
1.4379
0
0
7.5129
10
20
52.6682
53.9739
59.9295
43.1555
48.7544
50.6463
66.2413
66.0735
74.7356
34.8028
49.2289
51.1163
39.5592
49.2289
51.8214
40.1392
50.7711
51.7039
19.0985
19.9536
24.7944
62.877
62.5148
63.3373
67.4014
68.9205
75.2056
21.1137
23.3689
25.9694
37.355
41.5816
47.2303
52.2021
14.1582
28.7582
36.2694
61.352
26.7327
30.7116
38.5588
22.2772
30.7116
43.8685
30.9406
34.9563
37.6738
36.6337
39.7004
57.1429
41.3366
46.1923
49.4311
38.2426
45.8177
47.914
29.8267
27.3408
33.8812
33.0446
37.8277
48.2933
33.4158
37.9526
46.2705
16.5842
23.5955
25.4109
17.3267
19.4757
23.8938
28.4653
35.8302
38.4324
64.2327
68.04
30
g
10
2
3
0
0
8h
10
2
3
0
0
64.8366
73.057
8
8
i
j
10
20
30
10
37.1173
40.1307
45.5959
36.9898
42.2222
47.1503
37.3724
38.9542
45.7254
30.4847
33.3333
39.2487
43.4949
45.6209
47.9275
65.3061
66.2745
72.6684
14.9235
17.3856
22.2798
28.699
2
3
0
0
8k
10
2
3
0
0
8
8
8
8
l
10
20
30
10
m
n
o
2
3
0
0
Consideration of the structure–activity relationships of
these novel compounds (8a–t) suggested that the
10
20
introduction of a bulky trifluoromethyl group (CF ) at the
3
30
position ortho to the benzylidine ring led to an increase
in the anticancer activity compared with a halogen
substituent at the same position. A similar trend was also
observed for compounds bearing a trifluoromethyl (CF3)
group at the para position of the benzene ring compared
10
2
3
0
0
8p
10
2
3
10
20
30
10
2
3
10
0
0
42.3488
45.3584
58.0046
59.6679
63.4548
72.6218
73.9027
75.2056
13.9211
15.777
38.4314
42.0984
50.3827
52.0261
57.3834
66.9643
71.5033
73.7047
2.6785
with a methoxy group (OCH ) at the same position.
3
8
8
q
r
Taken together, the results of this study revealed that
compounds 8h, 8n, and 8r exhibited the greatest
anticancer activities of all of the compounds tested
against HeLa cells and HepG2 cells. However, the
in vitro anticancer activity of compound 8r against HeLa,
HepG and MCF-7 cell lines is superior to the marketed
0
0
71.6814
4.5792
5.8676
14.0329
5.8168
12.2347
8s
2
3
10
0
0
5.2287
15.0259
1.403
2,
27.1445
9.2807
drugs Paclitaxel and SAHA. It is noteworthy that this
compound contained methane sulfonyl group at the ortho
position and trifluoromethyl group at the para position of
the benzylidine ring.
8t
20
25.7414
20.2614
(
Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
1
13
Table 3
(400 MHz for H NMR and 100 MHz for C NMR),
Bruker BioSpin Corp., Germany. Molecular weights for
all the synthesized compounds were checked by LC-MS
(
Continued)
Percentage growth inhibition in different cell lines
6
200 series Agilent Technology (Agilent, Bangalore,
Compound
Paclitaxel
Concn.(μg)
HeLa
HepG
2
MCF-7
India). The chemical shifts are reported in parts per million
(δ) with reference to TMS as an internal standard. The sig-
nals are designed as follows: s, singlet; d, doublet; t, triplet;
m, multiplet; and brs, broad singlet. IR spectra for all the
compounds were recorded using a Bruker Alpha FTIR
spectrometer using a diamond attenuated total reflection
3
0
50.1763
40.6032
42.586
37.9534
32.6531
37.3856
51.8135
21.0459
29.1503
40.6736
19.2162
34.1584
39.3258
53.3502
21.2871
34.7066
48.799
10
2
3
0
0
52.879
SAHA
10
23.6659
35.2313
45.5934
2
3
0
0
(ATR) single reflectance module (24 scans). Elemental
HeLa: Cervical carcinoma.
HepG : Liver carcinoma.
MCF-7: Breast carcinoma.
analysis was carried out with a Perkin-Elmer model 240-
C apparatus (Perkin-Elmer, Bangalore, India). The results
of elemental analysis (C, H, and N) were within ± 0.4%
of the calculated amounts.
2
CONCLUSION
Ethyl 5-amino-1H-pyrazole-4-carboxylate (2).
To a
solution of ethylcyanoacetate (1) (25g, 221.0 mmol) in
dimethylformamide (25 mL) and acetic acid (37.5mL),
dimethylformamide dimethylacetal (47.40g, 397.8 mmol)
was added drop wise at room temperature under nitrogen
over a period of 30min and then stirred at room
temperature for 2 h. The reaction mixture was cooled to
0°C and added hydrazine hydrate (25 mL, 80%) drop
wise over a period of 45min and then heated to 50°C for
2 h. Completion of the reaction was monitored by TLC.
After completion of the reaction, the reaction mixture
was diluted with ice cold water (1 L) and then extracted
to ethyl acetate (2 × 250mL). The combined ethyl acetate
layer was dried over anhydrous sodium sulfate, filtered,
and evaporated under reduced pressure. Crude material
obtained was purified by column chromatography over
silica gel, eluted with 2–5% methanol in chloroform to
afford ethyl 5-amino-1H-pyrazole-4-carboxylate (2) as an
off-white solid (24 g, 70%). MP: 106.7–108.9°C; IR
A novel series of imidazolone fused pyrazolo[1,5-a]
pyrimidine derivatives has been designed and synthesized
using a convergent approach, and the structures of these
1
13
compounds were confirmed by H NMR, C NMR, ESI-
MS, and IR analyses. These new compounds were tested
for their in vitro antiproliferative activity using an MTT
assay. Out of the 20 derivatives prepared in the current
study, compounds 8h, 8n, and 8r exhibited good
anticancer activities tested against HeLa cells and HepG2
cells. However, the in vitro anticancer activity of
compound 8r against HeLa, HepG and MCF-7 cell lines
2
,
is superior to the marketed drugs Paclitaxel and SAHA.
The results of our in vitro anticancer studies revealed
that the majority of these derivatives showed high levels
of potency against HeLa cells, HepG , and MCF-7 cell
2
lines. Further structure–activity relationship studies on
these compounds are therefore currently in progress in
our laboratory.
ꢀ
1
(ATR, cm ) υ: 1125.41 (C–O), 1337.61 (C–N), 1496.40
C–C), 1615.86 (N–H bend), 1662.37 (ester C = O),
(
2
1
972.92 (C–H), 3193.79 (N–H stretch); H NMR
EXPERIMENTAL
(400 MHz, DMSO-d ) δ (ppm): 1.23 (t, J =7.2 Hz, 3H,
6
ester–CH ), 4.16 (q, J = 6.9 Hz, 2H, ester–CH ), 5.99 (bs,
3
2
Chemistry chemicals were of analytical grade and
obtained from Sigma-Aldrich Co. The purification of all
intermediates and final compounds was carried out by
column chromatography using Merck silica gel with 230–
2H, pyrazole–NH ), 7.47 (bs, 1H, pyrazole–CH), 11.84
2
13
(bs, 1H, pyrazole–NH); C NMR (100MHz, DMSO-d6)
δ: 14.92, 59.10, 94.00, 139.93, 151.86, 164.27; LC-MS
(ESI, m/z): 156.7 (M + H). Anal. Calcd. for C H N O
9 3 2
6
4
00mesh size. The purity of synthesized compounds was
(155.16): C, 46.45; H, 5.85; N, 27.08. Found: C, 46.39;
H, 5.94; N, 27.19.
determined by thin layer chromatography experiments,
performed on alumina-backed silica gel 40 F254 plates
Ethyl5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate
(
(
Merck, Darmstadt, Germany). Thin-layer chromatography
TLC) observation of these plates were carried out by
(3). Ethyl 5-amino-1H-pyrazole-4-carboxylate (2) (10 g,
64.4 mmol) was dissolved in acetic acid (20 mL), and acetyl
acetone (6.45g, 64.4 mmol) was added drop wise to it at
room temperature, and the resulting solution was heated to
82°C for 8 h under a nitrogen atmosphere. Completion of
the reaction was monitored by TLC. Then after, the
reaction mixture was concentrated under reduced pressure
to remove excess acetic acid, and residue was stirred with
illuminating under UV (254nm) lamp and KMnO stain
solution. Melting points were determined using Buchi B-
5
and are uncorrected. All H NMR and C NMR spectra
were recorded on Bruker AM-300 (300 MHz for
NMR and 75MHz for C NMR) and Bruker AM-400
4
40 instrument (Buchi India Pvt. Ltd., Mumbai, India)
1
13
1
H
1
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
diisopropyl ether at room temperature for 30min.
Precipitated solid was filtered, washed with diisopropyl
ether, and dried under high vacuum to afford ethyl 5,7-
dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3) as a
pale yellow solid (12.7 g, 90%). MP: 101.9–103.1°C; IR
vacuum at 55–60°C for 1 h. The crude product was further
recrystallized from suitable solvent system to yield the title
compounds (6a–e).
[(4-Methoxyphenyl) carbonyl] amino} Acetic Acid (6a). This
compound was prepared by reacting glycine in aqueous
sodium hydroxide solution with 4-methoxybenzoyl chloride
5a. It was obtained as a pale yellow solid after drying process
and on further crystallized from THF: Toluene (1:4, V) at
room temperature to obtain [(4-methoxyphenyl) carbonyl]
amino} acetic acid (6a) as an off-white solid (4.4g, 79%).
ꢀ
1
(
(
2
ATR, cm ) υ: 1031.98 (C–N), 1123.05 (C–N), 1181.78
C–N), 1241.32 (C–O), 1549.20 (C–C), 1683.38 (C¼O),
1
920.75 (C–H), 3054.82 (C–H), 3099.87 (C–H); H NMR
(
300 MHz, DMSO-d ) δ (ppm): 1.31 (t, J= 7.2 Hz, 3H,
6
ester–CH ), 2.57 (s, 3H, pyrimidine–CH ), 2.70 (s, 3H,
3
3
ꢀ
1
pyrimidine–CH ), 4.27 (q, J= 7.2Hz, 2H, ester–CH ), 7.11
MP: 174.2–176.2°C; IR (ATR, cm ) υ: 1184.11 (ether–C–
O), 1221.56 (acid–C–O), 1264.43 (C–N stretch of amide),
1507.19 (C–C of aromatic), 1611.75 (amide C¼O), 1742.97
3
2
13
(
s, 1H, pyrazole–CH), 8.52 (s, 1H, pyrimidine–CH);
C
NMR (75 MHz, DMSO-d ) δ: 14.79, 16.86, 24.85, 59.69,
6
1
1
01.19, 110.93, 146.75, 146.87, 147.34, 162.13, 162.58;
(acid C¼O), 3365.89 (N–H amide); H NMR (300MHz,
LC-MS (ESI, m/z): 220.7 (M + H). Anal. Calcd. for
DMSO-d ) δ (ppm): 3.82 (s, 3H, Ar–OMe), 3.90 (d, J=6Hz,
6
C H N O (219.25): C, 60.26; H, 5.98; N, 19.17. Found:
2H, glycine–CH ), 7.02 (d, J=8.7Hz, 2H, Ar–H and Ar–H),
11
13
3
2
2
C, 60.20; H, 6.07; N, 19.26.
7.86 (d, J=9Hz, 2H, Ar–H and Ar–H), 8.71(t, J=6Hz, 1H,
amide–NH), 12.42 (bs,1H, acid–OH); C NMR (100MHz,
13
5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4).
To a suspension of ethyl 5,7-dimethylpyrazolo[1,5-a]
pyrimidine-3-carboxylate (3) (10g, 45.6 mmol) in ethanol
DMSO-d ) δ: 41.64, 55.80, 114.01, 126.55, 129.57, 162.17,
166.46, 172.00; LC-MS (ESI, m/z): 210.4 (M+H). Anal.
6
(100mL) was added 80% hydrazine hydrate (8.55g,
Calcd. for C H NO (209.20): C, 57.41; H, 5.30; N, 6.70.
10
11
4
1
7
36.8mmol) drop wise at 0°C and then heated to 72°C for
h under nitrogen atmosphere. Completion of the reaction
Found: C, 57.34; H, 5.38; N, 6.81.
({[4-(Trifluoromethyl) phenyl] carbonyl} amino) Acetic
Acid (6b). This compound was prepared by treating glycine
in aqueous sodium hydroxide with 4-trifluoromethylbenzoyl
chloride 5b. It was obtained as yellow solid after drying
process and on further crystallized from THF: n-Heptane
was monitored by TLC. After completion of the reaction, the
reaction medium was concentrated under reduced pressure
and residue obtained was stirred with ice cold ethanol for
30min. Precipitated solid was filtered, washed with cold
(
1:4 V) at room temperature to obtain ({[4-(trifluoromethyl)
ethanol, and dried under high vacuum to obtain 5,7-
Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4) as
an off-white solid (7.86 g, 84%). MP: 158.3–159.8°C; IR
phenyl] carbonyl} amino) acetic acid (6b) as an off-white
solid (4.9 g, 75%), MP: 157.4–159.2°C; IR (ATR, cm ) υ:
1
1
ꢀ
1
ꢀ
1
016.92 (ꢀC–F), 1046.24 (ꢀC–F), 1331.43 (acid–C–O),
(
(
3
ATR, cm ) υ: 1035.43 (C–O), 1194.30 (C–N), 1262.26
C–N), 1559.68 (C–C), 1664.51 (C¼O), 2955.95 (C–H),
038.81 (C–H), 3210.03 (N–H), 3307.80 (N–H), 3348.28
638.98 (amide–C¼O), 1746.81 (acid–C¼O), 2986.13
1
(O–H), 3329.02 (amide–N–H); H NMR (300 MHz, DMSO-
1
d ) δ (ppm): 3.96 (d, J=5.7Hz, 2H, glycine–CH –), 7.89
(N–H); H NMR (400MHz, DMSO-d ) δ (ppm): 2.60 (s,
6
2
6
(d, J= 8.1Hz, 2H, Ar–H and Ar–H), 8.08 (d, J=7.8Hz, 2H,
3
H, pyrimidine–CH ), 2.72 (s, 3H, pyrimidine–CH ), 4.50
3
3
Ar–H and Ar–H), 9.124 (t, J= 5.4 Hz, 1H, amide–NH), 12.70
(
bs, 2H, NH ), 7.10 (s, 1H, pyrimidine–H), 8.50 (s, 1H,
2
13
13
(bs, 1H, acid–OH); C NMR (100 MHz, DMSO-d ) δ:
pyrazole–H), 8.89 (bs, 1H, amide–NH);
C NMR
6
4
1.76,
120.33,
123.03,
125.74,
and
128.45
(
100MHz, DMSO-d ) δ: 16.94, 24.78, 103.54, 110.53,
6
1
(
1
q, JC–F =271Hz,ꢀCF ), 125.83, 125.87, 125.91, and
1
2
5
45.20, 145.51, 147.53, 161.97, 162.34; LC-MS (ESI, m/z):
3
3
25.94 (q, J = 4 Hz, ArC and ArC), 128.63 (ArC and
06.6 (M +H). Anal. Calcd. for C H N O (205.22): C,
C–F
9
11 5
2
ArC), 131.34, 131.65, 131.97, and 132.29 (q, J =32Hz),
1
2.68; H, 5.40; N, 34.13. Found: C, 52.61; H, 5.51; N, 34.19.
C–F
38.04, 165.84, 171.56; LC-MS (ESI, m/z): 248.6 (M + H).
General Procedure for the Synthesis of Hippuric Acid
Derivatives (6a–e).
Glycine (2g, 26.64 mmol) was
dissolved in sodium hydroxide (10% aqueous solution,
0mL) at 0°C, and the corresponding acid chlorides (5a–e)
26.64 mmol) were added drop wise. After addition was
Anal. Calcd. for C H F NO (247.18): C, 48.59; H, 3.26; N,
5.67. Found: C, 48.52; H, 3.32; N, 5.74.
10
8 3
3
2
(
{[(4-Methylphenyl) carbonyl] amino} Acetic Acid (6c). This
compound was prepared by reacting glycine in sodium
hydroxide with p-toluoyl chloride 5c. It was obtained as
yellow solid after drying process and was further crystallized
from THF: Toluene (1:5, V) at room temperature to afford
{[(4-methylphenyl) carbonyl] amino} acetic acid (6c) off-
white solid (3.96g, 77%). MP: 163.2–164.9°C; IR (ATR,
complete, reaction medium was slowly allowed to reach
room temperature (25°C) and vigorously stirred for 2–3 h.
Completion of the reaction was monitored by TLC.
After completion of the reaction, the reaction mixture
was poured to ice cold water and acidified with 4 N
aqueous hydrochloric acid under stirring. The reaction
medium was stirred for 30 min, and the precipitated solid
was filtered, washed with cold water, and dried under
ꢀ
1
cm ) υ: 1304 (ꢀC–O), 1638.40 (amide–C¼O), 1739.27
1
(acid–C¼O), 2934.21 (ꢀO–H), 3420.90 (amide–N–H); H
NMR (300MHz, DMSO-d ) δ (ppm): 2.37 (s, 3H, Ar–Me),
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
3
.92 (d, J=5.7Hz, 2H, glycine–CH –), 7.29 (d, J=6.6Hz, 2H,
at room temperature (25°C). The precipitated solid was
2
Ar–H and Ar–H), 7.78 (d, J=8.1Hz, 2H, Ar–H and Ar–H),
filtered, washed with cold water, and dried under vacuum at
55–60°C for 3h. Solid obtained previously was further
purified by silica gel column chromatography using 2–5%
of methanol in chloroform as the eluent system. The
obtained solid was further recrystallized from ethanol to
afford the title compounds (7a–t).
8
.76 (t, J=5.6Hz, 1H, amide–NH), 12.45 (bs, 1H, acid–OH);
1
3
C NMR (75MHz, DMSO-d ) δ: 21.36, 41.58, 127.66,
6
1
1
6
29.27, 131.49, 141.69, 166.76, 171.81; LC-MS (ESI, m/z):
94.4 (M +H). Anal. Calcd. for C H NO (193.20): C,
10
11
3
2.17; H, 5.74; N, 7.25. Found: C, 62.11; H, 5.83; N, 7.36.
(
4Z)-4-(2-Fluorobenzylidene)-2-(4-methoxyphenyl)-1,3-oxazol-
(4H)-one (7a). This compound was prepared by reaction of
[(4-methoxyphenyl) carbonyl] amino} acetic acid (6a) with
-fluoro benzaldehyde. It was obtained as a pale yellow solid
{
[(3,5-Dimethylphenyl) carbonyl] amino} Acetic Acid
5
{
2
(
(
6d). This compound was prepared by reacting glycine in
aqueous sodium hydroxide with 3,5-dimethylbenzoyl
chloride 5d. It was obtained as a pale green solid
after drying process and was further crystallized from THF:
n-Heptane (1: 5V) at room temperature to obtain {[(3,5-
dimethylphenyl) carbonyl] amino} acetic acid (6d) as an off-
white solid (4.19g, 76%). MP: 167.5–168.9°C; IR (ATR,
ꢀ
1
710mg, 80%). MP: 204.2–205.1°C; IR (ATR, cm ) υ:
41.18 (C–H bend), 1020.42 (C–F), 1095.72 (C–O), 1163.39
C–O), 1204.61 (C–O), 1265.65 (C–O), 1305.65 (C–N),
424.97 (C–C), 1500.41 (C–C), 1549.04 (C–C), 1600.54 (C–
8
(
1
1
ꢀ
1
cm ) υ: 1309 (ꢀC–O), 1700.61 (amide–C¼O), 1743.60
C), 1644.42 (C =C), 1780.31 (C= O), 3099.31 (C–H); H
NMR (300MHz, DMSO-d ) δ (ppm): 3.90 (s, 3H, Ar–
1
(
acid–C¼O), 2971.98 (O–H), 3312.21 (amide–N–H); H
6
NMR (300MHz, DMSO-d ) δ (ppm): 2.38 (s, 6H, Ar-Me),
OMe), 7.17 (s, 1H, benzylidene–H), 7.19 (d, J= 7.3Hz, 2H,
Ar–H and Ar–H), 7.20–7.44 (m, 2H, Ar–H), 7.54–7.60 (m,
6
3
.91 (d, J=5.7Hz, 2H, glycine–CH ), 7.09 (s, 1H, Ar–H),
2
7
.62 (s, 2H, Ar–H and Ar–H), 8.86 (t, J=5.4Hz, 1H, amide–
1H, Ar–H), 8.11 (d, J=7.2Hz, 2H, Ar–H and Ar–H), 8.83 (t,
13
13
NH), 12.65 (bs, 1H, acid-OH); C NMR (100MHz,
DMSO-d ) δ: 21.30, 41.63, 125.89, 132.38, 132.57,
J=5.8Hz, 1H, Ar–H); C NMR (100MHz, DMSO-d ) δ:
6
2
6
55.63, 114.58, 115.45, and 115.67 (d, J =22 Hz), 117.70,
120.73, and 120.80 (d, J =7 Hz), 122.01 and 122.12
= 11Hz), 124.58, 130.63, 132.48, and 132.60
JC–F = 12 Hz), 134.52, 160.63, and 163.17(d,
JC–F =254 Hz), 164.05, 164.12, 167.46; LC-MS (ESI, m/z):
C–F
3
137.54, 167.16, 171.85; LC-MS (ESI, m/z): 208.4 (M
C–F
3
+
H). Anal. Calcd. for C H NO (207.23): C, 63.76; H,
11
13
3
(d,
d,
J
C–F
2
6.32; N, 6.76. Found: C, 63.69; H, 6.39; N, 6.85.
(
1
[
(3,5-Dimethoxyphenyl) carbonyl] amino} Acetic Acid
(
6e). This compound was prepared by reacting glycine
2
98.6 (M+ H). Anal. Calcd. for C H FNO (297.29): C,
17 12 3
in aqueous sodium hydroxide with 3,5-dimethoxybenzoyl
chloride (5e). It was obtained as a pale yellow solid after
drying process and was further crystallized from
THF: Toluene (1:4, V) at room temperature to obtain
6
8.68; H, 4.07; N, 4.71. Found: C, 68.62; H, 4.17; N, 4.78.
(4Z)-4-(2,5-Dimethylbenzylidene)-2-(4-methoxyphenyl)-1,3-oxazol-
5(4H)-one (7b). This compound was prepared by reaction of
{[(4-methoxyphenyl) carbonyl] amino} acetic acid (6a) with
2,5-dimethyl benzaldehyde. It was obtained as a pale yellow
solid (558 mg, 76%). MP: 172.0–173.6°C; IR (ATR, cm )υ:
834.66 (C–H bend), 1018.39 (C–O), 1089.57 (C–O), 1164.99
(C–O), 1255.89 (C–O), 1305.07 (C–N), 1403.39 (C–C),
1500.81 (C–C), 1553.10 (C–C), 1602.22 (C–C), 1642.26
[(3,5-dimethoxyphenyl) carbonyl] amino} acetic acid (6e)
ꢀ
1
as an off-white solid (4.58g, 72%). MP: 178.1–179.7°C;
ꢀ
1
IR (ATR, cm ) υ: 1312 (ꢀC–O), 1690.59 (amide
C¼O), 1758.97 (acid C¼O), 2912.92 (O–H), 3317.27
1
(
amide N–H); H NMR (300 MHz, DMSO-d ) δ (ppm):
6
1
3
.79 (s, 6H, Ar–OMe and Ar–OMe), 3.91 (d, J = 5.7Hz,
(C¼C), 1776.98 (C¼O), 3068.69 (C–H); H NMR
2
H, glycine–CH –), 6.67 (t, J= 2.1Hz, 1H, Ar–H), 7.03
(400MHz, DMSO-d ) δ (ppm): 2.38 (s, 3H, Ar–Me), 2.44 (s,
2
6
(
1
(
d, J = 2.1Hz, 2H, Ar–H and Ar–H), 8.82 (t, J= 5.7 Hz,
H, amide–NH), 12.63 (bs, 1H, acid–OH); C NMR
3H, Ar–Me), 3.89 (s, 3H, Ar–OMe), 7.18–7.22 (m,4H, ArH),
1
3
7.30 (s, 1H, benzylidene–H), 8.08 (d, J=8 Hz, 2H, Ar–H),
13
100 MHz, DMSO-d ) δ: 41.72, 55.85, 103.84, 105.63,
8.55 (s, 1H, Ar–H); C NMR (100 MHz, DMSO-d ) δ:
6
6
1
2
5
36.38, 160.83, 166.53, 171.80; LC-MS (ESI, m/z):
19.62, 21.30, 55.58, 114.50, 117.96), 127.28, 130.40, 130.58,
131.88, 132.04, 132.41, 133.16, 135.92, 136.84, 163.59,
40.4 (M + H). Anal. Calcd. for C H NO (239.23): C,
1
1
13
5
5.23; H, 5.48; N, 5.85. Found: C, 55.16; H, 5.57; N, 5.96.
163.85, 168.16; LC-MS (ESI, m/z): 308.13 (M +H). Anal.
General Procedure for the Synthesis of Substituted
Calcd. for C H NO (307.35): C, 74.25; H, 5.58; N, 4.56.
19
17
3
Oxazolones (7a–t).
To a suspension of substituted acid
6a–e) (500mg, 2.39 mmol) in acetic anhydride (5 mL),
sodium acetate (1.19 mmol) and corresponding aldehyde
2.39 mmol) were taken and heated to 90°C for 4h under
Found: C, 74.19; H, 5.64; N, 4.65.
(
(4Z)-4-(2-Methoxybenzylidene)-2-(4-methoxyphenyl)-1,3-oxazol-
5
{
2
(4H)-one (7c). This compound was prepared by reaction of
[(4-methoxyphenyl) carbonyl] amino} acetic acid (6a) with
-methoxybenzaldehyde. It was obtained as a pale yellow
(
argon atmosphere. Completion of the reaction was
monitored by TLC. After completion of the reaction, the
reaction mixture was slowly warmed to room temperature
25°C) and poured into ice cold water to precipitate the
product. The resulted medium was stirred for further 30min
ꢀ
1
solid (577mg, 78%). MP: 200.7–201.8°C; IR (ATR, cm )
υ: 836.60 (C–H bend), 1024.38 (C–O), 1097.39 (C–O),
1172.90 (C–O), 1219.90 (ꢀC–O), 1256.44 (C–O), 1307.67
(C–O), 1307.67 ꢀ(C–N), 1423.58 (C–C), 1500.65 (C–C),
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
1
553.47 (ꢀC–C), 1599.59 (C–C), 1644.14 (ꢀC¼C), 1780.84 Calcd. for C H BrFNO (376.18): C, 54.28; H, 2.95; N,
1
7
11
3
1
(
C¼O), 3017.06 (C–H); H NMR (400MHz, DMSO-d ) δ
3.72. Found: C, 54.19; H, 3.04; N, 3.81.
6
(4Z)-4-(4-Chlorobenzylidene)-2-[4-(trifluoromethyl) phenyl]-
(ppm): 3.89 (s, 3H, Ar–OMe), 3.92 (s, 3H, Ar–OMe), 7.12–
1
,3-oxazol-5(4H)-one (7f).
This compound was prepared
7.19 (m, 4H, ArH), 7.48–7.51 (m, 2H, ArH and
by reaction of ({[4-(trifluoromethyl) phenyl] carbonyl}
amino) acetic acid (6b) with 4-chlorobenzaldehyde. It was
obtained as an off-white solid (576mg, 81%). MP: 208.7–
benzylidene–H), 8.08 (d, J= 8Hz, 2H, Ar–H), 8.77 (d,
J=4Hz, 1H, Ar–H); C NMR (100 MHz, DMSO-d ) δ:
1
3
6
55.59, 55.68, 110.74, 114.47, 118.14, 120.98, 122.87,
124.43, 130.34), 132.62, 132.77, 132.78, 159.15, 162.92,
163.73, 168.18; LC-MS (ESI, m/z): 310.7 (M +H). Anal.
ꢀ
1
2
10.1°C; IR (ATR, cm ) υ: 725.07 (C–Cl), 821.38 (C–H
bend), 956.15 (C–F), 994.14 (C–F), 1027.66 (C–F),
102.55 (C–O), 1268.63 (C–O), 1318.99 (C–N), 1407.78
C–C), 1452.15 (C–C), 1499.82 (C–C), 1551.82 (C–C),
1
Calcd. for C H NO (309.32): C, 69.89; H, 4.89; N, 4.53.
Found: C, 69.82; H, 4.96; N, 4.64.
18
15
4
(
1
1
647.10 (C¼C), 1788.68 (C¼O), 3060.35 (C–H); H NMR
(
4Z)-4-(2-Chloro-3,6-difluorobenzylidene)-2-(4-methoxyphenyl)-
(400MHz, DMSO-d ) δ (ppm): 7.47 (s, 1H, benzylidene–
6
1,3-oxazol-5(4H)-one (7d). This compound was prepared by
H), 7.63 (d, J=12Hz, 2H, Ar–H), 8.01 (d, J=8Hz, 2H,
reaction of {[(4-methoxyphenyl) carbonyl] amino} acetic
acid (6a) with 2-chloro-3,6-difluoro benzaldehyde. It was
obtained as an off-white solid (592 mg, 71%). MP:
13
Ar–H), 8.33 (t, J=8 Hz, 4H, Ar–H); C NMR (100MHz,
DMSO-d ) δ: 119.46, 122.16, 124.87, and 127.57
6
1
ꢀ
1
(
q, JC–F = 271Hz), 125.96, 126.00, 126.04, and 126.07
174.8–175.4°C; IR (ATR, cm ) υ: 782.11 (C–Cl),
839.30 (C–H bend), 975.95 (C–F), 1021.12 (C–F),
1098.88 (C–O), 1171.38 (C–O), 1236.38 (C–O), 1309.47
3
(
q, J =3.6Hz), 128.71, 129.41, 131.73, 131.80, 133.13,
C–F
1
33.76, 134.26, 134.58, 134. 91, and 135.24
2
(q, J =32.7Hz), 137.91, 162.56, 166.82; LC-MS (ESI,
(C–N), 1417.36 (C–C), 1471.19 (C–C), 1504.75 (C–C),
C–F
m/z): 352.7 (M+ H). Anal. Calcd. for C H ClF NO (351.71):
C, 58.06; H, 2.58; N, 3.98. Found: C, 58.01; H, 2.67; N, 4.07.
1
557.95 (C–C), 1601.39 (C–C), 1660.96 (C¼C), 1791.97
17
9
3
2
1
(C¼O), 3035.48 (C–H); H NMR (300MHz, DMSO-d )
6
δ (ppm): 3.87 (s, 3H, Ar–OMe), 7.14–7.19 (m, 3H, ArC
(4Z)-4-(2,4-Dimethoxybenzylidene)-2-[4-(trifluoromethyl) phenyl]-1,
3-oxazol-5(4H)-one (7g).
This compound was prepared by
and benzylidene–H), 7.44–7.50 (tt, J =4.4Hz, J =8.8Hz,
1
2
reaction of ({[4-(trifluoromethyl) phenyl] carbonyl}
amino) acetic acid (6b) with 2,4-dimethoxy benzaldehyde.
It was obtained as a pale yellow solid (603mg, 78%). MP:
1H, Ar–H), 7.60–7.66 (tt, J =4.8Hz, J =8.8Hz, 1H,
1 2
13
Ar–H), 8.04 (d, J= 8.8Hz, 2H, Ar–H);
C NMR
(100 MHz, DMSO-d ) δ: 55.64, 114.57, 114.62–115.29,
6
ꢀ
1
2
12.1–213.0°C; IR (ATR, cm ) υ: 851.11 (C–H bend),
91.55 (C–F), 978.43 (C–F), 1012.75 (C–F), 1063.49 (C–
117.19–117.71, 119.61, 121.89–122.71, 130.60, 130.95,
8
138.61, 139.06, 153.51–157.57, 163.35, 164. 27, 166.77,
O), 1092.84 (C–O), 1128.50 (C–O), 1165.25 (C–O),
321.73 (C–N), 1409.48 (C–C), 1486.52 (C–C), 1559.16
and 164.79, 164.32, 164.43, 166.18; LC-MS (ESI, m/z):
50.4 (M + H). Anal. Calcd. for C H ClF NO (349.72):
1
3
17
10
2
3
(
3
C–C), 1585.37 (C–C), 1657.54 (C¼C), 1793.14 (C¼O),
C, 58.39; H, 2.88; N, 4.01. Found: C, 58.30; H, 2.97;
N, 4.10.
1
061.21 (C–H); H NMR (400MHz, DMSO-d ) δ (ppm):
6
3
.89 (s, 3H, Ar–OMe), 3.94 (s, 3H, Ar–OMe), 6.69 (d,
(4Z)-4-(2-Bromo-5-fluoro benzylidene)-2-(4-methoxyphenyl)-1,3-
oxazol-5(4H)-one (7e).
This compound was pre pared by
J=2.4Hz, 1H, Ar–H), 6.78 (dd, J =6.8Hz, J =8.8Hz,
1 2
reaction of {[(4-methoxy phenyl) carbonyl] amino} acetic
acid (6a) with 2-bromo-5-fluorobenzaldehyde. It was
obtained as a pale yellow solid (625 mg, 70%). MP: 203.8–
1H, Ar–H), 7.59 (s, 1H, benzylidene–H), 7.98 (d, J=8Hz,
2H, Ar–H), 8.27 (d, J=8Hz, 2H, Ar–H), 8.78 (d,
13
J=9.2Hz, 1H, Ar–H); C NMR (100MHz, DMSO-d ) δ:
6
ꢀ
1
2
04.6°C; IR (ATR, cm ) υ: 690.23 (C–Br), 836.61 (C–H
bend), 1025.55 (C–F), 1102.15 (C–O), 1165.23 (C–O),
240.23 (C–O), 1268.85 (C–O), 1314.45 (C–N), 1457.94
C–C), 1505.50 (C–C), 1555.47 (C–C), 1603.84 (C–C),
55.65, 55.75, 97.70, 106.56, 115.98, 119.60, 122.30,
1
125.01, and 129.72 (q, JC–F =270.7Hz), 125.83, 125.86,
3
1
and 125.90 (t,
J
C–F =3.6Hz), 127.94, 128.22, 129.46,
2
(
1
129.57, 133.41, 133.74, 134.07, and 134.39 (q, JC–
1
653.40 (C¼C), 1785.19 (C¼O), 2975.12 (C–H); H NMR
=33Hz), 134.79, 160.41, 161.47, 164.65, 167.76; LC-
F
(400 MHz, DMSO-d ) δ (ppm): 3.90 (s, 3H, Ar–OMe), 7.20
MS (ESI, m/z): 378.8 (M+H). Anal. Calcd. for
6
(d, J= 6.8 Hz, 2H, Ar–H), 7.27 (s, 1H, benzylidene–H),
C H F NO (377.32): C, 60.48; H, 3.74; N, 3.71.
19
14
3
4
7
.32–7.37 (dt, J =3.9Hz, J =8.1Hz, 1H, Ar–H), 7.83 (t,
Found: C, 60.41; H, 3.82; N, 3.83.
1
2
J=9.2 Hz, 1H, Ar–H), 8.12 (d, J=6.8 Hz, 2H, Ar–H), 8.62
(4Z)-4-(3-Chlorobenzylidene)-2-[4-(trifluoromethyl) phenyl]-
13
(
dd, J =5.68Hz, J =7.8Hz, 1H, Ar–H);
C NMR
1,3-oxazol-5(4H)-one (7h).
This compound was prepared
1
2
(
100 MHz, DMSO-d ) δ: 55.68, 114.70, 117.30, 118.76, and
18.99 (d, JC–F =24 Hz), 119.65 and 119.90 (d,
by reaction of ({[4-(trifluoromethyl) phenyl] carbonyl}
amino) acetic acid (6b) with 3-chlorobenzaldehyde. It was
obtained as an off-white solid (532mg, 75%). MP: 129.3–
130.3°C; IR (ATR, cm ) υ: 822. 44 (C–Cl), 852.39 (C–H
bend), 888.71 (C–F), 978.32 (C–F), 1025.02 (C–F), 1166.10
6
2
1
2
JC–F3= 25Hz), 121.34, 125.94, 130.94, 134.32, and 134.35
3
ꢀ1
(d, JC–F = 8Hz), 134.75 and 134.84 (d, JC–F =9Hz),
1
1
35.85, 160.52, and 162.98 (d, JC–F = 245 Hz), 164.48,
164.96, 167.10; LC-MS (ESI, m/z): 376.6 (M+ H). Anal.
(C–O), 1275.00 (C–O), 1323.62 (C–N), 1413.96 (C–C),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
1
463.64 (C–C), 1503.16 (C–C), 1605.68 (C–C), 1647.10
(4Z)-4-(2,5-Dimethylbenzylidene)-2-(4-methylphenyl)-1,3-oxazol-
1
(
C¼C), 1794.12 (C¼O), 3074.76 (C–H);
H
5(4H)-one (7k). This compound was prepared by reaction of
{[(4-methylphenyl) carbonyl] amino} acetic acid (6c) with
2,5-dimethyl benzaldehyde. It was obtained as a pale yellow
NMR (300MHz, DMSO-d ) δ (ppm): 7.46 (s, 1H,
6
benzylidene–H), 7.58–7.60 (m, 2H, Ar–H), 8.02 (d,
J= 8.4 Hz, 2H, Ar–H), 8.32 (d, J=8.3Hz, 2H, Ar–H),
ꢀ
1
solid (580mg, 77%). MP: 157.1–157.8°C; IR (ATR, cm ) υ:
866.58 (C–H bend), 1095.61 (C–O), 1170.76 (C–O), 1290.13
(C–N), 1322.29 (C–N), 1411.48 (C–C), 1497.60 (C–C),
13
8.31–8.36 (m, 1H, Ar–H), 8.37 (s, 1H, Ar–H); C NMR
(100 MHz, DMSO-d ) δ: 119.43, 122.14, 124.85, 127.57
6
1
(
q, J =271.3 Hz), 125.96, 126.00, 126.04, 126.07 (q,
JC–F = 4 Hz), 128.64, 128.79, 130.17, 130.71, 131.33,
31.42, 131.99, 133.79, 134.36, 134.69, 135.02, 135.34
1552.05 (C–C), 1607.66 (C–C), 1645.02 (C¼C), 1788.40
C–F
3
1
(C¼O), 3024.82 (C–H); H NMR (300MHz, DMSO-d ) δ
6
1
(ppm): 2.37 (s, 3H, Ar–Me), 2.43 (s, 6H, Ar–Me and Ar–Me),
7.21 (s, 2H, Ar–H), 7.33 (s, 1H, benzylidene–H), 7.44 (d,
J= 8.1Hz, 2H, Ar–H), 7.99 (d, J=7.8Hz, 2H, Ar–H), 8.52 (s,
2
(q, JC–F = 33Hz), 134.84), 135.01, 162.96, 166.57; LC
MS (ESI, m/z): 352.6 (M + H). Anal. Calcd. for
C H ClF NO (351.71): C, 58.06; H, 2.58; N, 3.98.
Found: C, 58.02; H, 2.65; N, 4.09.
1
3
17
9
3
2
1H, Ar–H); C NMR (100MHz, DMSO-d ) δ ppm: 19.49,
6
2
1.18, 21.81, 122.81, 128.04, 128.27), 129.62, 130.50,
131.85, 131.95, 132.43, 132.94, 135.86, 136.87, 144.18,
63.58, 167.91; LC-MS (ESI, m/z): 292.7 (M +H).Anal.
Calcd. for C H NO (291.35): C, 78.33; H, 5.88; N, 4.81.
(
4Z)-4-(2-Fluorobenzylidene)-2-(4-methylphenyl)-1,3-oxazol-5
4H)-one (7i). This compound was prepared by reaction of
[(4-methylphenyl) carbonyl] amino} acetic acid (6c) with 2-
fluoro benzaldehyde. It was obtained as an off-white solid
(
{
1
19
17
2
Found: C, 78.28; H, 5.96; N, 4.89.
ꢀ
1
(
8
(
1
553 mg, 76%). MP: 166.8–168.1°C; IR (ATR, cm ) υ:
71.89 (C–H bend), 981.53 (C–F), 1097.13 (C–O), 1199.84
C–O), 1291.88 (C–N), 1415.88 (C–C), 1487.25 (C–C),
546.61 (C–C), 1606.95 (C–C), 1649.54 (C¼C), 1799.72
(4Z)-4-(2-Bromo-5-fluorobenzylidene)-2-(4-methylphenyl)-1,3-
oxazol-5(4H)-one (7l).
This compound was prepared by
reaction of {[(4-methylphenyl) carbonyl] amino} acetic
acid (6c) with 2-bromo-5-fluorobenzaldehyde. It was
obtained as a pale yellow solid (670mg, 72%). MP:
1
(
C¼O), 3060.59 (C–H); H NMR (300MHz, DMSO-d ) δ
6
ꢀ
1
(ppm): 2.42 (s, 3H, Ar–Me), 7.23 (s, 1H, benzylidene–H),
161.8–163.4°C; IR (ATR, cm ) υ: 678.94 (C–Br), 852.06
(C–H bend), 988.94 (C–F), 1107.67 (C–O), 1173.46 (C–
O), 1324.80 (C–N), 1414.41 (C–C), 1474.31 (C–C),
7.32–7.41 (m, 2H, Ar–H), 7.44 (d, J= 8.1Hz, 2H, Ar–H),
7
8
.53–7.60 (m, 1H, Ar–H), 8.02 (d, J= 8.1Hz, 2H, Ar–H),
.81 (t, J= 7.5 Hz, 1H, Ar–H); C NMR (75 MHz, DMSO-
13
1511.12 (C–C), 1560.25 (C–C), 1656.01 (C¼C), 1804.03
2
1
d ) δ ppm: 21.83, 115.32, and 115.61 (d, J =21.6Hz,
(C¼O), 3082.46 (C–H); H NMR (400MHz, DMSO-d ) δ
6
C–F
6
3
121.43 and 121.52 (d, J = 7.42 Hz), 121.78 and 121.92
(ppm): 2.43 (s, 3H, Ar–Me), 7.29 (s, 1H, benzylidene-H),
7.30–7.35 (dt, J =3.2Hz, J =8Hz, 1H, Ar–H), 7.46 (d,
C–F
2
(d,
JC–F =10.65 Hz), 122.55, 124.51, and 124.56
1
2
3
(d, J = 3.52 Hz), 128.44, 129.69, 132.60, 132.68, 134.29,
J=8Hz, 2H, Ar–H), 7.84 (t, J=8.8Hz, 1H, Ar–H), 8.03
(d, J=8Hz, 2H, Ar–H), 8.61 (dd, J =7.2Hz, J =10.4Hz,
C–F
1
144.61, 160.17, and 163.56 (d, J =254.7 Hz), 164.25,
C–F
1
2
13
167.19; LC MS (ESI, m/z): 282.7 (M+ H). Anal. Calcd. for
1H, Ar–H); C NMR (100MHz, DMSO-d
21.94, 118.96, and 119.19 (d, JC–F = 23.3Hz), 119.76 and
C–F = 24.9 Hz), 121.49 and 121.53
C–F =3.3Hz), 122.29, 126.83, and 126.86
(d, JC–F = 2.6 Hz), 128.79, 129.90, 134.30, and 134.38
6
) δ (ppm):
2
C H FNO (281.29): C, 72.59; H, 4.30; N, 4.98. Found: C,
17
12
2
2
72.52; H, 4.38; N, 5.09.
120.01 (d,
J
3
(
4Z)-4-(3-Chlorobenzylidene)-2-(4-methylphenyl)-1,3-oxazol-5
4H)-one (7j). This compound was prepared by reaction of
[(4-methylphenyl) carbonyl] amino} acetic acid (6c) with
-chloro benzaldehyde. It was obtained as an off-white
solid (562 mg, 73%). MP: 151.3–152.3°C; IR (ATR,
(d,
J
3
(
{
3
2
2
(d, J = 8.1 Hz), 134.59 and 134.68 (d, J =8.8Hz),
C–F C–F
135.25,
135.67,
145.27, 160.51, and
162.96
1
(d, JC–F = 245 Hz), 165.29, 166.94; LC MS (ESI, m/z):
362.9 (M+2H). Anal. Calcd. for C17 11BrFNO (360.19):
ꢀ
1
cm ) υ: 825.04 (C–Cl), 879.20 (C–H bend), 1161.64
C–O), 1278. 90 (C–O), 1362.45 (C–N), 1422.00 (C–C),
457.73 (C–C), 1507.13 (C–C), 1564.39 (C–C), 1652.91
H
2
(
1
C, 56.69; H, 3.08; N, 3.89. Found: C, 56.62; H, 3.17; N,
3.98.
1
(4Z)-2-(3,5-Dimethylphenyl)-4-[4-fluoro-2-(trifluoromethyl) benzy
(
C¼C), 1788.20 (C¼O), 3009.98 (C–H); H NMR
lidene]-1,3-oxazol-5(4H)-one (7m). This compound was prepared
by reaction of {[(3,5-dimethylphenyl) carbonyl] amino} acetic
acid (6d) with 4-fluoro-2-trifluoro methyl benzaldehyde. It was
obtained as an off-white solid (700 mg, 81%). MP: 156.2–
(300MHz, DMSO-d ) δ (ppm): 2.44 (s, 1H, Ar–Me),
6
7.32 (s, 1H, benzylidene–H), 7.47 (d, J=8.1Hz, 2H, Ar–
H), 7.56 (dd, J =3.6Hz, J =6.4Hz, 2H, Ar–H), 8.03 (d,
J= 8.1 Hz,2H, Ar–H), 8.28 (t, J=6.3 Hz, 2H, Ar–H), 8.35
1
2
ꢀ
1
13
1
9
57.6°C; IR (ATR, cm ) υ: 808.09 (C–H bend), 837.05 (C–F),
(s, 1H, Ar–H); C NMR (100 MHz, DMSO-d ) δ ppm:
6
05.10 (C–F), 983.26 (C–F), 1046.97 (C–F), 1107.47 (C–O),
1
1
1
7.19, 117.74, 123.84, 124.09, 125.05, 125.26, 125.62,
25.99, 126.97, 129.73, 130.06, 130.53, 140.06, 159.64,
62.58; LC MS (ESI, m/z): 298.6 (M +H). Anal. Calcd.
1157.08 (C–O), 1289.56 (C–N), 1318.97 (C–N), 1433.33 (C–C),
1492.90 (C–C), 1560.39 (C–C), 1604.66 (C–C), 1655.35
1
for C H ClNO (297.74): C, 68.58; H, 4.06; N, 4.70.
Found: C, 68.51; H, 4.12; N, 4.79.
(C¼C), 1807.65 (C¼O), 3081.77 (C–H); H NMR (300 MHz,
17
12
2
DMSO-d ) δ (ppm): 2.40 (s, 6 H, Ar–Me), 7.20 (s, 1H, Ar–H),
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
7
.25 (s, 1H, Ar–H), 7.47 (s, 1H, Ar–H), 7.77 (s,1H, Ar–H), 7.85
(4Z)-4-(2,4-Dimethoxybenzylidene)-2-(3,5-dimethylphenyl)-1,3-
oxazol-5(4H)-one (7p).
This compound was prepared by
(dt, J =8.9Hz, J = 5.2 Hz, 1H, Ar–H), 9.03 (dt, J =8.6Hz,
1
2
1
13
reaction of {[(3,5-dimethylphenyl) carbonyl] amino} acetic
acid (6d) with 2, 4-dimethoxybenzaldehyde. It was obtained
as an off-white solid (619 mg, 76%). MP: 209.9–211.6°C; IR
J2=5.6Hz, 1H, Ar–H). C NMR (100 MHz, DMSO-d ) δ
6
2
(ppm): 21.18, 113.99–114.42 (m, JC–F=25Hz), 119.07 and
2
1
19.27 (d, J = 21 Hz), 118.95, 121.65, 124.38, and 127.11 (q,
C–F
ꢀ
1
1
3
(ATR, cm ) υ: 898.72 (¼C–H bend), 1032.17 (C–O),
1111.31 (C–O), 1168.28 (C–O), 1224.17 (C–O), 1284.19
(C–N), 1461.01 (C–C), 1499.76 (C–C), 1559.28 (C–C),
JC–F= 271 Hz), 123.36, 123.38, and 123.40 (t, JC–F=3Hz),
3
124.86, 126.37, 127.66, and 127.694 (d, JC–F= 2.5Hz), 131.80–
2
2
132.49 (dq, J1C–F=24Hz, J2C–F=7 Hz), 135.22, 135.24,
1
1601.21 (C–C), 1644.53 (C¼C), 1774.14 (C¼O), 3010.95
136.03, 136.12, 138.91, 161.54, and 164.08 ( JC–F=253.7 Hz),
1
(
C–H), 3053.23 (C–H), 3090.52 (C–H). H NMR (400MHz,
165.65, 166.85; LC MS (ESI, m/z): 364.4 (M+ H). Anal. Calcd.
CDCl ) δ (ppm): 2.41 (s, 6H, Ar–Me), 3.90 (s, 6H, Ar–
3
for C H F NO (363.31): C, 62.81; H, 3.61; N, 3.86. Found:
C, 62.76; H, 3.69; N, 3.95.
19
13 4
2
OMe), 6.45 (d, J=2.4Hz, 1H, Ar–H), 6.68 (dd, J =6.4Hz,
1
J = 2.4Hz, 1H, Ar–H), 7.21 (s, 1H, Ar–H), 7.78 (d,
(4Z)-2-(3,5-Dimethylphenyl)-4-[4-(methylsulfonyl)-2-(trifluorome
2
13
thyl)benzylidene]-1,3-oxazol-5(4H)-one (7n).
This compound
J=3.2Hz, 3H, Ar–H), 8.90 (d, J=8.8Hz, 1H, Ar–H);
C
was prepared by reaction of {[(3,5-dimethylphenyl)
NMR (75 MHz, CDCl ) δ (ppm): 21.13, 55.47, 55.59, 97.65,
3
carbonyl] amino} acetic acid (6d) with 4-methyl sulf-onyl-
106.21, 116.18, 125.67, 125.78, 130.25, 134.10, 134.51,
2-trifluoro methyl benzaldehyde. It was obtained as an off-
138.47, 160.98, 162.14, 163.95, 168.22; LC-MS (ESI, m/z):
white solid (846mg, 83%). MP: 199.8–201.6°C; IR (ATR,
338.5 (M +H). Anal. Calcd. for C20
H19NO (337.38): C,
4
ꢀ
1
cm ) υ: 848.88 (¼C–H bend), 1012.53 (C–F), 1059.35
C–F), 1158.09 (C–F), 1206.06 (C–O), 1255.44 (C–O),
313.02 (C–N), 1354.73 (C–N), 1425.59 (C–C), 1464.99
71.20; H, 5.68; N, 4.15. Found: C, 71.11; H, 5.77; N, 4.26.
(
4Z)-2-(3,5-Dimethoxyphenyl)-4-[4-fluoro-2-(trifluoromethyl)
(
1
benzylidene]-1,3-oxazol-5(4H)-one (7q). This compound was
prepared by reaction of [(3,5-dimethoxyphenyl) carbonyl]
amino} acetic acid (6e) with 4-fluoro-2-trifluoro methyl
benzaldehyde. It was obtained as an off-white solid (660mg,
(
1
C–C), 1561.78 (C–C), 1602.92 (C–C), 1656.13 (C¼C),
1
798.20 (C¼O), 3014.21 (C–H); H NMR (300MHz,
DMSO-d ) δ (ppm): 2.39 (s, 6H, Ar–Me), 3.33 (s, 3H,
6
ꢀ
1
8
0%). MP: 158.1–159.6°C; IR (ATR, cm ) υ: 837.08 (¼C–
Ar–SO Me), 7.22 (s, 1H, Ar–H), 7.41(s, 1H, Ar–H), 7.78
2
H bend), 1044. 78 (C–F), 1106.69 (C–F), 1156.24 (C–F),
1208.26 (C–O), 1257.44 (C–O), 1288.66 (C–N), 1319.77
(
s, 2H, Ar–H), 8.31(s, 1H, Ar–H), 8.43 (d, J=8.7Hz, 1H,
13
Ar–H), 9.09 (d, J=8.4Hz, 1H, Ar–H);
C NMR
(C–N), 1432.43 (C–C), 1491.80 (C–C), 1561.23 (C–C),
(
100MHz, DMSO-d ) δ (ppm): 21.17, 55.78, 106.56,
6
1
602.76 (C–C), 1653.35 (ꢀC¼C), 1799.65 (C¼O), 3078.76
1
07.14,
118.88,
121.62,
124.36,
and
127.10
1
1
3
(C–H); H NMR (300MHz, DMSO-d ) δ (ppm): 3.84 (s,
(q, J =274Hz), 122.56 and 122.58 (d, J =2.2Hz),
6
C–F
C–F
3
6H, Ar–OMe and Ar–OMe), 6.89 (s, 1H, Ar–H), 7.22 (s,
1
1
1
1
25.42, and 125.48 (d, JC–F =5.9Hz), 126.28, 130.72,
30.57, 130.88, 131.20, and 131.51 (q, JC–F =31Hz),
34.52, 135.28, 136.17, 136.56, 137.89, 140.89, 166.06,
66.88; LC-MS (ESI, m/z): 424.6 (M+H). Anal. Calcd.
2
3H, Hz, Ar–H), 7.83 (dt, J =9Hz, J =5.16Hz, 2H, Ar–H),
1 2
13
9
.03 (dt, J =8.7Hz, J = 5.7 Hz, 1H, Ar–H); C NMR
1 2
(
100 MHz, DMSO-d ) δ (ppm): 44.46, 113.69–114.48 (m,
6
2
2
JC–F = 25 Hz), 119.06 and 119.26 (d, J = 21 Hz), 118.97,
for C H F NO S (423.41): C, 56.73; H, 3.81; N, 3.31.
C–F
20
16 3
4
1
1
21.67, 124.40, and 127.13 (q, J = 271 Hz), 123.37,
Found: C, 56.66; H, 3.89; N, 3.39.
C–F
3
(
4Z)-4-(3-Chlorobenzylidene)-2-(3,5-dimethylphenyl)-1,3-oxazol-
(4H)-one (7o). This compound was prepared by reaction of
[(3,5-dimethylphenyl) carbonyl] amino} acetic acid (6d)
123.39, and 123.41 (t, JC–F = 3Hz), 124.82, 126.33, 127.63,
3
5
{
and 127.66 (d, JC–F =2.5 Hz), 131.80–132.49 (dq,
2
2
J1C–F =24Hz, J2C–F = 7 Hz), 135.29, 136.06, 138.98,
1
with 3-chloro benzaldehyde. It was obtained as a pale
1
61.27, 161.54, and 164.08 ( J = 253.7 Hz), 165.67,
C–F
yellow solid (600 mg, 80%). MP: 156.2–157.7°C; IR
166.88; LC-MS (ESI, m/z): 396.0 (M + H). Anal. Calcd. for
ꢀ
1
(
ATR, cm ) υ: 788. 65 (C–Cl), 888.09 (C–H bend),
166.29 (C–O), 1221.37 (C–O), 1275.06 (C–N), 1327.63
C–N), 1431.79 (C–C), 1462.45 (C–C), 1563.40 (C–C),
599.23 (C–C), 1653.60 (C¼C), 1789.10 (C¼O), 3070.49
C H F NO (395.31): C, 57.73; H, 3.31; N, 3.54. Found:
19
13 4
4
1
(
C, 57.66; H, 3.40; N, 3.64.
(4Z)-2-(3,5-Dimethoxyphenyl)-4-[4-(methylsulfonyl)-2-(trifluorom
ethyl) benzylidene]-1,3-oxazol-5(4H)-one (7r). This compound
1
1
(C–H); H NMR (300 MHz, DMSO-d ) δ (ppm): 2.40 (s,
was prepared by reaction of [(3,5-dimethoxyphenyl)
carbonyl] amino} acetic acid (6e) with 4-methane sulfonyl-2-
trifluoro methyl benzaldehyde. It was obtained as an off-
white solid (750 mg, 79%). MP: 198.2–199.8°C; IR (ATR,
6
6H, Ar–Me), 7.37 (d, J= 8.1 Hz, 2H, Ar–H), 7.57 (d,
J=8.1 Hz, 2H, Ar–H), 7.75 (s, 2H, Ar–H), 8.32 (s, 2H, Ar–
13
H); C NMR (100 MHz, DMSO-d ) δ (ppm): 21.25,
6
ꢀ
1
125.07, 126.29, 129.07, 130.06, 130.38, 130.81, 131.7,
cm ) υ: 847.98 (C–H bend), 913.10 (C–F), 966.79 (C–F),
1011.73 (C–F), 1058.15 (C–O), 1157.07 (C–O), 1205.96
(C–O), 1256.34 (C–O), 1312.02 (C–N), 1354.33 (C–N),
1424.39 (C–C), 1464.79 (C–C), 1560.78 (C–C), 1602.72
134.45, 134.82, 135.25, 135.63, 138.79, 164.59, 167.29;
LC-MS (ESI, m/z): 312.8 (M + H). Anal. Calcd. for
C H ClNO (311.77): C, 69.35; H, 4.53; N, 4.49. Found:
18
14
2
1
C, 69.28; H, 4.59; N, 4.54.
(C–C), 1655.13 (C¼C), 1799.20 (C¼O), 3013.21 (C–H); H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
NMR (300 MHz, DMSO-d ) δ (ppm): 3.39 (s, 3H, Ar–
(200 mg, 0.974mmol) and the corresponding oxazolone
derivatives (7a–t) (0.974mmol) were suspended in acetic
acid (2 mL) and heated to 110°C for 6h under argon
atmosphere. Completion of the reaction was monitored
by TLC. After completion of the reaction, the reaction
mixture was poured to ice cold water, stirred for 30min.
The precipitated solid was filtered, washed with cold
water, and dried under vacuum at 55–60°C for 1–2 h. The
solid obtained was further purified by silica gel column
chromatography using 2–5% of methanol in chloroform
as the eluent system and was further recrystallized from
ethanol to yield the title compounds (8a–t).
6
SO Me), 3.87 (s, 6H, Ar–OMe), 6.93 (s, 1H, Ar–H), 7.25 (s,
2
1
H, Ar–H), 7.27 (s, 2H, Ar–H), 8.32 (s, 1H, Ar–H), 8.44 (d,
13
J=8.1 Hz, 1H, Ar–H), 9.13 (d, J= 8.1 Hz, 1H, Ar–H);
C
NMR (100MHz, DMSO-d ) δ (ppm): 44.45, 55.79, 106.59,
6
1
07.34, 118.85, 121.59, 124.33, and 127.07 (q,
1
3
JC–F =274 Hz), 122.53 and 122.55 (d, JC–F =2.2Hz),
3
125.39 and 125.45 (d, JC–F = 5.9 Hz), 126.29, 130.76,
2
130.58, 130.89, 131.21, and 131.52 (q, JC–F =31Hz),
134.54, 136.51, 137.91, 141.36, 161.22, 166.04, 166.85;
LC-MS (ESI, m/z): 456.5 (M + H). Anal. Calcd. for
C H F NO S (455.41): C, 52.75; H, 3.54; N, 3.08. Found:
20
16 3
6
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-
C, 52.68; H, 3.62; N, 3.14.
[
1-(2-fluoro-phenyl)-meth-(Z)-ylidene]-2-(4-methoxy phenyl)-5-
(
4Z)-4-(3-Chlorobenzylidene)-2-(3,5-dimethoxyphenyl)-1,3-
oxo-4,5-dihydro-imidazol-1-yl]-amide (8a). This compound
was prepared by reaction of 5,7-dimethyl pyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(2-
fluorobenzylidene)-2-(4-methoxy phenyl)-1,3-oxazol-5(4H)-
one (7a). It was obtained as a pale yellow solid (382mg,
oxazol-5(4H)-one (7s).
This compound was prepared by
reaction with [(3,5-dimethoxyphenyl) carbonyl] amino}
acetic acid (6e) with 3-chloro benzaldehyde. It was obtained
as an off-white solid (557mg, 78%). MP: 153.4–154.8°C; IR
ꢀ
1
(
ATR, cm ) υ: 781.46 (C–Cl), 886.57 (¼C–H bend),
007.52 (C–O), 1061.55 (C–O), 1101.47 (C–O), 1202.32
C–O), 1317.87 (C–N), 1359.96 (C–N), 1429.01 (C–C),
471.40 (C–C), 1563.86 (C–C), 1602.33 (C–C), 1649.70
ꢀ
1
8
1%). MP: 146.7–148.1°C; IR (ATR, cm ) υ: 756.22 (C–
H bend), 1026.48 (C–N), 1175.38 (C–O), 1198.66 (C–O),
257.63 (C–N), 1299.19 (C–N), 1501.61 (C–C), 1556.58
C–C), 1632.67 (C¼C),1676.49 (C¼O),1726.68 (C¼O),
1
(
1
1
(
1
(
C¼C), 1808.81 (C¼O), 3095.64 (C–H); H NMR
1
2936.24 (C–H), 3331.17 (N–H); H NMR (300MHz,
(300MHz, DMSO-d ) δ (ppm): 3.87 (s, 3H, Ar–OMe), 6.88
6
DMSO-d ) δ (ppm): 2.68 (s, 3H, pyrimidine–Me), 2.77 (s,
(s, 1H, Ar–H), 7.21(d, J=8.2Hz, 2H, Ar–H), 7.37 (d,
6
3
H, pyrimidine–Me), 3.80 (s, 3H, Ar–OMe), 7.08 (d,
J=8.7Hz, 2H, Ar–H), 7.21 (s, 1H, benzylidene–H), 7.23 (s,
H, pyrazole–CH), 7.33–7.46 (m, 2H, Ar–H), 7.56–7.68
J= 3.9 Hz, 1H, Ar–H), 7.57 (d, J= 8.2 Hz, 2H, Ar–H), 8.28
13
(t, J=6.4Hz, 1H, Ar–H), 8.35 (s, 1H, Ar–H); C NMR
1
(
100MHz, DMSO-d ) δ (ppm): 55.72, 106.15, 106.53,
6
1
1
3
6
26.96, 129.87, 130.11, 130.50, 131.02, 131.90, 134.29,
(m, 1H, Ar–H), 8.13 (d, J= 8.7 Hz, 2H, Ar–H), 8.62 (s, 1H,
pyrimidine–H), 8.98 (t, J=6.3Hz, 1H, Ar–H), 10.69 (s, 1H,
34.90, 135.11, 161.09, 164.20, 167.20; LC-MS (ESI, m/z):
44.9 (M+H). Anal. Calcd. for C H ClNO (343.77): C,
13
Amide–NH); C NMR (100 MHz, DMSO-d ) δ (ppm):
18
14
4
6
2.89; H, 4.10; N, 4.07. Found: C, 62.80; H, 4.19; N, 4.18.
16.96, 24.70, 55.97, 101.77, 114.81, 115.96, and 116.17 (d,
2
2
(4Z)-4-(2, 4-Dimethoxybenzylidene)-2-(3,5-dimethoxyphenyl)-
JC–F =21 Hz), 116.37 and 116.44 (d, J = 7Hz), 119.92,
C–F
1,3-oxazol-5(4H)-one (7t). This compound was prepared by
3
1
22. 17, 122.28 (d, J = 11Hz), 125.54, 131.03, 132.95,
C–F
reaction with [(3,5-dimethoxyphenyl) carbonyl] amino}
acetic acid (6e) with 2,4-dimethoxy benzaldehyde. It was
obtained as an off-white solid (623mg, 81%). MP: 185.9–
3
and 133.03 (d, JC–F = 8Hz), 138.06, 145.93, 146.48,
1
1
1
47.80, 161.07, 160.46, and 162.97 (d, JC–F =251 Hz),
61.82, 163.13, 163.15, 168.88; LC-MS (ESI, m/z): 485.4
-1
1
(
1
(
87.3°C; IR (ATR, cm ) υ: 827.10 (¼C–H bend), 1012.52
C–O), 1033.68 (C–O), 1058.80 (C–O), 1112.45 (C–O),
163.95 (C–O), 1209.32 (C–O), 1279.67 (C–N), 1308.14
C–N), 1423.67 (C–C), 1463.78 (C–C), 1502.18 (C–C),
(
M+ H). Anal. Calcd. for C H FN O (484.49): C, 64.46;
26 21 6 3
H, 4.37; N, 17.35. Found: C, 64.39; H, 4.45; N, 17.46.
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 4-[1-
(2,5-dimethyl-phenyl)-meth-(Z)-ylidene]-2-(4-methoxy-phenyl)-5-
oxo-4,5-dihydro-imidazol-1-yl]-amide (8b).
1
564.87 (C–C), 1601.69 (C–C), 1649.29 (ꢀC¼C), 1775.22
This compound
1
(
(
(
(
C¼O), 3097.29 (C–H); H NMR (300MHz, DMSO-d ) δ
was prepared by reaction with 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(2,5-
dimethylbenzylidene)-2-(4-methoxyphenyl)-1,3-oxazol-5
(4H)-one (7b). It was obtained as a pale yellow solid (388mg,
6
ppm): 3.85 (s, 6H, Ar–OMe), 3.88 (s, 3H, Ar–OMe), 3.93
s, 3H, Ar–OMe), 6.68 (d, J=2.3Hz, 1H, Ar–H), 6.77–6.87
m, 2H, Ar–H), 7.17 (d, J=2.1Hz, 2H, Ar–H), 7.53 (s, 1H,
13
ꢀ1
Ar–H), 8.77 (d, J=9.0Hz, 1H, Ar–H); C NMR (100 MHz,
78%). MP: 138.2–139.4°C; IR (ATR, cm ) υ: 839.67 (C–H
DMSO-d ) δ (ppm): 55.60, 55.70, 97.72, 105.63, 105.66,
bend), 1028.29 (C–N), 1112.49 (C–O), 1181.20 (C–O),
1256.94 (C–N), 1301.72 (C–N), 1500.66 (C–C), 1556.38
(C–C), 1631.52 (C¼C), 1684.29 (C¼O), 1729.62 (C¼O),
6
106.35, 116.14, 126.50, 127.78, 130.07, 134.65, 161.00,
161.21, 161.71, 164.24, 168.24; LC-MS (ESI, m/z): 370.6
1
(
M+H). Anal. Calcd. for C H NO (369.38): C, 65.03; H,
2922.28 (C–H), 3245.30 (N–H); H NMR (300MHz,
20
19
6
5.18; N, 3.79. Found: C, 65.09; H, 5.22; N, 3.86.
DMSO-d ) δ (ppm): 2.35 (s, 3H, Ar–Me), 2.44 (s, 3H, Ar–
6
General Procedure for the Synthesis of (8a–t).
Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
5,7-
Me), 2.67 (s, 3H, pyrimidine–Me), 2.76 (s, 3H, pyrimidine–
Me), 3.78 (s, 3H, Ar–OMe), 7.06 (d, J=9.2Hz, 2H, Ar–H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
7
.18–7.22 (m, 3H, Ar–H), 7.29 (s, 1H, benzylidene–H), 8.09
16.96, 24.70, 55.95, 101.69, 111.28, 114.76, 119.26, and 119.
2
(d, J=9.2Hz, 2H, Ar–H), 8.61 (s, 1H, pyrazole–CH), 8.66 (s,
51 (d, J1C–F = 18.75 Hz), 119.58, 119.61, and 119.84
13
2
3
C–F C–F
1H, pyrimidine–CH), 10.66 (s, 1H, amide–NH); C NMR
(d, J1 = 17.25 Hz), 121.3 6 and 121. 40 (d, J =4Hz),
3
(100MHz, DMSO-d ) δ (ppm): 16.96, 21.63, 24.85, 55.93,
121.85, 131.17, 135.00, and 135.13 (d, JC–F =9.75Hz),
6
101.71, 111.29, 114.78, 125.38, 126.83, 129.91, 130.89,
131.03, 132.45, 133.27, 135.68, 136.09, 146.31, 146.56
147.27, 160.14, 161.44, 162.47, 163.06, 168.93; LC-MS
135.25, 139.11, 145.93, 146.48, 147.81, 159.93, and 163.08
(d, J1C–F = 236.25Hz), 161.03, 162.92, 163.16, 163.42,
168.87; LC-MS (ESI, m/z): 537.4 (M+ H). Anal. Calcd. for
1
(
ESI, m/z): 495.3 (M+H). Anal. Calcd. for C H N O
C H ClF N O (536.93): C, 58.16; H, 3.57; N, 15.65.
2
8
26
6
3
26 19
2 6 3
(
494.56): C, 68.00; H, 5.30; N, 16.99. Found: C, 67.93; H,
.38; N, 17.08.
Found: C, 58.08; H, 3.68; N, 15.76.
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-
[1-(2-bromo-5-fluoro-phenyl)-meth-(Z)-ylidene]-2-(4-methoxy-
phenyl)-5-oxo-4,5-dihydro-imidazol-1-yl]-amide (8e).
5
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {2-
4-methoxy-phenyl)-4-[1-(2-methoxy-phenyl)-meth-(Z)-ylidene]-
-oxo-4,5-dihydro-imidazol-1-yl}-amide(8c). Thiscompound
(
This
compound was prepared by reaction of 5,7-
Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
5
was prepared by reaction of 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(2-
methoxybenzylidene)-2-(4-meth oxyphenyl)-1,3-oxazol-
(200mg) with (4Z)-4-(2-bromo-5-fluorobenzylidene)-2-(4-
methoxyphenyl)-1,3-oxazol-5(4H)-one(7e).Itwasobtainedas
a pale yellow solid (432mg, 79%). MP: 172.1–173.7°C; IR
5
(4H)-one (7c). It was obtained as a pale yellow solid
ꢀ
1
ꢀ1
(379mg, 76%). MP: 138.9–140.2°C; IR (ATR, cm ) υ:
(ATR, cm ) υ: 906.54 (¼C–H bend), 1027.16 (C–N),
7
1
57.16 (C–H bend), 1027.70 (C–N), 1112.18 (C–O),
181.88 (C–O), 1253.70 (C–N), 1302.14 (C–N), 1499.77
1104.62 (C–O), 1118.13 (C–O), 1172.08 (C–O), 1261.25 (C–
N), 1236.46 (C–N), 1299.54 (C–N), 1423.56 (C–C), 1458.06
(C–C), 1500.62 (C–C), 1559.11 (C–C), 1627.10
(
1
C–C), 1555.95 (C–C), 1630.71 (C¼C), 1684.79 (C¼O),
1
728.81 (C¼O), 2939.39 (C–H), 3253.74 (N–H); H NMR
(C¼C),1674.78 (C¼O), 1734.83 (C¼O), 3068.53 (C–H),
1
(400MHz, DMSO-d ) δ (ppm): 2.66 (s, 3H, pyrimidine–
3213.39(N–H); HNMR(300MHz, DMSO-d )δ(ppm):2.68
6
6
Me), 2.76 (s, 3H, pyrimidine–Me), 3.78 (s, 3H, Ar–OMe),
(s, 3H, pyrimidine–Me), 2.73 (s, 3H, pyrimidine–Me), 3.80 (s,
3H, Ar-OMe), 7.09 (d, J=9Hz, 2H, Ar–H), 7.21 (s, 1H,
benzylidene–H),7.29(s,1H,pyrazole–CH),7.31–7.36(m,1H,
Ar–H), 7.82–7.87(m, 1H, Ar–H), 8.13(d, J=9Hz, 2H, Ar–H),
8.63 (s, 1H, pyrimidine–CH), 8.83 (dd, J =3Hz, J =10.5Hz,
3.92 (s, 3H, Ar–OMe), 7.05 (d, J=8.8Hz, 2H, Ar–H),
7.10–7.14 (m, 2H, Ar–H), 7.20 (s, 1H, benzylidene–H),
7.45–7.49 (m, 1H, Ar–H), 7.52 (s, 1H, pyrazole–CH), 8.09
(d, J=8.8Hz, 2H, Ar–H), 8.61 (s, 1H, pyrimidine–CH),
1
1
2
3
8
.92 (d, J= 6.4Hz, 1H, Ar–H), 10.65 (s, 1H, amide–NH);
1H, Ar–H), 10.71 (s, 1H, Amide–NH); C NMR (75MHz,
1
3
C NMR (100MHz, DMSO-d ) δ (ppm): 16.96, 19.73,
DMSO-d ) δ (ppm): 16.94, 24.69, 56.00, 101.69, 111.28,
6
6
2
2
1
1
1
1.62, 24.83, 55.92, 101.76, 111.32, 114.83, 121.13,
25.46, 126.93, 128.29, 129.94, 130.88, 131.09, 132.47,
36.83, 146.41, 146.59, 147.33, 160.18, 16 1.42, 162.54,
62.85, 163.18, 168.76; LC-MS (ESI, m/z): 497.3 (M+ H).
114.95, 119.26, and 119. 51 (d, J
119.61–119.84 (d, J
(d, JC–F =4Hz), 121.85, 131.17, 135.00, and 135.13
(d, J =9.75Hz), 135.25, 139.11, 145.93, 146.48, 147.81,
= 18.75 Hz), 119.58,
1C–F
2
=17.25Hz), 121.3 6 and 121.40
1
C–F
3
3
C–F
1
Anal. Calcd. for C H N O (496.53): C, 65.31; H, 4.87;
159.93, and 163.08 (d, J = 236.25Hz), 161.03, 162.92,
2
7
24
6
4
C–F
N, 16.93. Found: C, 65.23; H, 4.98; N, 17.02.
163.16, 163.42, 168.87; LC-MS (ESI, m/z):LC-MS(ESI, m/z):
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-(2-
chloro-3,6-difluoro-phenyl)-meth-(Z)-ylidene]-2-(4-methoxy-phenyl)-
-oxo-4,5-dihydro-imidazol-1-yl]-amide (8d). This compound was
prepared by reaction of 5,7-Dimethylpyrazolo[1,5-a]pyrimidine-
-carbohydrazide (4) (200mg) with (4Z)-4-(2-chloro-3,6-difluoro
5
65.4 (M+ 2H). Anal. Calcd. for C H BrFN O (563.39): C,
26 20 6 3
5
5.43;H,3.58;N,14.92.Found:C,55.36;H,3.67;N,15.04.
5
5,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-1-
(
4-chloro-phenyl)-meth-(Z)-ylidene]-5-oxo-2-(4-trifluoromethyl-
3
phenyl)-4,5-dihydro-imidazol-1-yl]-amide (8f). This compound
was prepared by reaction of 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(4-
chlorobenzylidene)-2-[4-(trifluoro methyl) phenyl]-1,3-
oxazol-5(4H)-one (7f). It was obtained as a pale yellow solid
benzylidene)-2-(4-methoxyphenyl)-1,3-oxazol-5(4H)-one (7d). It
was obtained as an off-white solid (433mg, 83%). MP: 188.7–
ꢀ
1
1
90.2°C; IR (ATR, cm ) υ: 839.73(C-H bend), 1026.33 (C–
N), 1118.84 (C–O), 1181.32 (C–O), 1260.71 (C–N), 1296.93
C–N), 1476.00 (C–C), 1502.89 (C–C), 1555.80 (C–C),
605.01 (C¼C), 1685.14 (C¼O),1742.75 (C¼O), 3071.05
ꢀ
1
(
1
(
(
7
400mg, 74%). MP: 276.8–278.7°C; IR (ATR, cm ) υ:
57.15 (C–H bend), 1017.44 (C–F), 1065.78 (C–N), 1123.24
(C–O), 1176.81 (C–O), 1233.00 (C–N), 1300.93 (C–N),
321.35 (C–N), 1418.54 (C–C), 1495.28 (C–C), 1556.45 (C–
C), 1588.22 (C–C), 1625. 91 (–C¼C), 1687.02 (C¼O),
1
C–H), 3239.96 (N–H); H NMR (300 MHz, DMSO-d ) δ
6
(ppm): 2.68 (s, 3H, pyrimidine–Me), 2.77 (s, 3H, pyrimidine–
1
Me), 3.77 (s, 3H, Ar–OMe), 7.03 (d, J=9Hz, 2H, Ar–H),
1
7
7
.19 (s, 1H, benzylidene–H), 7.23 (s, 1H, pyrazole–CH), 7.46–
.50 (m, 1H, Ar–H), 7.58–7.62 (m, 1H, Ar–H), 7.97 (d,
J=9 Hz, 2H, Ar–H), 8.63 (s, 1H, pyrimidine–CH), 10.67 (s,
1
(
741.20 (C¼O), 3040.33 (C–H), 3192.63 (N–H); H NMR
400MHz, DMSO-d ) δ (ppm): 2.67 (s, 3H, pyrimidine–Me),
6
2.76 (s, 3H, pyrimidine–Me), 7.21 (s, 1H, benzylidene–H),
13
1H, Amide–NH); C NMR (100MHz, DMSO-d ) δ (ppm):
6
7.43 (s, 1H, pyrazole–CH), 7.61 (d, J=8Hz, 2H, Ar–H), 7.92
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
(
d, J=8 Hz, 2H, Ar–H), 8.28 (d, J=8 Hz, 2H, Ar–H), 8.41 (d,
2.76 (s, 3H, pyrimidine–Me), 7.22 (s, 1H, benzylidene–H),
7.42 (s, 1H, pyrazole–CH), 7.57 (d, J= 5.1 Hz, 2H, Ar–H),
7.94 (d, J= 8.1 Hz, 2H, Ar–H), 8.29 (d, J= 8.2 Hz, 2H, Ar–H),
8.35 (t, J=6.1 Hz, 1H, Ar–H), 8.47 (s, 1H, Ar–H), 8.61 (s, 1H,
J= 8Hz, 2H, Ar–H), 8.61 (s, 1H, pyrimidine–CH), 10.68 (s,
1
1
13
H, amide–NH); C NMR (75MHz, DMSO-d ) δ (ppm):
6
6.93, 24.71, 101.58, 111.26, 120.1, 122.81, 125.52, and
1
13
1
28.23 (q, JC–F =271Hz), 126.18 and 126.22 (d,
pyrimidine–CH), 10.69 (s, 1H, Amide–NH); C NMR
3
JC–F =4 Hz), 128.60, 129.49, 129.74, 131.84, 131.72,
(75MHz, DMSO-d ) δ (ppm): 16.92, 24.72, 101.57, 111.23,
6
2
1
1
1
1
32.04, 132.36, and 132.68 (q, JC–F = 32Hz), 133.05,
34.69, 136.21, 136.87, 145.95, 146.50, 147.81, 160.73,
61.21, 163.20, 168.58; LC-MS (ESI, m/z): 539.4 (M +H).
120.08, 122.79, 125.50, and 128.21 (q,
125.78, 126.20, and 126.24 (q, JC–F = 4 Hz), 128.12), 128.36,
JC–F =271Hz),
3
128.92, 129.09, 129.74, 131.64, 131.96, 132.28, and 132.60
2
Anal. Calcd. for C H ClF N O (538.92): C, 57.95; H,
(q, JC–F = 32 Hz), 133.34, 135.98, 136.76, 136.84, 145.93,
26
18
3 6 2
3
.37; N, 15.59. Found: C, 57.88; H, 3.46; N, 15.71.
146.58, 147.78, 158.19, 161.51, 164.41, 168.56; LC-MS (ESI,
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-
m/z): 539.4 (M+ H). Anal. Calcd. for C H ClF N O
26
18
3 6 2
(2,4-dimethoxy-phenyl)-meth-(Z)-ylidene]-5-oxo-2-(4-trifluoromethyl-
(538.92): C, 57.95; H, 3.37; N, 15.59. Found: C, 57.88; H,
phenyl)-4,5-dihydro-imidazol-1-yl]-amide (8g). This compound
was prepared by reaction of 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200 mg) with (4Z)-4-(2,4-
dimethoxy benzylidene)-2-[4-(trifluoromethyl) phenyl]-1,3-
oxazol-5(4H)-one (7g). It was obtained as a pale yellow
3
.48; N, 15.70.
5,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {4-[1-(2-
fluoro-phenyl)-meth-(Z)-ylidene]-5-oxo-2-p-tolyl-4,5-dihydro-imidazol-
1-yl]-amide (8i). This compound was prepared by reaction of
5,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
(200mg) with (4Z)-4-(2-fluorobenzylidene)-2-(4-methylphen
yl)-1,3-oxazol-5(4H)-one (7i). It was obtained as a pale yellow
ꢀ
1
solid (435mg, 77%). MP: 265.9–267.7°C; IR (ATR, cm )
υ: 756.80 (¼C–H bend), 1026.17 (C–F), 1068.52 (C–N),
ꢀ
1
1107.59 (C–O), 1166.52 (C–O), 1232.39 (C–N), 1282.96
solid (377 mg, 80%). MP: 180.3–182.7°C; IR (ATR, cm ) υ:
758.48 (¼C–H bend), 1032.28 (C–F), 1121.69 (C–N), 1158.72
(C–O), 1190.93 (C–O), 1235.21 (C–N), 1295.47 (C–N),
1374.43 (C–N), 1446.62 (C–C), 1499.98 (C–C), 1554.78 (C–
C), 1633.85 (ꢀC¼C), 1680.70 (C¼O), 1730.84 (C¼O),
(
1
C–N), 1321.29 (C–N), 1421.90 (C–C), 1465.22 (C–C),
506.10 (C–C), 1558.86 (C–C), 1603.90 (C¼C), 1683.26
C¼O), 1719.93 (C¼O), 2963.09 (C–H), 3366.08 (N–H);
(
1
H NMR (400MHz, DMSO-d ) δ (ppm): 2.67 (s, 3H,
6
1
pyrimidine–Me), 2.76 (s, 3H, pyrimidine–Me), 3.89 (s, 3H,
3172.81 (C–H), 3353.08 (N–H); H NMR (400 MHz, DMSO-
Ar–OMe), 3.95 (s, 3H, Ar–OMe), 6.69 (s, 1H, Ar–H), 6.77
d ) δ (ppm): 2.34 (s, 3H, Ar–Me), 2.68 (s, 3H, pyrimidine–
6
(
(
d, J= 8Hz, 1H, Ar–H), 7.20 (s, 1H, benzylidene–H), 7.61
s, 1H, pyrazole–CH), 7.89 (d, J=8Hz, 2H, Ar–H), 8.25 (d,
J= 8Hz, 2H, Ar–H), 8.60 (s, 1H, pyrimidine–CH), 8.92 (d,
Me), 2.76 (s, 3H, pyrimidine–Me), 7.20 (s, 1H, benzylidene–
H), 7.28 (s, 1H, pyrazole–CH),7.33 (d, J=8Hz, 2H, Ar–H),
7.34–7.43 (m, 2H, Ar–H), 7.53–7.58 (m, 1H, Ar–H), 8.03 (d,
J=8Hz, 2H, Ar–H), 8.61 (s, 1H, pyrimidine–CH), 8.96 (t,
13
J=12Hz, 1H, Ar–H), 10.65 (s, 1H, amide–NH); C NMR
13
(100MHz, DMSO-d ) δ (ppm): 16.96, 24.72, 56.16, 56.55,
J=8Hz, 1H, Ar–H), 10.68 (s, 1H, amide–NH); C NMR
(75MHz, DMSO-d ) δ (ppm): 16.97, 21.61, 24.71, 101.71,
111.24, 116.02, and 116.23 (d, JC–F = 21 Hz), 117.28 and
6
9
1
8.37, 101.70, 101.80, 111.26, 120.14, 122.85, 125.56, and
6
1
2
28.27 (q,
JC–F = 271Hz), 126.19 and 126.23
3
3
2
(d, J =4 Hz), 128.42, 129.18, 131.70, 132.02, 132.34,
117.35 (d, JC–F = 7 Hz), 122.03 and 122.14 (d, JC–F =11Hz),
C–F
2
and 132.66 (q, JC–F =32Hz), 132.24, 133.72, 134.72,
1
1
125.01, 125.57, 129.02, 129.83, 133.10, 133.19, 133.28 (d,
3
45.94, 146.50, 147.81, 158.17, 161.23, 161.57, 163.17,
64.41, 168.56; LC-MS (ESI, m/z): 565.5 (M+ H). Anal.
JC–F = 9Hz), 137.99, 143.34), 145.91, 146.46, 147.81, 161.01,
1
160.53, and 163.04 (d,
168.79; LC-MS (ESI, m/z): 469.4 (M + H). Anal. Calcd. for
(468.49): C, 66.66; H, 4.52; N, 17.94. Found: C,
JC–F =251 Hz), 162.45, 163.14,
Calcd. for C H F N O (564.53): C, 59.57; H, 4.11; N,
28 23 3 6 4
1
4.89. Found: C, 59.49; H, 4.20; N, 14.98.
5
C H21FN O
26 6 2
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-(3-
chloro-phenyl)-meth-(Z)-ylidene]-5-oxo-2-(4-trifluoromethyl-phenyl)-
,5-dihydro-imidazol-1-yl]-amide (8h).
66.59; H, 4.59; N, 18.06.
5,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-(3-
chloro-phenyl)-meth-(Z)-ylidene]-5-oxo-2-p-tolyl-4,5-dihydro-imidazol-
1-yl]-amide (8j). This compound was prepared by reaction of
4
This compound was
prepared by reaction of 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(3-
chlorobenzylidene)-2-[4-(trifluoromethyl) phenyl]-1,3-oxazol-5
5,7-dimethyl pyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
(200mg) with (4Z)-4-(3-chlorobenzylidene)-2-(4-methylpheny
l)-1,3-oxazol-5 (4H)-one (7j). It was obtained as an off-white
(4H)-one (7h). It was obtained as an off-white solid (429 mg,
ꢀ
1
ꢀ1
8
2%). MP: 203.8–204.6°C; IR (ATR, cm ) υ: 680.43 (¼C–
solid (401 mg, 85%). MP: 211.5–212.9°C; IR (ATR, cm ) υ:
H bend), 850.26 (C–Cl), 1017.04 (C–F),1066.94 (C–N),
682.29 (C–Cl), 777.23 (¼C–H bend), 1119.70 (C–N),
1146.46 (C–O), 1187.32 (C–O), 1233.97 (C–N), 1295.59 (C–
N), 1368.77 (C–N), 1422.56 (C–C), 1500.42 (C–C), 1556.96
(C–C), 1635.22 (ꢀC¼C), 1684.99 (C¼O), 1733.72 (C¼O),
1
130.09 (C–O), 1167.69 (C–O), 1234.15 (C–N), 1271.13 (C–
N), 1324.64 (C–N), 1419.52 (C–C), 1444.23 (C–C), 1495.80
C–C), 1559.20 (C–C), 1646.02 (ꢀC¼C), 1683.87 (C¼O),
(
1
1
1
738.30 (C¼O), 2956.07 (C–H), 3316.04 (N–H); H NMR
3003.87 (C–H), 3212.42 (N–H); H NMR (300 MHz,
(300MHz, DMSO-d ) δ (ppm): 2.68 (s, 3H, pyrimidine–Me),
DMSO-d ) δ (ppm): 2.34 (s, 3H, Ar–Me), 2.68 (s, 3H,
6
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
pyrimidine–Me), 2.76 (s, 3H, pyrimidine–Me), 7.21 (s, 1H,
benzylidene–H), 7.29 (s, 1H, pyrazole–CH), 7.33 (d,
J=8.1Hz, 2H, Ar–H), 7.55 (d, J=6.0Hz, 2H, Ar–H), 8.01 (d,
J=8.1 Hz, 2H, Ar–H), 8.33 (d, J= 5.4Hz, 1H, Ar–H), 8.47 (s,
7.34 (d, J=8.4Hz, 2H, Ar–H), 7.37 (s, 1H, Ar–H), 7.83–
7.87 (m, 1H, Ar–H), 8.02 (d, J= 8.4 Hz, 2H, Ar–H), 8.32 (s,
1H, pyrazole–CH), 8.61 (s, 1H, pyrimidine–CH), 8.80 (d,
13
J= 7.2 Hz, 1H, Ar–H), 10.69 (s, 1H, amide–NH); C NMR
(75MHz, DMSO-d ) δ (ppm): 16.91, 21.58, 24.67, 101.57,
1
H, Ar–H), 8.61 (s, 1H, pyrimidine–CH), 10.66 (s, 1H,
6
13
2
Amide–NH); C NMR (100MHz, DMSO-d ) δ (ppm):
111.23, 119. 46, and 119.76 (d, JC–F = 22.65 Hz, 119. 58
and 119.91 (d, JC–F = 24.9 Hz), 121.47, 122.74, 124.69,
129.07, 129.88, 134.83, and 134.94 (d,
135.19 and 135.03 (d,
6
2
1
6.98, 21.60, 24.72, 101.72, 111.26, 125.94, 126.10, 128.95,
29.56, 130.52, 131.12, 131.40, 131.93, 133.93, 136.52,
37.84, 143.25, 145.91, 146.46, 147.82, 161.01, 162.23,
63.14, 168.85; LC-MS (ESI, m/z): 485.4 (M + H). Anal.
Calcd. for C H ClN O (484.95): C, 64.40; H, 4.36; N,
3
1
1
1
J
C–F =8.6Hz),
3
JC–F = 8.6 Hz), 139.03, 143.68,
145.86, 146.45, 147.81, 159.89, and 163.67 78
1
(d,
JC–F =283.8Hz), 160.97, 163.12, 163.67, 168.71;
26
21
6 2
1
7.33. Found: C, 64.31; H, 4.45; N, 17.43.
LC-MS (ESI, m/z): 548.3 (M + H). Anal. Calcd. for
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {4-
1-(2,5-dimethyl-phenyl)-meth-(Z)-ylidene]-5-oxo-2-p-tolyl-4,5-
dihydro-imidazol-1-yl]-amide (8k).
C H BrFN O (547.39): C, 57.05; H, 3.68; N, 15.35.
26
20
6 2
[
Found: C, 56.98; H, 3.76; N, 15.46.
This compound was
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-(3,5-
dimethyl-phenyl)-4-[1-(4-fluoro-2-trifluoromethyl-phenyl)-meth-(Z)-
ylidene]-5-oxo-4,5-dihydro-imidazol-1-yl]-amide (8m).
prepared by reaction of 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200 mg) with (4Z)-4-
This
(
5
2,5-dimethylbenzylidene)-2-(4-methylphenyl)-1,3-oxazol-
compound was prepared by reaction with 5,7-Dimet
hylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4) (200 mg)
with (4Z)-2-(3,5-dimethyl phenyl)-4-[4-fluoro-2-(trifluorome
thyl)benzylidene]-1,3-oxazol-5(4H)-one (7m). It was obtained
as an off-white solid (418 mg, 78%). MP: 221.8–222.8°C. IR
(4H)-one (7k). It was obtained as a pale yellow solid
ꢀ
1
(376mg, 78%). MP: 195.7–197.2°C; IR (ATR, cm ) υ:
8
1
18.46 (¼C–H bend), 1037.41 (C–N), 1120.50 (C–O),
185.51 (C–O), 1235.89 (C–N), 1298.10 (C–N), 1379.99
ꢀ
1
(C–N), 1443.01 (C–C), 1501.55 (C–C), 1557.31 (C–C),
(ATR, cm ) υ: 776.78 (¼C–H bend), 859.77 (C–F), 896.27
(C–F), 911.36 (C–F), 951.15 (C–F), 1054.05 (C–N), 1126.03
(C–O), 1157.68 (C–O), 1230.14 (C–N), 1286.34 (C–N),
1319.97 (C–N), 1432.58 (C–C), 1495.29 (C–C), 1560.08 (C–
C), 1598.26 (C–C), 1627.71 (ꢀC¼C), 1685.71 (C¼O),
1
3
633.55 (ꢀC¼C), 1684.33 (C¼O), 1725.80 (C¼O),
1
028.47 (C–H), 3250.45 (N–H); H NMR (400MHz,
DMSO-d ) δ (ppm): 2.33 (s, 3H, Ar–Me), 2.35 (s, 3H, Ar–
Me), 2.45 (s, 3H, Ar–Me), 2.68 (s, 3H, pyrimidine–Me),
2
7
1
1
6
1
.76 (s, 3H, pyrimidine–Me), 7.20 (s, 1H, Ar–H), 7.17–
.23 (m, 2H, Ar–H), 7.32 (d, J= 8Hz, 2H, Ar–H), 7.35 (s,
H, benzylidene–H), 7.99 (d, J=8 Hz, 2H, Ar–H), 8.60 (s,
H, pyrazole–CH), 8.64 (s, 1H, pyrimidine–CH), 10.65
1726.11 (C¼O), 3042.56 (C–H), 3242.38 (N–H); H NMR
(300MHz, DMSO-d ) δ (ppm): 2.32 (s, 6H, Ar–Me and Ar–
6
Me), 2.69 (s, 3H, pyrimidine–Me), 2.76 (s, 3H, pyrimidine–
Me), 7.21 (d, J=3.9Hz, 2H, Ar–H), 7.26 (s, 1H,
benzylidene–H), 7.73 (s, 1H, pyrazole–CH), 7.80–7.84 (m,
3H, Ar–H), 8.60 (s, 1H, pyrimidine-CH), 9.10 (dd,
1
3
(s,1H, amide–NH); C NMR (100MHz, DMSO-d ) δ
6
(ppm): 17.10, 19.75, 21.30, 21.67, 24.86, 101.38, 110.37,
1
1
1
25.35, 128.63, 129.36, 129.87, 130.38, 131.43, 132.54,
33.19, 135.75, 136.15, 136.99, 142.35, 146.40, 146.59,
4 7.44, 160.06, 161.56, 162.35, 169.45; LC-MS (ESI,
J =2.7Hz, J =8.7Hz, 1H, Ar–H), 10.70 (s, 1H, Amide–
1 2
13
NH); C NMR (100MHz, DMSO-d ) δ (ppm): 16.97, 21.12,
6
22.61, 24.72, 101.59, 111.38, 114.81, and 115.01
2
m/z): 479.5 (M+ H). Anal. Calcd. for C H N O
(d,
J1C–F =21 Hz), 120.13, 120.48, and 120.70
2
8 26 6 2
2
(478.56): C, 70.28; H, 5.48; N, 17.56. Found: C, 70.21; H,
(d, J =22Hz), 119.61, 122.33, 125.05, and 127.77 (q,
C–F
1
3
5
.57; N, 17.65.
5
JC–F =272 Hz), 128.02 and 128.09 (d, J = 7Hz), 129.17,
C–F
30.81, 130.89, 131.11, and 131.19 (dq, J1C–F =22Hz,
J2C–F = 8Hz), 136.14, 137. 68, 139.78, 145.62, 146.81,
48.13, 161.54, 162.57 (d, J =253 Hz), 163.34, 163.67,
2
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {4-[1-
2-bromo-5-fluoro-phenyl)-meth-(Z)-ylidene]-5-oxo-2-p-tolyl-4,5-
dihydro-imidazol-1-yl]-amide (8l).
1
(
2
This compound was
1
1
C–F
prepared by reaction with 5,7-Dimethyl pyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(2-
bromo-5-fluorobenzylidene)-2-(4-methylphenyl)-1,3-oxazol-
168.89; LC-MS (ESI, m/z): 551.5 (M+ H). Anal. Calcd. for
C H F N O (550.52): C, 61.09; H, 4.03; N, 15.27. Found:
28 22 4 6 2
C, 61.02; H, 4.09; N, 15.38.
5(4H)-one (7l). It was obtained as a pale yellow solid (406mg,
5,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-(3,5-
ꢀ
1
74%). MP: 254.4–255.5°C. IR (ATR, cm ) υ: 595.82 (C–
dimethyl-phenyl)-4-[1-(4-methanesulfonyl-2-trifluoromethyl-phenyl)-
meth-(Z)-ylidene]-5-oxo-4,5-dihydro-imidazol-1-yl]-amide (8n).
This compound was prepared by reaction of 5,7-
Br), 754.20 (¼C–H bend), 903.53 (C–F), 1029.77 (C–N),
114.55 (C–O), 1187.83 (C–O), 1235.31 (C–N), 1298.39
C–N), 1369.62 (C–N), 1417.85 (C–C), 1452.51 (C–C),
500.22 (C–C), 1557.37 (C–C), 1630.76 (ꢀC¼C), 1687.64
C¼O), 1737.65 (C¼O), 3068.88 (C–H), 3268.16 (N–H);
1
(
1
(
Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide
(4)
(200mg) with (4Z)-2-(3,5-dimethylphenyl)-4-[4-(methane
sulfonyl)-2-(trifluoromethyl) benzylidene]-1,3-oxazol-5(4H)-
one (7n). It was obtained as a pale yellow solid (476mg,
1
H NMR (400MHz, DMSO-d ) δ (ppm): 2.33 (s, 3H, Ar–
6
ꢀ
1
Me), 2.68 (s, 3H, pyrimidine–Me), 2.76 (s, 3H, pyrimidine–
Me), 7.21(s, 1H, benzylidene–H), 7.31–7.35 (m, 1H, Ar–H),
80%). MP: 270.1–271.4°C; IR (ATR, cm ) υ: 761.59 (¼C–
H bend), 856.89 (C–F), 910.46 (C–F), 959. 96 (C–F),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
1
057.05 (C–N), 1152.68 (C–O), 1188.32 (C–O), 1239.61 (C–
1558.22 (C–C), 1599.70 (C–C), 1631.98 (ꢀC¼C–), 1675.73
N), 1311.18 (C–N), 1381.77 (C–C), 1440.82 (C–C), 1491.39
(C¼O), 1711.46 (C¼O), 3186.05 (C–H), 3211.12 (N–H);
1
(
1
C–C), 1558.77 (C–C), 1627.80 (ꢀC¼C), 1686.71 (C¼O),
H NMR (300 MHz, DMSO-d ) δ (ppm): 2.24 (s, 6H, Ar–
6
1
746.83 (C¼O), 3011.01 (C–H), 3276.28 (N–H); H NMR
Me and Ar–Me), 2.69 (s, 3H, pyrimidine–Me), 2.76 (s, 3H,
pyrimidine–Me), 3.88 (s, 3H, Ar–OMe), 3.94 (s, 3H, Ar–
OMe), 6.68 (s, 1H, Ar–H), 6.77 (d, J=8.7 Hz, 1H, Ar–H),
7.18 (s, 1H, Ar–H), 7.20 (s, 1H, benzylidene–H), 7.52 (s, 1H,
pyrazole–CH), 7.68 (s, 2H, Ar–H), 8.58 (s, 1H, pyrimidine–
CH), 8.91 (d, J= 8.7Hz, 1H, Ar–H), 10.63 (s, 1H, Amide–
(300 MHz, DMSO-d ) δ (ppm): 2.25 (s, 6H, Ar–Me), 2.69 (s,
6
3H, pyrimidine–Me), 2.76 (s, 3H, pyrimidine–Me), 3.40 (s,
3H, Ar–SO Me), 7.22 (s, 1H, benzylidene–H), 7.25 (s, 1H,
2
Ar–H), 7.30 (s, 1H, Ar–H), 7.76 (s, 2H, Ar–H), 8.31 (s, 1H,
pyrazole–CH), 8.43 (d, J=8.7Hz, 1H, Ar–H), 8.61(s, 1H,
pyrimidine–CH), 9.18 (d, J= 8.4Hz, 1H, Ar–H), 10.73 (s, 1H,
13
NH). C NMR (100MHz, DMSO-d ) δ (ppm): 16.98,
6
13
Amide–NH); C NMR (100MHz, DMSO-d ) δ (ppm):
21.28, 24.69, 56.10, 56.49, 98.40, 101.91, 107.55, 111.19,
115.80, 121.73, 126.51, 128.20, 133.53, 134.16, 134.56,
138.15, 145.80, 146.42, 147.80, 159.79, 160.84, 161.20,
162.98, 163.93, 168.85; LC-MS (ESI, m/z): 525.4 (M+ H).
Anal. Calcd. for C H N O (524.58): C, 66.40; H, 5.38; N,
6
16.97, 21.75, 22.24, 24.55, 43.60, 101.46, 111.39, 119.74,
1
122.47, 125.20, 127.93 (q, J =273Hz), 125.32, 125.44,
C–F
3
and 125.50 (d, J =6Hz), 128.17, 128. 78, 129.08, 129.39,
C–F
2
1
1
1
29.69 (q, J = 31Hz), 128.96, 131.86, 135.33, 135.70,
36.08, 136.30, 140.51, 141.89, 145.96, 146.43, 147.94,
60.82, 163.22, 165.41, 168.77; LC-MS (ESI, m/z): 611.4 (M
C–F
29 28 6 4
16.02. Found: C, 66.32; H, 5.47; N, 16.13.
5,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-
(3,5-dimethoxy-phenyl)-4-[1-(4-fluoro-2-trifluoromethyl-phenyl)-
+
H). Anal. Calcd. for C H F N O S (610.62): C, 57.04; H,
29 25 3 6 4
meth-(Z)-ylidene]-5-oxo-4,5-dihydro-imidazol-1-yl]-amide (8q).
This compound was prepared by reaction with 5,7-
Dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
(200mg) with (4Z)-2-(3,5-dimethoxyphenyl)-4-[4-fluoro-2-
(trifluoromethyl) benzylidene]-1,3-oxazol-5(4H)-one (7q). It
was obtained as an off-white solid (460mg, 81%). MP:
4
.13; N, 13.76. Found: C, 56.97; H, 4.22; N, 13.87.
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-
3-chloro-phenyl)-meth-(Z)-ylidene]-2-(3,5-dimethyl-phenyl)-5-oxo-
,5-dihydro-imidazol-1-yl]-amide (8o).
(
4
This compound was
prepared by reaction with 5,7-Dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(3-
chlorobenzylidene)-2-(3,5-di methyl phenyl)-1,3-oxazol-5
ꢀ
1
198.1–199.8°C; IR (ATR, cm ) υ: 730.31 (¼C–H bend),
838.88 (C–F), 876.43 (C–F), 900.95(C–F), 962.14(C–F),
1055.69 (C–N), 1121.18 (C–O), 1199.74 (C–O), 1229.74
(C–N), 1311.59 (C–N), 1348.34 (C–N), 1424.96 (C–C),
1492.57 (C–C), 1551.56 (C–C), 1592.26 (C–C), 1628.49
(4H)-one (7o). It was obtained as a pale yellow solid (398mg,
ꢀ
1
82%). MP: 188.9–190.6°C. IR (ATR, cm ) υ: 682.23 (C–
Cl), 755.75 (¼C–H bend), 1034.16 (C–N), 1160.90 (C–O),
192.74 (C–O), 1238.72 (C–N), 1274.84 (C–N), 1311.39 (C–
N), 1385.87 (C–C), 1434.50 (C–C), 1500.40 (C–C), 1556.60
1
(ꢀC¼C), 1685.85 (C¼O), 1726.14 (C¼O), 3116.34 (C–H),
1
(
3
C–C), 1656.03 (C¼O), 1727.00 (C¼O), 3062.96 (C–H),
3375.13 (N–H); H NMR (300MHz, DMSO-d ) δ (ppm):
6
1
193.21 (N–H); H NMR (300 MHz, DMSO-d ) δ (ppm):
6
2.66 (s, 3H, pyrimidine–Me), 2.75 (s, 3H, pyrimidine–Me),
2.25 (s, 6H, Ar–Me and Ar–Me), 2.69 (s, 3H, pyrimidine–
3.71 (s, 6H, Ar–OMe and Ar–OMe), 6.72 (s, 1H, Ar–H),
7.20 (s, 1H, Ar–H), 7.25 (s, 1H, benzylidene H), 7.29 (s,
1H, pyrazole–CH), 7.77–7.84 (m, 2H, Ar–H), 8.60 (s, 1H,
Me), 2.76 (s, 3H, pyrimidine–Me), 7.20 (s, 1H, benzylidene–
H), 7.30 (s, 2H, Ar–H and Ar–H), 7.55 (s, 2H, Ar–H), 7.71 (s,
2H, Ar–H), 8.34 (d, J=5.7Hz, 1H, Ar–H), 8.42 (s, 1H,
pyrimidine–CH), 9.12 (t, J=6.3Hz, 1H, Ar–H), 10.71(s,
13
pyrazole–CH), 8.59 (s, 1H, pyrimidine–CH), 10.66 (s, 1H,
Amide–NH); C NMR (75 MHz, DMSO-d ) δ (ppm): 16.92,
1
H, Amide–NH). C NMR (100MHz, DMSO-d ) δ (ppm):
6
13
6
17.82, 22.91, 57.43, 101.55, 104.93, 107.09, 111.30,
2
24.54, 55.86, 101.63, 104.65, 106.92, 111.28, 126.97,
129.58, 130.69, 131.23, 131.58, 132.25, 133.87, 136.29,
137.60, 145.86, 146.45, 147.88, 160.81, 162.31, 163.18,
168.72; LC-MS (ESI, m/z): 499.5 (M+ H). Anal. Calcd. for
1
14.82, and 115.02 (d, J = 20 Hz), 120.05 and 120.13 (d,
C–F
3
2
JC–F = 8Hz), 120.47 and 120.69 (d, J = 22 Hz), 119.60,
22.32, 125.04, and 127.76 (q, J = 272 Hz), 128.03 and
28.09 (d, JC–F = 6 Hz), 129.19, 130.81, 130.89,
C–F
1
1
1
C–F
3
C H ClN O (498.98): C, 64.99; H, 4.65; N, 16.84. Found:
C, 64.91; H, 4.72; N, 16.93.
2
2
27
23
6
2
131.11,131.19 (dq, J1 =22Hz, J
= 8Hz), 137.04,
C–F
2C–F
1
37.12, 138.46, 145.90, 146.42, 147.93, 160.83, 161.32,
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-
2,4-dimethoxy-phenyl)-meth-(Z)-ylidene]-2-(3,5-dimethyl-phenyl)-
-oxo-4,5-dihydro-imidazol-1-yl]-amide (8p). This compound
1
and 163.83 (d, J = 251 Hz), 163.19, 164.01, 168.86; LC-
C–F
(
5
MS (ESI, m/z): 583.6 (M + H). Anal. Calcd. for
C H F N O (582.52): C, 57.73; H, 3.81; N, 14.43.
28 22 4 6 4
was prepared by reaction with 5,7-dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200mg) with (4Z)-4-(2,4-
dimethoxybenzylidene)-2-(3,5-dimethylphenyl)-1,3-oxazol-5
Found: C, 57.66; H, 3.89; N, 14.55.
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-
3,5-dimethoxy-phenyl)-4-[1-(4-methanesulfonyl-2-trifluoromethyl-
phenyl)-meth-(Z)-ylidene]-5-oxo-4,5-dihydro-imidazol-1-yl]-amide
(8r).
(
(4H)-one (7p). It was obtained as a pale yellow solid (425 mg,
ꢀ
1
8
3%). MP: 196.8–198.1°C. IR (ATR, cm )υ:752.57 (¼C–H
This compound was prepared by reaction with 5,7-
dimethylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
bend), 1030.29 (C–N), 1108.46 (C–O), 1161.01 (C–O),
188.57 (C–O), 1206.25 (C–O), 1238.14 (C–N), 1275.50
C–N), 1430.26 (C–C), 1463.27 (C–C), 1501.01 (C–C),
1
(
(200 mg) with (4Z)-2-(3,5-dimethoxyphenyl)-4-[4-(methanes
ulfonyl)-2-(trifluoromethyl)benzylidene]-1,3-oxazol-5(4H)-one
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. K. A.K., Y. D. Bodke, A. N. Gowda, G. Sambasivam, and K. G. Bhat
Vol 000
(
2
9
1
7r). It was obtained as a pale yellow solid (513 mg, 82%). MP:
obtained as a pale yellow solid (424mg, 83%). MP:
ꢀ
1
ꢀ1
47.2–249.0°C. IR (ATR, cm ) υ: 766.95 (¼C–H bend),
216.8–218.0°C; IR (ATR, cm ) υ: 756.63 (¼C–H bend),
06.29 (C–F), 932.38 (C–F), 964.94 (C–F), 1063.33 (C–N),
1031.09 (C–N), 1054.25 (C–O), 1114.92 (C–O), 1158.76
(C–O), 1187.80 (C–O), 1204.79 (C–O), 1232.29 (C–O),
1276.28 (C–N), 1294.06 (C–N), 1311.61 (C–N), 1425.22
(C–C), 1457.34 (C–C), 1502.42 (C–C), 1558.42 (C–C),
153.49 (C–O), 1193.51 (C–O), 1230.47 (C–N), 1273.44 (C–
N), 1308.74 (C–N), 1375.57 (C–N), 1451.77(C–C), 1494.82
(
1
C–C), 1558.69 (C–C), 1599.02 (C–C), 1615.49 (ꢀC¼C),
689.43 (C¼O), 1746.50 (C¼O), 3003.72 (C–H), 3288.64 (N–
1592.13 (C–C), 1629.57 (ꢀC¼C–), 1678.76 (C¼O),
1
1
H); H NMR (300 MHz, DMSO-d ) δ (ppm): 2.66 (s, 3H,
pyrimidine–Me), 2.76 (s, 3H, pyrimidine–Me), 3.40 (s, 3H, Ar–
1714.35 (C¼O), 2985.04 (C–H), 3182.32 (N–H);
H
6
NMR (300MHz, DMSO-d ) δ (ppm): 2.66 (s, 3H,
6
SO Me), 3.72 (s, 6H, Ar–OMe and Ar–OMe), 6.74 (s, 1H, Ar–
H), 7.21 (s, 1H, benzylidene–H), 7.27 (s, 2H, Ar–H), 7.33 (s,
pyrimidine–Me), 2.75 (s, 3H, pyrimidine–Me), 3.71 (s,
6H, Ar–OMe and Ar–OMe), 3.88 (s, 3H, Ar–OMe), 3.94
(s, 3H, Ar–OMe), 6.67 (d, J=4.8Hz, 2H, Ar–H), 6.77 (d,
J=8.7Hz, 1H, Ar–H), 7.19 (s, 2H, Ar–H), 7.21 (s, 1H,
benzylidene–H), 7.54 (s, 1H, pyrazole–CH), 8.59 (s, 1H,
pyrimidine–CH), 8.92 (d, J=8.7Hz, 2H, Ar–H), 10.64 (s,
2
1H, pyrazole–CH), 8.32 (s, 1H, Ar–H), 8.43 (d, J= 8.4 Hz, 1H,
Ar–H), 8.62 (s, 1H, pyrimidine–CH), 9.19 (d, J= 8.4 Hz, 1H,
13
Ar–H), 10.74 (s, 1H, Amide–NH); C NMR (100 MHz,
DMSO-d ) δ (ppm): 16.98, 24.56, 43.61, 55.94, 101.47,
6
13
1
05.39, 107.20, 111.36, 119.14, 119.73, 122.46, 125.19,
1H, Amide–NH). C NMR (75MHz, DMSO-d ) δ
6
1
3
127.92 (q, J = 273Hz), 125.43 and 125.49 (d, J =6Hz),
(ppm): 16.96, 24.52, 55.79, 55.83, 56.11, 56.50, 98.41,
101.80, 104.08, 106.72, 107.64, 111.22, 115.74, 122.23,
130.02, 133.90, 134.67, 134.76, 145.85, 146.38, 14 7.84,
159.37, 160.76, 160.82, 160. 97, 161.31, 163.08, 164.07,
168.81; LC-MS (ESI, m/z): 557.5 (M+H). Anal. Calcd.
for C H N O (556.58): C, 62.58; H, 5.07; N, 15.10.
C–F
C–F
2
1
1
1
6
28. 77, 129.07, 129.38, 129.68 (q, JC–F =31Hz), 128.94,
31.88, 135.32, 136.31, 140.54, 141.84, 145.93, 146.47,
47.99, 160.85, 163.25, 165.40, 168.76; LC-MS (ESI, m/z):
43.4 (M+ H). Anal. Calcd. for C H F N O S (642.62): C,
29 25 3 6 6
5
4.20; H, 3.92; N, 13.08. Found: C, 54.11; H, 3.99; N, 13.17.
29 28 6 6
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [4-[1-
3-chloro-phenyl)-meth-(Z)-ylidene]-2-(3,5-dimethoxy-phenyl)-5-
oxo-4,5-dihydro-imidazol-1-yl]-amide (8s).
Found: C, 62.51; H, 5.15; N, 15.21.
(
This compound
was prepared by reaction with 5,7-dimethylpyrazolo[1,5-a]
pyrimidine-3-carbohydrazide (4) (200 mg) with (4Z)-4-(3-
chlorobenzylidene)-2-(3,5-dimethoxyphenyl)-1,3-oxazol-5
ANTICANCER ACTIVITY
All compounds were screened for their in vitro anticancer
activity against representative human cancer cell line (HeLa
cell line) by MTT assay. This is a colorimetric assay that
measures the reduction of yellow 3-(4,5-dimethythiazol-2-
yl)-2,5-diphenyl tetrazolium bromide (MTT) by
mitochondrial succinate dehydrogenase. The MTT enters
the cells and passes into the mitochondria where it is
reduced to an insoluble, colored (dark purple) formazan
product. The cells are then solubilized with an organic
solvent (e.g., dimethyl sulfoxide and isopropanol) and then
released solubilized formazan reagent is measured
spectrophotometrically. Because reduction of MTT can
only occur in metabolically active cells, the level of
activity is a measure of the viability of these cells.
The 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) was made a solution in such a way that
0 mg was dissolved in 10 mL of Hank’s balanced solution.
The cell lines were maintained in 96 wells micro titer plate
containing MEM media supplemented with 10% heat
inactivated fetal calf serum, containing 5% of mixture of
Gentamycin, Penicillin (100 Units/mL) and Streptomycin
(
8
4H)-one (7s). It was obtained as an off-white solid (433 mg,
4%). MP: 201.8–203.5°C. IR (ATR, cm ) υ: 755.66 (¼C–
ꢀ
1
H bend), 850.06 (C–Cl), 1060.23 (C–N), 1115.28 (C–O),
155.18 (C–O), 1197.37 (C–O), 1234.78 (C–O), 1259.22
C–N), 1307.24 (C–N), 1331.30 (C–N), 1428.38 (C–C),
498.78 (C–C), 1596.49 (C–C), 1651.31(ꢀC¼C–), 1681.68
C¼O), 1729.03 (C¼O), 2935.04 (C–H), 3197.00 (N–H);
1
(
1
(
1
H NMR (300 MHz, DMSO-d ) δ (ppm): 2.66 (s, 3H,
6
pyrimidine–Me), 2.76 (s, 3H, pyrimidine–Me), 3.72 (s, 6H,
Ar–OMe and Ar–OMe), 6.71(s, 1H, Ar–H), 7.19 (s, 1H,
benzylidene–H), 7.25 (s, 2H, Ar–H), 7.33 (s, 1H, pyrazole–
CH), 7.55 (s, 2H, Ar–H), 8.30 (d, J= 3.9 Hz, 1H, Ar–H),
8
1
1
1
1
1
.48 (s, 1H, Ar–H), 8.60 (s, 1H, pyrimidine–CH), 10.68 (s,
13
H, Amide–NH); C NMR (75 MHz, DMSO-d ) δ (ppm):
6
6.94, 24.52, 55.85, 101.65, 104.67, 106.93, 111.25, 126.93,
29.50, 130.66, 131.14), 131.51, 132.04, 133.94, 136.35,
37.63, 145.88, 146.41, 147.87, 160.82, 162.23, 163.14,
68.77; LC-MS (ESI, m/z): 531.5 (M +H). Anal. Calcd. for
1
C H ClN O (530.98): C, 61.08; H, 4.37; N, 15.83.
27
23
6 4
Found: C, 61.01; H, 4.46; N, 15.95.
5
,7-Dimethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-
2,4-dimethoxy-phenyl)-4-[1-(3,5-dimethoxy-phenyl)-meth-(Z)-
ylidene]-5-oxo-4,5-dihydro-imidazol-1-yl]-amide (8t).
(
(100μg/mL) in presence of 5% CO at 37°C for 3–4days.
2
This
compound was prepared by reaction with 5,7-dime
thylpyrazolo[1,5-a]pyrimidine-3-carbohydrazide (4)
200 mg) with (4Z)-4-(2,4-dimethoxy benzylidene)-2-
3,5-dimethoxyphenyl)-1,3-oxazol-5(4H)-one (7t). It was
Then after, remove the supernatant and replace MEM media
with Hank’s balanced solution, and the cells were incubated
overnight. The in vitro growth inhibitions of test compounds
were assessed by calorimetric or spectrophotometric method.
This helps to determine the conversion of MTT into
(
(
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Design, Synthesis, and Evaluation of the Anticancer Properties of a Novel Series
of Imidazolone Fused Pyrazolo[1,5-a]pyrimidine Derivatives
formazan blue by living cells. Remove the supernatant from
the plate, add fresh Hank’s balanced salt solution, and treated
with different concentration of compound (approx diluted
with DMSO). The marketed anticancer drug Paclitaxel was
tested as a reference compound in the assay. The control
group contains only DMSO. After 24h of incubation at 37°C
[10] Schenone, S.; Brullo, C.; Bruno, O.; Bondavalli, F.; Mosti, L.;
Maga, G.; Crespan, E.; Carraro, F.; Manetti, F.; Tintori, C.; Botta, M. Eur
J Med Chem 2008, 43, 2665.
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Acknowledgments. We would like to thank the Management
Team at Anthem Biosciences Pvt. Ltd., Bangalore, India, for their
valuable support and allocation of sufficient resources to allow for
the completion of this work. We would also like to thank the An-
alytical Chemistry Team at the Department of Analytical chemis-
try, Anthem Biosciences, Bangalore, India, for carrying out all of
the analytical work described in this study. Lastly, we would like
to thank the Molecular Biology Team at the Maratha Mandal In-
stitute of Technology, Belagavi, Karnataka, India, for conducting
the anti-proliferative studies and MTT assays.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet