Synthesis of amido-linked oxazolyl/thiazolyl/imidazolyl pyrazoles and isoxazoles

Article abstract of DOI:10.1002/jhet.2185

The amido-linked oxazolyl/thiazolyl/imidazolyl pyrazoles and isoxazoles were prepared from the synthetic intermediates oxazolyl/thiazolyl/imidazolyl acrylamides adpoting1,3-dipolar cycloaddition of nitrile imines and nitrile oxides.

Full text of DOI:10.1002/jhet.2185

Month 2014
Synthesis of Amido-linked Oxazolyl/Thiazolyl/Imidazolyl Pyrazoles and
Isoxazoles
Padmavathi Venkatapuram,* Sreelatha Tumma, Seenaiah Dandu, and Premakumari Chokkappagari
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
*
E-mail: vkpuram2001@yahoo.com
Received October 27, 2013
DOI 10.1002/jhet.2185
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The amido-linked oxazolyl/thiazolyl/imidazolyl pyrazoles and isoxazoles were prepared from the syn-
thetic intermediates oxazolyl/thiazolyl/imidazolyl acrylamides adpoting1,3-dipolar cycloaddition of nitrile
imines and nitrile oxides.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
synthesis of pyrazoles involve the approaches based either
on the condensation of hydrazines with 1,3-dicarbonyl com-
pounds [11] and their 1,3-dielectrophilic equivalents includ-
ing α,β-unsaturated aldehydes and ketones [12] or on the
intermolecular 1,3-dipolar cycloaddition of diazoalkanes
and nitrilimines with alkenes and alkynes [13]. A number
of synthetic methods have been developed to construct the
isoxazole core structure including the [3+ 2] cycloaddition
of alkynes/alkenes to nitrile oxides [14], intramolecular cy-
clization of α,β-unsaturated oximes [15], and intermolecular
cyclization of oximes with compounds having double/triple
bonds [16]. The present communication deals with the
synthesis of oxazolyl, thiazolyl, imidazolyl pyrazoles, and
isoxazoles linked by amido moiety.
Nitrogen-containing five-membered heteroaromatic
compounds are important motifs of pharmaceuticals and
functional materials. Typically, oxazoles, thiazoles, and im-
idazoles are often found in a number of naturally occurring
and synthetic molecules with interesting biological activities
such as antiviral, antifungal, antibacterial, antihypertensive,
anti-inflammatory, and antitumor [1–3]. The presence of
pyrazole motif in several blockbuster drugs and pesticides
including Sildenafil (Viagra), Celecoxib (Celebrex),
Rimonabant (Acomplia), Fipronil, and Pyracolfos made this
heterocycle a popular synthetic target for pharmaceutical and
agrochemical industries [4]. Isoxazoles exhibit a wide range
of biological activities including analgesic [5], anti-inflam-
matory [5], antinociceptive [6], and anticancer activities
[
7]. Besides, pyrazoles and isoxazoles bearing carboxamide
RESULTS AND DISCUSSION
moieties demonstrated to have significant pharmacological
applications viz., cyclooxygenase-2 (COX-2) selective inhib-
itors, Celecoxib [8], Rofecoxib [9], and Valdecoxib [10],
which are currently prescribed for the treatment of arthritis
and inflammatory diseases. Typical methods for the
The synthetic intermediates N-(4-aryloxazol-2-yl)acrylam-
ide (4), N-(4-arylthiazol-2-yl)acrylamide (5), and N-(4-aryl-
1H-imidazol-2-yl)acrylamide (6) were prepared as follows.
The reaction of 2-oxazolylamine/2-thiazolylamine/2-
©
2014 HeteroCorporation

P. Venkatapuram, S. Tumma, S. Dandu, and P. Chokkappari
Vol 000
imidazolyl-amine with 3-chloropropanoic acid chloride
produced 3-chloro-N-(4-aryloxazol-2-yl)-propanamide
1)/3-chloro-N-(4-arylthiazol-2-yl)propanamide (2)/3-
chloro-N-(4-aryl-1H-imidazol-2-yl)propanamide (3).
Dehydrohalogenation of latter compounds in the presence
of base resulted in 4, 5, and 6. The olefin moiety present in
in xylene resulted in 1,3-diphenyl-N-(4-aryloxazol-2-yl)-
1H-pyrazole-4-carboxamide (13), 1,3-diphenyl-N-(4-
arylthiazol-2-yl)-1H-pyrazole-4-carboxamide (14), and 1,
3-diphenyl-N-(4-aryl-1H-imidazol-2-yl)-1H-pyrazole-4-
carboxamide (15). The IR spectra of 13, 14, and 15 displayed
absorption bands at 1652–1687 (C═O), 1623–1647 (C═C),
(
À1
4, 5, and 6 was used to develop pyrazoles and isoxazoles
1563–1593 (C═N), and 3237–3342 cm (NH) (Table 2). In
1
adopting 1,3-dipolar cycloaddition methodology. The
cycloaddition of nitrile imines generated from araldehyde
phenylhydrazones in the presence of chloramine-T to
the H-NMR spectra of these compounds, the absence of
AMX splitting pattern and the presence of a singlet at δ
7.16 in 13a, at 7.05 in 14a, and at 7.25ppm in 15a due to
C –H of pyrazole confirmed their formation. Adopting sim-
4 gave 4,5-dihydro-1,3-diphenyl-N-(4-aryloxazol-2-yl)-
1H-pyrazole-4-carboxamide (7). Similarly the compounds
4,5-dihydro-1,3-diphenyl-N-(4-arylthiazol-2-yl)-1H-pyrazole-
4-carboxamide (8) and 4,5-dihydro-1,3-diphenyl-N-(4-
5′
ilar methodology, the compounds 4,5-dihydro-3-phenyl-N-
(4-aryloxazol-2-yl)isoxazole-4-carboxamide (10), 4,
5-dihydro-3-phenyl-N-(4-arylthiazol-2-yl)isoxazole-4-
carboxamide (11), and 4,5-dihydro-3-phenyl-N-(4-aryl-1H-
imidazol-2-yl)-isoxazole-4-carboxamide (12) were prepared
by the cycloaddition of nitrile oxides generated from
araldoximes in the presence of chloramine-T to 4, 5, and 6,
respectively. The IR spectra of 10, 11, and 12 displayed
absorption bands at 1653–1684 (C═O), 1622–1644 (C═C),
aryl-1H-imidazol-2-yl)-1H-pyrazole-4-carboxamide (9) were
prepared by the reaction of 5 and 6 with araldehyde
phenylhydrazones (Scheme 1 and Table 1). The infrared
(IR) spectra of 7, 8, and 9 showed absorption bands at
1
650–1685 (C═O), 1620–1641 (C═C), 1587–1623
À1
1
(C═N), and 3235–3326cm (NH). The H-NMR spectra
À1
of 7a, 8a, and 9a displayed an AMX splitting pattern for
methine and methylene protons of pyrazoline ring. Thus,
three double doublets observed at δ 4.34, 3.64, and
1588–1626 (C═N), and 3239–3331 cm (NH) (Table 2).
1
The H-NMR spectra of 10a, 11a, and 12a showed
three double doublets at δ 4.46, 4.38, and 4.49 ppm due
2
4
.93ppm in 7a; at 4.32, 3.61, and 2.91 ppm in 8a; and at
.47, 3.76, and 3.05 ppm in 9a were assigned to HA,
to H ; at 3.79, 3.62, and 3.86 ppm due to H ; and at
A
M
2.85, 2.76, and 2.87 ppm due to H . The coupling con-
X
H , and H , respectively. The coupling constant values
stant value JAM ≈ 13.0, JAX ≈ 7.0, and JMX ≈ 11.0 indi-
cated that HA, HM are cis, HA, H are trans and H , H
X
are geminal. Oxidation of the compounds 10–12 with
chloranil in xylene produced 3-phenyl-N-(4-aryloxazol-2-yl)
M
X
JAM ≈ 12.5, JAX ≈ 6.6, JMX ≈ 10.5 indicated that HA, HM
are cis, HA, HX are trans, and H , H are geminal.
X
M
M
X
Aromatization of the compounds 7, 8, and 9 with chloranil
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Amido-linked Oxazolyl/Thiazolyl/Imidazolyl Pyrazoles and Isoxazoles
Table 1
Physical and analytical data of compounds 4–18.
Analysis (%) calcd/found
Yield
Compound
mp (°C)
(%)
Mol. formula (MW)
C
H
N
4
4
4
5
5
5
6
6
6
7
7
7
8
8
8
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
a
b
c
a
b
c
a
b
c
a
b
c
a
137–139
128–130
152–154
135–137
125–127
156–158
159–161
165–167
188–190
154–156
142–144
163–165
172–174
158–160
193–195
164–166
149–151
175–177
143–145
136–138
152–154
164–166
140–142
176–178
155–157
129–131
162–164
184–186
179–181
205–207
173–175
195–197
212–214
197–199
185–187
223–225
177–179
165–167
184–186
159–161
183–185
191–193
180–182
167–169
200–202
71
66
74
69
67
73
70
68
76
75
79
81
80
76
78
81
79
76
72
70
75
69
66
72
70
67
72
67
66
64
68
65
66
67
68
65
66
68
67
69
67
65
67
69
68
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
C
C
25
H
H
20
N
N
4
4
4
O
O
O
2
2
2
(408.48)
(422.50)
(442.92)
73.63 (73.51)
74.04 (73.91)
67.69 (67.80)
70.80 (70.73)
71.31 (71.21)
65.30 (65.42)
73.78 (73.69)
74.17 (74.09)
67.86 (67.95)
68.54 (68.46)
69.06 (69.15)
61.94 (62.05)
65.23 (65.31)
66.19 (66.10)
59.53 (59.45)
68.72 (68.66)
69.26 (69.35)
62.15 (62.21)
73.96 (73.88)
74.35 (74.26)
68.02 (68.10)
71.00 (71.07)
71.60 (71.53)
65.78 (65.71)
74.13 (74.05)
74.33 (74.44)
68.34 (68.26)
68.95 (68.88)
69.63 (69.56)
62.29 (62.39)
65.60 (65.69)
66.54 (66.46)
59.68 (59.76)
69.15 (69.08)
69.85 (69.76)
62.45 (62.56)
4.87 (4.94)
5.31 (5.25)
4.27 (4.32)
4.79 (4.75)
5.12 (5.06)
4.13 (4.17)
5.25 (5.19)
5.57 (5.50)
4.60 (4.56)
4.59 (4.54)
5.00 (4.93)
3.89 (3.84)
4.39 (4.33)
4.66 (4.71)
3.73 (3.68)
4.90 (4.85)
5.18 (5.24)
4.08 (4.12)
4.52 (4.46)
4.85 (4.79)
3.93 (3.89)
4.34 (4.29)
4.67 (4.62)
3.79 (3.75)
4.76 (4.72)
5.10 (5.05)
4.17 (4.12)
4.00 (3.95)
4.43 (4.38)
3.25 (3.31)
3.71 (3.77)
4.23 (4.18)
3.22 (3.17)
4.23 (4.27)
4.62 (4.68)
3.64 (3.59)
13.63 (13.72)
13.34 (13.26)
12.73 (12.65)
13.31 (13.20)
12.85 (12.78)
12.12 (12.21)
17.26 (17.19)
16.53 (16.61)
15.74 (15.85)
12.73 (12.61)
12.19 (12.10)
11.54 (11.43)
12.14 (12.03)
11.43 (11.56)
11.07 (10.95)
16.94 (16.86)
16.25 (16.17)
15.19 (15.27)
13.66 (13.79)
13.42 (13.33)
12.80 (12.71)
13.35 (13.26)
12.91 (12.84)
12.15 (12.26)
17.18 (17.27)
16.82 (16.70)
16.05 (15.92)
12.76 (12.68)
12.03 (12.17)
11.35 (11.49)
12.19 (12.10)
11.74 (11.63)
11.13 (11.00)
17.06 (16.96)
16.34 (16.27)
15.44 (15.36)
26
22
25
C H19ClN
C
C
25
26
H
H
20
N
N
19ClN
4
4
4
OS (424.55)
OS (438.57)
OS (458.99)
22
C
25
H
C
C
25
26
H
H
21
N
N
20ClN
5
5
5
O (407.50)
O (421.52)
O (441.94)
(333.35)
(347.37)
(367.79)
S (349.42)
S (363.44)
S (383.86)
(332.37)
(346.39)
(366.81)
(406.46)
(420.49)
(440.90)
b
c
23
C
25
H
0a
0b
0c
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
C
C
19
H
15
N
N
3
3
3
O
O
O
3
3
3
20
H
17
19
C H14ClN
C
19
H
H
15
N
N
3
3
3
O
O
O
2
2
2
C
20
17
19
C H14ClN
C
C
19
20
H
H
16
N
N
4
4
4
4
4
4
O
O
O
O
O
O
2
2
2
2
2
2
18
C
C
19
H15ClN
C
C
25
26
H
H
18
N
N
20
25
H17ClN
C
C
25
26
H
H
18
N
N
17ClN
4
4
4
OS (422.53)
OS (436.56)
OS (456.97)
20
C
25
H
C
C
25
26
H
H
19
N
N
18ClN
5
5
5
O (405.48)
O (419.51)
O (439.92)
(331.33)
(345.36)
(365.77)
S (347.40)
S (361.43)
S (381.84)
(330.35)
(344.38)
(364.79)
21
C
25
H
C
C
19
H
13
N
N
3
3
3
O
O
O
3
3
3
20
H
15
19
C H12ClN
C
19
H
H
13
N
N
3
3
3
O
O
O
2
2
2
C
20
15
19
C H12ClN
C
C
19
20
H
H
14
N
N
4
4
4
O
O
O
2
2
2
16
19
C H13ClN
isoxazole-4-carboxamide (16), 3-phenyl-N-(4-arylthiazol-2-
yl)isoxazole-4-carboxamide (17), and 3-phenyl-N-(4-aryl-
D O was added. The structures of all the compounds
2
were further established by C-NMR and elemental
analyses.(Table 3)
1
3
1H-imidazol-2-yl)isoxazole-4-carboxamide (18) (Scheme 1
and Table 1). The IR spectra of 16, 17, and 18 presented
absorption bands at 1657–1689 (C═O), 1628–1648
CONCLUSIONS
À1
(
C═C), 1592–1624 (C═N), and 3247–3337 cm (NH).
1
The H-NMR spectra of 16a, 17a, and 18a displayed
The 1,3-dipolar cycloaddition of nitrile imines and nitrile
oxides generated from araldehyde phenylhydrazones and
araldoximes in the presence of chloramines-T to oxazolyl/
thiazolyl/imidazolyl acrylamides resulted in a variety of
a singlet at δ 6.85, 6.77, and 6.89 due to C –H of
5
′
isoxazole unit and a broad singlet at 8.56, 8.53, and
.64 ppm due to NH. The latter signal disappeared when
8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Venkatapuram, S. Tumma, S. Dandu, and P. Chokkappari
Vol 000
Table 2
Infrared data of compounds 4–18.
À1
IR (KBr) cm
Compound
NH
C═O
C═C
C═N
4
4
4
5
5
5
6
6
6
7
7
7
8
8
8
9
9
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
a
b
c
a
b
c
a
b
c
a
b
c
a
3318
3314
3325
3298
3277
3289
3307
3302
3315
3322
3320
3328
3241
3235
3244
3317
3309
3326
3289
3281
3294
3246
3239
3251
3320
3316
3331
3241
3237
3249
3247
3239
3255
3336
3333
3342
3293
3286
3298
3255
3247
3261
3327
3319
3337
1649
1630
1635
1636
1629
1642
1643
1638
1647
1671
1668
1675
1656
1650
1661
1681
1678
1685
1674
1670
1679
1658
1653
1664
1684
1680
1687
1676
1672
1679
1657
1652
1663
1683
1680
1687
1677
1673
1681
1662
1657
1666
1686
1682
1689
1623
1618
1626
1625
1623
1629
1628
1624
1631
1638
1635
1641
1632
1628
1636
1624
1620
1627
1639
1634
1643
1626
1622
1632
1631
1627
1638
1630
1629
1633
1636
1633
1640
1645
1641
1647
1646
1635
1648
1631
1628
1637
1638
1633
1642
1572
1567
1576
1574
1568
1579
1581
1583
1589
1579
1567
1583
1592
1588
1605
1597
1589
1593
1599
1591
1606
1594
1590
1608
1598
1588
1610
1575
1568
1582
1586
1577
1592
1589
1583
1594
1621
1617
1624
1597
1592
1602
1604
1596
1612
b
c
0a
0b
0c
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
amido-linked bis heterocycles oxazolyl/thiazolyl/imidazolyl
pyrazoles and isoxazoles.
EXPERIMENTAL
General.
Melting points were determined in open
capillaries on a Mel-Temp apparatus and are uncorrected. The
purity of the compounds was checked by TLC (silica gel H,
BDH, ethyl acetate:hexane, 1:4). The IR spectra were recorded
on a Thermo Nicolet IR 200 FTIR spectrometer (Thermo
Electron Scientific 5225 Verona Road, Madison WI 53711-4995
USA) as KBr pellets, and the wavenumbers were given in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Amido-linked Oxazolyl/Thiazolyl/Imidazolyl Pyrazoles and Isoxazoles
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Venkatapuram, S. Tumma, S. Dandu, and P. Chokkappari
Vol 000
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Amido-linked Oxazolyl/Thiazolyl/Imidazolyl Pyrazoles and Isoxazoles
À1
1
cm . The H-NMR spectra were recorded in CDCl /DMSO-d
3
6
13
on a Jeol JNM λ-400 MHz. The C-NMR spectra were recorded in
CDCl /DMSO-d on a Jeol JNM spectrometer (USA) operating at
3
6
100MHz. All chemical shifts are reported in δ (ppm) using TMS
as an internal standard. The microanalyses were performed on
Perkin-Elmer 240C elemental analyzer (Corporate Headquarters
9
40 Winter Street, Waltham, Massachusetts 02451 USA). The
compounds 3-chloro-N-(4-aryloxazol-2-yl)propanamide (1)/3-
chloro-N-(4-arylthiazol-2-yl)propanamide (2)/3-chloro-N-(4-aryl-
1
H-imidazol-2-yl)-propanamide (3) were prepared as per the
literature procedure [17].
N-(4-Aryloxazol-2-yl)acrylamide (4a–c)/N-(4-arylthiazol-2-yl)
acrylamide (5a–c)/N-(4-aryl-1H-imidazol-2-yl)acrylamide (6a–c):
general procedure. To the compound 1/2/3 (1 mmol) in benzene
(6 mL), triethylamine (2 mL) in benzene (2 mL) was added
dropwise while stirring. After addition was completed, the
mixture was warmed gently for 5 min. Then, it was cooled and
filtered. The filtrate was washed successively with water, dil.
HCl, sat. NaHCO
dried (an. Na SO
3
solution, and brine. The organic layer was
), and the solvent was removed in vacuo.
2
4
The resultant compound was purified by recrystallization from
benzene-cyclohexane.
4
,5-Dihydro-1,3-diphenyl-N-(4-aryloxazol-2-yl)-1H-pyrazole-4-
carboxamide (7a–c)/4,5-dihydro-1,3-diphenyl-N-(4-arylthiazol-2-yl)-
H-pyrazole-4-carboxamide (8a–c)/4,5-dihydro-1,3-diphenyl-
1
N-(4-aryl-1H-imidazol-2-yl)-1H-pyrazole-4-carboxamide (9a–c):
general procedure. The compound 4/5/6 (1mmol), araldehyde
phenylhydrazones (1.2 mmol), and chloramine-T (1.2mmol) in
methanol (20 mL) were refluxed for 20–22h. The precipitated inor-
ganic salts were filtered off. The filtrate was concentrated, and the
residue was extracted with dichloromethane. The organic layer
2 4
was washed with water, brine, and dried (an. Na SO ). The solvent
was removed under vacuum. The resultant residue was purified by
column chromatography (silica gel, 60–120 mesh) using hexane-
ethyl acetate (4:1) as eluent.
4
(
4
,5-Dihydro-3-phenyl-N-(4-aryloxazol-2-yl)isoxazole-4-carboxamide
10a–c)/4,5-dihydro-3-phenyl-N-(4-arylthiazol-2-yl)isoxazole-
-carboxamide (11a–c)/4,5-dihydro-3-phenyl-N-(4-aryl-1H-
imidazol-2-yl)isoxazole-4-carboxamide (12a–c): general pro-
cedure. A mixture of compound 4/5/6 (1 mmol), araldoxime
(
1.2 mmol), chloramine-T (1.2 mmol), and methanol (20 mL)
was refluxed for 16–18 h. The precipitated inorganic salts were
filtered off. The filtrate was concentrated and the residue was
extracted with dichloromethane. The organic layer was washed
with water, brine, and dried (an. Na SO ). The solvent was
2
4
removed under reduced pressure. The resultant residue was
purified by column chromatography (silica gel, 60–120 mesh)
using hexane-ethyl acetate (4:1) as eluent.
1
,3-Diphenyl-N-(4-aryloxazol-2-yl)-1H-pyrazole-4-carboxamide
13a–c)/1,3-diphenyl-N-(4-arylthiazol-2-yl)-1H-pyrazole-4-
carboxamide (14a–c)/1,3-diphenyl-N-(4-aryl-1H-imidazol-2-yl)-
H-pyrazole-4-carboxamide (15a–c)/3-phenyl-N-(4-aryloxazol-2-yl)-
(
1
isoxazole-4-carboxamide (16a–c)/3-phenyl-N-(4-arylthiazol-2-yl)
isoxazole-4-carboxamide (17a–c)/3-phenyl-N-(4-aryl-1H-
imidazol-2-yl)isoxazole-4-carboxamide (18a–c): general proce-
dure. A mixture of 7/8/9/10/11/12 (1 mmol) and chloranil
(
1.4 mmol) in xylene (10 mL) was refluxed for 20–22 h. Then,
the reaction mixture was treated with a 5% NaOH solution. The
organic layer was separated and washed with water. It was dried
over anhydrous Na
rotary evaporator. The resultant solid was recrystallized from
-propanol.
2 4
SO , and the solvent was removed on a
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Venkatapuram, S. Tumma, S. Dandu, and P. Chokkappari
Vol 000
Acknowledgments. The authors are grateful to Board of
Research in Nuclear Sciences (BRNS-DAE), Mumbai for
financial assistance under major research project.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet