Synthesis, Characterization, and Antioxidant Activity of a New Class of Amido linked Azolyl Thiophenes

Article abstract of DOI:10.1002/jhet.3177

A new class of amido linked azolyl thiophenes was prepared from the synthetic intermediates azolyl amines and 5-chlorothiophene-2-carbonyl chloride adopting conventional and ultrasonication methodologies. It was observed that the reaction took place in shorter reaction times with higher yields under ultrasonication. The structures of the synthesized compounds were characterized by spectral parameters and also tested for antioxidant activity. Among all the tested compounds, methoxy substituted oxazolyl thiophene carboxamide (8c) displayed promising antioxidant activity. Besides, the electron donating groups on the phenyl ring enhanced the antioxidant activity when compared with the electron withdrawing groups.

Full text of DOI:10.1002/jhet.3177

1410
Synthesis, Characterization, and Antioxidant Activity of a New Class of
Amido linked Azolyl Thiophenes
Vol 55
*
and Padmaja Adivireddy
Sreenivasulu Thatha, Nagarjuna Ummadi, Padmavathi Venkatapuram,
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
*
E-mail: adivireddyp@yahoo.co.in
Received November 22, 2017
DOI 10.1002/jhet.3177
Published online 19 April 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new class of amido linked azolyl thiophenes was prepared from the synthetic intermediates azolyl
amines and 5-chlorothiophene-2-carbonyl chloride adopting conventional and ultrasonication methodolo-
gies. It was observed that the reaction took place in shorter reaction times with higher yields under
ultrasonication. The structures of the synthesized compounds were characterized by spectral parameters
and also tested for antioxidant activity. Among all the tested compounds, methoxy substituted oxazolyl thio-
phene carboxamide (8c) displayed promising antioxidant activity. Besides, the electron donating groups on
the phenyl ring enhanced the antioxidant activity when compared with the electron withdrawing groups.
J. Heterocyclic Chem., 55, 1410 (2018).
INTRODUCTION
[17], anticonvulsant [18], antitumor [19–22], anticancer
[23–25], antimicrobial [16,26,27], antimalarial [28],
antiviral [29], and antioxidant [30–32] activities. On the
other hand, amide bonds occur in many drugs and
biomolecules [33,34]. They also find many applications
due to their high polarity, stability, and conformational
flexibility. It is well known that the combination of two
or more types of heterocycles linked by amide moiety
into one molecular frame work would afford a novel
entity with enhanced pharmacological activities [35,36].
The exploration of new, efficient, and inexpensive
synthetic methods based on green chemistry in organic
synthesis is always in demand. Ultrasound activation is
used successfully to promote reaction rates of a number
of chemical transformations. Motivated by the previously
mentioned findings and as part of a continuing effort
towards the development of biologically active
heterocycles [37–39], synthesis and antioxidant activity
of a new class of amido linked azolyl thiophenes have
been taken up.
Among nitrogen and sulfur-containing five-membered
heteroarenes-thiophenes, oxazoles, thiazoles, and
imidazoles have gained prominence due to their unique
biological and physical properties. Thiophenes are
prevalent in many natural and synthetic products with a
broad spectrum of biological activites. Besides,
thiophenes are of particular interest for both medicinal
and synthetic chemists because they are useful as
versatile intermediates in organic synthesis [1]. Oxazoles
occur as subunits in numerous natural products [2] such
as Leucamide A and its analogues, function as anticancer
reagents. Besides, oxazole is a precursor in many
biochemical and synthetic transformations [3–6]. The
pharmaceutical agents, namely, inthomycin C, oxaprozin,
pemoline, and bengazole A, contain oxazole motif. In
addition, thiazoles are useful in the treatment of allergies
[7], hypertension [8], inflammation [9], schizophrenia
[10], microbial [11,12], and HIV infections [13].
Sulfathiazole, bleomycin, and tiazofurin are some of the
drugs having thiazole moiety. On the other hand,
imidazole nucleus is a privileged scaffold in histidine,
Vit-B12, a component of DNA base structure, histamine,
and biotin. Moreover, imidazole derivatives exhibit anti-
inflammatory [14,15], antipyretic [16], antidepressant
RESULTS AND DISCUSSION
The amido linked oxazolyl thiophenes, thiazolyl
thiophenes, and imidazolyl thiophenes were synthesized
© 2018 Wiley Periodicals, Inc.

June 2018
Synthesis, Characterization, and Antioxidant Activity of a New Class of Amido
linked Azolyl Thiophenes
1411
from the synthetic intermediates 4-aryloxazol-2-amine (2),
4-arylthiazol-2-amine (3), 4-aryl-1H-imidazol-2-amine (5),
and 5-chlorothiophene-2-carbonyl chloride (7). The
compounds 2 and 3 were obtained by the reaction of
phenacyl bromide (1) with urea and thiourea in methanol
[40]. However, the reaction of compound 1 with acetyl
guanidine gave N-(4-aryl-1H-imidazol-2-yl)acetamide (4)
which on hydrolysis under acidic conditions [41]
produced compound 5. The chlorination of 5-
chlorothiophene-2-carboxylic acid (6) with thionyl
chloride in dichloromethane led to the formation of 7
[42] (Scheme 1). The 5-chloro-N-(4-aryloxazol-2-yl)
thiophene-2-carboxamide (8) was synthesized by
condensation of compound 2 with 7 in tetrahydrofuran in
the presence of 10% NaOH. In a similar way, the reaction
between compound 3 with 7 afforded 5-chloro-N-(4-
arylthiazol-2-yl)thiophene-2-carboxamide (9). Furthermore, 5-
chloro-N-(4-aryl-1H-imidazol-2-yl)-thiophene-2-carboxamide
(10) was prepared by the condensation of compound 5 with
7 in tetrahydrofuran in the presence of 10% NaOH.
The compounds 8–10 were also synthesized under
ultrasonication (Scheme 2 and Table 1). It was observed
that the target compounds were obtained in shorter reaction
times and in high yield under ultrasonication. The 1H
NMR spectra of 8a and 9a showed two doublets at δ
6.88, 6.83 ppm (C4’─H), 8.10, 8.06 ppm (C3’─H), and a
broad singlet at 9.25, 9.36 ppm (NHCO). In addition, a
singlet due to C5─H appeared at much downfield region
Scheme 1. Synthesis of azolyl amines and 5-chlorothiophene-2-carbonyl chloride.
Scheme 2. Synthesis of amido linked oxazolyl/thiazolyl/imidazolyl thiophenes.
Journal of Heterocyclic Chemistry
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S. Thatha, N. Ummadi, P. Venkatapuram, and P. Adivireddy
Vol 55
Table 1
much downfield region and merged with aromatic protons.
The signals due to NH protons disappeared when D2O
was added. The structures of all the new compounds were
also established by infrared (IR), 13C NMR, mass spectral
data, and microanalyses.
The preparation of compounds 8–10 under conventional and ultrasound
irradiation methods.
Conventional
Ultrasound
Time
(h)
Yield
(%)
Time
(min)
Yield
(%)
Entry Product
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
4.1
75
68
74
69
77
71
80
82
84
87
83
74
76
72
78
75
79
77
30
28
26
25
27
24
21
26
23
27
22
24
23
25
27
29
26
28
86
88
90
89
85
87
91
95
93
92
88
89
90
93
91
88
91
92
ANTIOXIDANT ACTIVITY
4.0
5.2
5.4
5.6
6.0
3.0
3.5
3.2
3.3
3.6
3.8
4.2
4.4
4.1
4.3
4.5
4.6
The compounds 8–10 were evaluated for antioxidant
activity by 2,2-diphenyl-1-picrylhydrazyl [43,44], nitric
oxide [45,46], and hydrogen peroxide (H2O2) [47]
methods at four concentrations (25, 50, 75, and
100 μg/mL). Ascorbic acid was used as the standard drug
in all the three methods. The perusal of results (Tables 2–4
and Figs. 1–3) indicated that oxazolyl thiophene
carboxamides (8) showed greater radical scavenging
activity than the thiazolyl thiophene carboxamides (9)
and imidazolyl thiophene carboxamides (10). However,
the compounds 9 displayed slightly higher activity than
the compounds 10. It was observed that compounds
8a–c, 9a–c, and 10a–c exhibited greater radical
scavenging activity when compared with the other
compounds. It was also noticed that with increasing
electron donating effect the antioxidant activity increases.
In fact, methoxy substituted compounds showed higher
activity than methyl substituted ones. This may be due to
inductive effect of methyl and mesomeric effect of
methoxy substituents. The methoxy substituted oxazolyl
9
10
11
12
13
14
15
16
17
18
1
and merged with aromatic protons. However, the H NMR
spectrum of 10a displayed two doublets and two broad
singlets at δ 6.78, 7.97, 9.80, and 11.50 ppm due to
C4’─H, C3’─H, NHCO, and NH of imidazole,
respectively. Besides, a singlet due to C5─H observed at
Table 2
% Scavenging activity of compounds 8–10 on 2,2-diphenyl-1-picrylhydrazyl radical.
Concentration (μg/mL)
Compd. No.
25
50
75
100
IC50
8a
44.26 0.21
50.69 0.14
62.47 0.44
69.23 0.27
49.31 0.19
8b
53.44 0.10
57.95 0.39
66.13 0.13
74.31 0.38
23.39 0.66
8c
55.52 0.45
59.64 0.53
69.16 0.54
79.52 0.35
22.51 0.32
8d
-
-
-
-
-
8e
23.22 0.34
26.42 0.83
35.55 0.49
42.43 0.27
117.84 0.22
8f
-
-
-
-
-
9a
34.38 0.55
40.32 0.15
49.17 0.79
59.52 0.21
76.26 0.14
9b
39.65 0.44
46.42 0.31
56.27 0.71
66.42 0.56
53.85 0.26
9c
48.32 0.59
56.17 1.07
66.18 0.63
72.13 0.62
25.86 0.20
9d
-
-
-
-
-
9e
11.12 0.49
16.66 0.28
28.37 0.31
33.53 0.67
149.12 0.44
9f
-
-
-
-
-
10a
26.42 0.98
34.73 0.36
45.06 0.58
55.20 0.95
90.57 0.68
10b
29.83 0.63
34.39 0.17
46.18 0.61
57.12 0.34
81.20 0.78
10c
36.56 0.42
41.42 0.25
53.11 0.82
62.68 0.43
70.60 0.36
10d
-
-
-
-
-
10e
7.13 1.14
12.76 0.48
20.16 0.95
28.47 0.64
175.62 0.12
10f
-
-
-
-
-
Ascorbic acid
Blank
58.30 0.98
-
64.29 0.47
-
72.44 0.36
-
81.20 0.59
-
21.44 0.42
-
-, no activity; , standard deviation.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis, Characterization, and Antioxidant Activity of a New Class of Amido
linked Azolyl Thiophenes
1413
Table 3
% Scavenging activity of compounds 8–10 on H2O2 radical.
Concentration (μg/mL)
Compd. No.
25
50
75
100
IC50
8a
35.15 0.16
42.67 0.50
50.18 0.63
62.32 0.43
74.73 0.19
8b
44.68 0.19
50.27 0.89
59.76 0.25
68.24 0.47
49.73 0.48
8c
45.52 0.45
54.64 0.23
62.86 0.34
71.52 0.55
45.75 0.42
8d
-
-
-
-
-
8e
15.74 0.59
20.65 0.28
31.21 1.12
39.32 0.40
127.16 0.34
8f
-
-
-
-
-
9a
26.38 0.68
36.25 0.87
56.18 0.62
56.22 0.57
88.93 0.25
9b
33.07 0.95
40.58 0.65
48.28 0.71
62.42 0.38
77.67 0.33
9c
42.01 0.59
48.54 0.57
56.18 0.63
66.83 0.39
51.50 0.79
9d
-
-
-
-
-
9e
8.15 1.01
10.19 0.28
21.76 0.31
33.53 0.98
149.12 0.57
9f
-
-
-
-
-
10a
23.84 1.17
27.68 0.44
39.56 0.65
51.36 0.38
97.35 0.74
10b
26.12 0.68
32.33 0.67
41.18 0.61
53.14 0.54
94.09 0.42
10c
32.56 0.42
39.01 0.34
47.51 0.89
60.89 0.64
78.93 1.02
10d
-
-
-
-
-
10e
5.41 1.14
9.76 0.68
14.62 0.65
26.12 0.74
191.42 0.11
10f
-
-
-
-
-
Ascorbic acid
Blank
49.46 0.60
-
59.21 0.27
-
68.59 0.35
-
75.38 0.47
-
25.27 0.32
-
-, no activity, , standard deviation.
Table 4
% Scavenging activity of compounds 8–10 on nitric oxide radical.
Concentration (μg/mL)
Compd. No.
25
50
75
100
IC50
8a
18.06 0.52
22.56 0.21
30.84 0.31
40.51 0.20
123.42 0.36
8b
22.88 0.44
28.29 0.11
33.02 0.39
43.55 0.61
114.81 0.31
8c
24.31 0.39
30.55 0.13
35.22 0.16
45.89 0.54
185.94 0.31
8d
-
-
-
-
-
8e
6.52 0.84
10.12 1.19
18.17 0.26
28.19 0.42
108.95 0.71
8f
-
-
-
-
-
9a
11.74 0.34
16.70 0.24
26.35 0.35
34.87 0.89
177.36 0.26
9b
14.14 1.16
21.43 0.56
29.75 0.20
38.20 0.14
143.38 0.39
9c
20.13 0.56
26.13 1.06
30.14 0.26
42.48 0.43
130.89 0.57
9d
-
-
-
-
-
9e
5.12 1.13
8.18 0.95
16.23 0.29
23.82 0.35
117.70 0.48
9f
-
-
-
-
-
10a
8.25 0.87
11.61 0.33
20.43 0.28
28.17 0.12
209.90 0.69
10b
12.73 0.29
16.63 0.53
26.32 0.42
35.73 0.35
177.49 1.01
10c
15.61 0.82
23.37 0.52
30.83 0.25
38.21 0.33
139.93 1.10
10d
-
-
-
-
-
10e
4.27 0.76
7.12 0.73
11.21 1.25
36.17 0.47
130.85 1.03
10f
-
-
-
-
-
Ascorbic acid
Blank
28.64 0.58
-
34.31 0.31
-
39.22 0.92
-
48.70 0.26
-
138.23 1.01
-
-, no activity; , standard deviation.
thiophene carboxamide (8c) displayed promising radical
scavenging activity among all the tested compounds
when compared with the standard drug. The bromo
substituted compounds showed the least activity. On the
other hand, the chloro and nitro substituted compounds
8d, 8f, 9d, 9f, 10d, and 10f exhibited no activity. The
structure–activity relationship of the compounds
revealed that amido linked oxazolyl thiophenes and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Thatha, N. Ummadi, P. Venkatapuram, and P. Adivireddy
Vol 55
Figure 1. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of the compounds 8–10. [Color figure can be viewed at wileyonlinelibrary.
com]
Figure 2. Hydrogen peroxide (H2O2) radical scavenging activity of the compounds 8–10. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 3. Nitric oxide (NO) radical scavenging activity of the compounds 8–10. [Color figure can be viewed at wileyonlinelibrary.com]
thiazolyl thiophenes displayed higher radical scavenging
activity than imidazolyl thiophenes. In general, it was
observed that unsubstituted, methyl, and methoxy
substituted compounds displayed higher radical
scavenging than the chloro, bromo, and nitro substituted
compounds.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

June 2018
Synthesis, Characterization, and Antioxidant Activity of a New Class of Amido
linked Azolyl Thiophenes
1415
CONCLUSIONS
tetrahydrofuran (5 mL), 10% NaOH (10 mL) was added.
To this, 5-chlorothiophene-2-carbonyl chloride (7) (0.513 g,
0.8 mmol) was added portion-wise while stirring at room
temperature and continued the stirring for 3–6 h at the same
temperature. Then, dil. HCl was slowly added to the reaction
mixture until pH 2. The resultant gummy substance was
purified by passing through a column of silica gel (60–120
mesh) using hexane-ethyl acetate (3:1) as eluent.
A
new class of heterocycles-oxazolyl thiophene
carboxamides, thiazolyl thiophene carboxamides, and
imidazolyl thiophene carboxamides were synthesized
from the simple substrates 4-aryloxazol-2-amine, 4-
arylthiazol-2-amine, 4-aryl-1H-imidazol-2-amine, and 5-
chlorothiophene-2-carbonyl
chloride
adopting
Ultrasound irradiation method.
To a solution of
conventional and ultrasonication methodologies. Indeed,
the reaction proceeded in shorter reaction times with
higher yields under ultrasonication than conventional
method. The structures of all compounds were
characterized by IR, 1HNMR, 13C NMR, and mass
spectral data and also evaluated for antioxidant activity.
Among all the tested compounds, methoxy substituted
oxazolyl thiophene carboxamide displayed promising
antioxidant activity. Besides, amido linked thiazolyl
thiophenes exhibited comparatively higher radical
scavenging activity than the imidazolyl thiophenes. It was
observed that compounds having electron donating
groups showed greater antioxidant activity than the
compounds having electron withdrawing groups.
compound 2/3/5 (0.642 g, 1 mmol) in tetrahydrofuran
(3 mL), 10% NaOH (10 mL) was added. Then, 5-
chlorothiophene-2-carbonyl chloride (7) (0.513 g,
0.8 mmol) was added to the contents of the flask and
subjected to ultrasound irradiation at a frequency of
46 KHz for 20–30 min at room temperature. Then, dil.
HCl was slowly added to the reaction mixture until pH 2.
The resultant gummy substance was purified by column
chromatography (silica gel, 60–120 mesh) using hexane-
ethyl acetate (3:1) as eluent.
5-Chloro-N-(4-phenyloxazol-2-yl)thiophene-2-carboxamide
(8a). Mp 147–149°C; IR (KBr cmꢀ1): 3,382 (NH), 1,674
1
(C═O), 1,626 (C═C), 1,575 (C═N); H NMR (400 MHz,
DMSO-d6): δ 6.88 (d, J = 4 Hz, 1H, C4’─H), 7.53–7.86
(m, 6H, Ar─H, C5─H), 8.10 (d, J = 4 Hz, 1H, C3’─H),
9.25 (bs, 1H, NHCO) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 126.7, 129.1, 131.2, 132.4, 133.7, 137.9,
140.3, 140.6, 141.5, 150.1, 151.8, 163.7 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 327.7370 [M + Na]. Anal. Calcd. for
C14H9ClN2O2S: C 55.18; H 2.98; N 9.19. Found: C
EXPERIMENTAL
General.
Melting points were determined in open
capillaries on a Mel-Temp apparatus (Ft-IR spectrometer-
Thermo Electron Scientific Instruments LLC, Madison,
WI) and are uncorrected. The purity of the compounds
was checked by thin-layer chromatography (silica gel H,
BDH, hexane/ethyl acetate, 3:1). The IR spectra were
55.29; H 3.00; N 9.39%.
5-Chloro-N-(4-(4-methylphenyl)oxazol-2-yl)thiophene-2-
carboxamide (8b). Mp 155–157°C; IR (KBr cmꢀ1): 3,365
(NH), 1,654 (C═O), 1,638 (C═C), 1,563 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 2.39 (s, 3H, Ar─CH3), 6.81 (d,
J = 3.6 Hz, 1H, C4’─H), 7.23–7.69 (m, 5H, Ar─H,
C5─H), 8.05 (d, J = 3.6 Hz, 1H, C3’─H), 9.32 (bs, 1H,
NHCO) ppm; 13C NMR (100 MHz, DMSO-d6): δ 23.2
(Ar─CH3), 126.4, 128.7, 129.9, 131.1, 132.9, 137.5,
139.7, 140.5, 141.8, 143.5, 152.2, 164.9 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 341.7641 [M + Na]. Anal. Calcd. for
C15H11ClN2O2S: C 56.52; H 3.48; N 8.79. Found: C
recorded on
a
Thermo Nicolet IR 200 FT–IR
spectrometer (Darmstadt, Germany) as KBr pellets, and
the wave numbers were given in cmꢀ1. The H NMR and
1
13C NMR spectra were recorded in hexadeuterated
dimethyl sulfoxide (DMSO-d6) on a Bruker spectrometer
(Germany) operating at 400 and 100 MHz. All chemical
shifts are reported in δ (ppm) using tetramethylsilane as
an internal standard. High-resolution mass spectra were
recorded on Micromass Q-TOF spectrometer (Woburn,
MA) using electrospray ionization. The antioxidant
activity was carried out by measuring the absorbance of
the test solutions using UV–Visible spectrophotometer,
Shimadzu UV-2450 (Shimadzu, Tokyo, Japan). The
microanalyses were determined using Perkin-Elmer 240C
elemental analyzer (Waltham, MA). Ultrasonication was
performed in a Bandelin (Berlin, Germany) sonorex RK
102 H ultrasonic bath operating at a frequency of 46 KHz.
56.65; H 3.52; N 9.03%.
5-Chloro-N-(4-(4-methoxyphenyl)oxazol-2-yl)thiophene-2-
carboxamide (8c). Mp 162–164°C; IR (KBr cmꢀ1): 3,389
(NH), 1,687 (C═O), 1,634 (C═C), 1,566 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 3.81 (s, 3H, Ar─OCH3), 6.79 (d,
0
J = 3.8 Hz, 1H, C4 ─H), 7.01–7.67 (m, 5H, Ar─H, C5─H),
8.03 (d, J = 3.8 Hz, 1H, C3’─H), 9.29 (bs, 1H, NHCO)
ppm; 13C NMR (100 MHz, DMSO-d6):
δ 56.6
General procedure for the synthesis of 5-chloro-N-(4-aryloxazol-
2-yl)thiophene-2-carboxamide (8) / 5-chloro-N-(4-arylthiazol-2-yl)
thiophene-2-carboxamide (9) / 5-chloro-N-(4-aryl-1H-imidazol-2-
yl)thiophene-2-carboxamide (10). Conventional method. To a
(Ar─OCH3), 139.2, 126.1, 127.4, 128.9, 129.4, 130.7,
136.1, 139.3, 140.5, 142.8, 151.7, 165.3 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 357.7645 [M + Na]. Anal. Calcd. for
stirred solution of compound 2/3/5 (0.642 g, 1 mmol) in
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S. Thatha, N. Ummadi, P. Venkatapuram, and P. Adivireddy
Vol 55
C15H11ClN2O3S: C 53.82; H 3.31; N 8.37. Found: C
53.92; H 3.30; N 8.46%.
C5─H), 7.93 (d, J = 3.6 Hz, 1H, C3’-H), 9.47 (bs, 1H,
NHCO) ppm; 13C NMR (100 MHz, DMSO-d6): δ 20.4
(Ar─CH3), 124.1, 127.4, 128.3, 129.2, 129.6, 129.8
136.5, 139.8, 140.3, 142.7, 151.4, 162.6 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: (m/z) 357.8267 [M + Na]. Anal. Calcd. for
C15H11ClN2OS2: C 53.81; H 3.31; N 8.37. Found: C
5-Chloro-N-(4-(4-chlorophenyl)oxazol-2-yl)thiophene-2-
carboxamide (8d). Mp 167–169°C. IR (KBr cmꢀ1): 3,371
(NH), 1,648 (C═O), 1,639 (C═C), 1,553 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 7.10 (d, J = 3.7 Hz, 1H, C4’─H),
7.57–7.98 (m, 5H, Ar─H, C5─H), 8.02 (d, J = 3.7 Hz, 1H,
C3’─H), 9.42 (bs, 1H, NHCO) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 128.3, 130.7, 131.9, 132.8, 133.6, 139.4,
142.1, 142.9, 143.2, 145.1, 154.3, 165.7 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 362.1786 [M + Na]. Anal. Calcd. for
C14H8Cl2N2O2S: C 49.58; H 2.38; N 8.26. Found: C
53.81; H 3.31; N 8.37%.
5-Chloro-N-(4-(4-methoxyphenyl)thiazol-2-yl)thiophene-2-
carboxamide (9c). Mp 173–175°C; IR (KBr cmꢀ1): 3,265
(NH), 1,684 (C═O), 1,639 (C═C), 1,567 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 3.79 (s, 3H, Ar─OCH3), 6.74 (d,
J = 3.8 Hz, 1H, C4’─H), 7.03–7.59 (m, 5H, Ar─H, C5─H),
7.91 (d, J = 3.8 Hz, 1H, C3’─H), 9.39 (bs, 1H, NHCO)
49.66; H 2.39; N 8.33%.
ppm; 13C NMR (100 MHz, DMSO-d6):
δ 50.8
N-(4-(4-Bromophenyl)oxazol-2-yl)-5-chlorothiophene-2-
carboxamide (8e). Mp 170–172°C. IR (KBr cmꢀ1): 3,385
(Ar─OCH3), 123.5, 125.4, 127.8, 128.9, 129.3, 135.6,
138.3, 138.7, 139.1, 141.4, 149.8, 162.7 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 373.8235 [M + Na]. Anal. Calcd. for
C15H11ClN2O2S2: C 51.35; H 3.16; N 7.98. Found: C
(NH), 1,682 (C═O), 1,642 (C═C), 1,572 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 7.07 (d, J = 3.9 Hz, 1H, C4’─H),
7.55–7.86 (m, 5H, Ar─H, C5─H), 8.19 (d, J = 3.9 Hz, 1H,
C3’─H), 9.38 (bs, 1H, NHCO) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 127.8, 130.6, 131.1, 131.9, 132.9, 138.5,
140.1, 141.9, 142.8, 144.3, 153.2, 164.9 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 404.6346 [M + Na]. Anal. Calcd. for
C14H8BrClN2O2S: C 43.83; H 2.10; N 7.30. Found: C
51.45; H 3.14; N 8.19%.
5-Chloro-N-(4-(4-chlorophenyl)thiazol-2-yl)thiophene-2-
carboxamide (9d). Mp 177–178°C; IR (KBr cmꢀ1): 3,254
(NH), 1,667 (C═O), 1,633 (C═C), 1,559 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 7.09 (d, J = 3.7 Hz, 1H, C4’─H),
7.54–8.04 (m, 5H, Ar─H, C5─H), 8.07 (d, J = 3.7 Hz, 1H,
C3’─H), 9.46 (bs, 1H, NHCO) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 127.2, 129.6, 131.8, 132.4, 132.7, 137.9,
140.1, 141.6, 142.8, 144.6, 153.9, 164.5 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 378.2417 [M + Na]. Anal. Calcd. for
C14H8Cl2N2OS2: C 47.33; H 2.27; N 7.89. Found: C
43.75; H 2.12; N 7.45%.
5-Chloro-N-(4-(4-nitrophenyl)oxazol-2-yl)thiophene-2-
carboxamide (8f). Mp 160–162°C; IR (KBr cmꢀ1): 3,392
(NH), 1,687 (C═O), 1,645 (C═C), 1,569 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 7.15 (d, J = 4 Hz, 1H, C4’─H),
7.69–8.14 (m, 5H, Ar─H, C5─H), 8.27 (d, J = 4 Hz, 1H,
C3’─H), 9.40 (bs, 1H, NHCO) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 129.3, 132.4, 133.5, 134.7,
135.1, 139.6, 142.9, 143.7, 144.2, 145.4, 155.6,
166.2 ppm (C-2, C-4, C-5, C-50, C-20, C-30, C-40, C═O,
aromatic carbons). HRMS: m/z 372.7354 [M + Na]. Anal.
Calcd. for C14H8ClN3O4S: C 48.08; H 2.31; N 12.01.
47.41; H 2.28; N 8.06%.
N-(4-(4-Bromophenyl)thiazol-2-yl)-5-chlorothiophene-2-
carboxamide (9e). Mp 184–186°C; IR (KBr cmꢀ1): 3,259
(NH), 1,675 (C═O), 1,638 (C═C), 1,561 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 7.02 (d, J = 4.2 Hz, 1H, C4’─H),
7.55–7.86 (m, 5H, Ar─H, C5─H), 8.17 (d, J = 4.2 Hz, 1H,
C3’─H), 9.42 (bs, 1H, NHCO) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 126.7, 129.4, 130.3, 130.9, 131.1, 136.5,
139.1, 139.9, 140.8, 142.8, 151.4, 163.7 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 422.6957 [M + Na]. Anal. Calcd. for
C14H8BrClN2OS2: C 42.07; H 2.02; N 7.01. Found: C
42.18; H 2.05; N 7.21%.
Found: C 48.20; H 2.34; N 12.23%.
5-Chloro-N-(4-phenylthiazol-2-yl)thiophene-2-carboxamide
(9a). Mp 158–160°C; IR (KBr cmꢀ1): 3,292 (NH), 1,676
1
(C═O), 1,633 (C═C), 1,569 (C═N); H NMR (400 MHz,
DMSO-d6): δ 6.83 (d, J = 4 Hz, 1H, C4’─H), 7.39–7.83
(m, 6H, Ar─H, C5─H), 8.06 (d, J = 4 Hz, 1H, C3’─H),
9.36 (bs, 1H, NHCO) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 125.2, 128.6, 129.4, 129.9, 130.3, 136.7,
139.1, 139.8, 140.7, 142.9, 151.5, 162.2 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 343.7976 [M + Na]. Anal. Calcd. for
C14H9ClN2OS2: C 52.42; H 2.83; N 8.73. Found: C
5-Chloro-N-(4-(4-nitrophenyl)thiazol-2-yl)thiophene-2-
carboxamide (9f).
Mp 180–181°C; IR (KBr) (cmꢀ1):
3,249 (NH), 1,665 (C═O), 1,640 (C═C), 1,551 (C═N);
1H NMR (400 MHz, DMSO-d6): δ 7.13 (d, J = 4 Hz,
1H, C4’─H), 7.61–8.11 (m, 5H, Ar─H, C5─H), 8.19 (d,
J = 4 Hz, 1H, C3’─H), 9.56 (bs, 1H, NHCO) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 127.5, 131.3, 131.5,
134.2, 135.6, 137.2, 142.3, 144.5, 145.8, 146.3, 158.7,
164.3 ppm (C-2, C-4, C-5, C-50, C-20, C-30, C-40, C═O,
aromatic carbons). HRMS: (m/z) 388.7946 [M + Na].
52.51; H 2.84; N 8.91%.
5-Chloro-N-(4-(4-methylphenyl)thiazol-2-yl)thiophene-2-
carboxamide (9b). Mp 164–166°C; IR (KBr cmꢀ1): 3,272
(NH), 1,686 (C═O), 1,643 (C═C), 1,577 (C═N); 1H NMR
(400 MHz, DMSO-d6): δ 2.37 (s, 3H, Ar─CH3), 6.76 (d,
J = 3.6 Hz, 1H, C4’─H), 7.26–7.61 (m, 5H, Ar─H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

June 2018
Synthesis, Characterization, and Antioxidant Activity of a New Class of Amido
linked Azolyl Thiophenes
1417
Anal. Calcd. for C14H8ClN3O3S2: C, 45.97; H, 2.20; N,
11.67%. Found: C, 46.04; H, 2.21; N, 11.49%.
5-Chloro-N-(4-phenyl-1H-imidazol-2-yl)thiophene-2-
N-(4-(4-Bromophenyl)-1H-imidazol-2-yl)-5-
chlorothiophene-2-carboxamide (10e). Mp 188–190°C; IR
(KBr cmꢀ1): 3,252 (NH), 1,673 (C═O), 1,637 (C═C),
carboxamide (10a).
Mp 169–170°C; IR (KBr cmꢀ1):
1
1,565 (C═N); H NMR (400 MHz, DMSO-d6): δ 7.10 (d,
3,255 (NH), 1,674 (C═O), 1,637 (C═C), 1,569 (C═N);
1H NMR (400 MHz, DMSO-d6): δ 6.78 (d, J = 3.2 Hz,
1H, C4’─H), 7.49–7.70 (m, 6H, Ar─H, C5─H), 7.97 (d,
J = 3.2 Hz, 1H, C3’─H), 9.80 (bs, 1H, NHCO), 11.50
(bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
124.5, 127.6, 128.1, 129.9, 130.9, 135.7, 138.4, 138.9,
143.4, 144.2, 152.3, 165.8 ppm (C-2, C-4, C-5, C-50, C-
20, C-30, C-40, C═O, aromatic carbons). HRMS: m/z
326.7545 [M + Na]. Anal. Calcd. for C14H10ClN3OS: C
55.36; H 3.32; N 13.83. Found: C 55.46; H 3.34; N
J = 3.9 Hz, 1H, C4’─H), 7.47–8.06 (m, 5H, Ar─H,
C5─H), 8.16 (d, J = 3.9 Hz, 1H, C3’─H), 9.80 (bs, 1H,
NHCO), 11.45 (bs, 1H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 128.2, 130.4, 130.7, 132.6, 139.4, 139.9,
140.4, 141.1, 143.5, 144.5, 150.6, 163.6 ppm (C-2, C-4,
C-5, C-50, C-20, C-30, C-40, C═O, aromatic carbons).
HRMS: m/z 405.6488 [M + Na]. Anal. Calcd. For
C14H9BrClN3OS: C 43.94; H 2.37; N 10.98. Found: C
43.88; H 2.36; N 11.13%.
5-Chloro-N-(4-(4-nitrophenyl)-1H-imidazol-2-yl)thiophene-
2-carboxamide (10f).
Mp 185–186°C; IR (KBr cmꢀ1):
14.06%.
5-Chloro-N-(4-(4-methylphenyl)-1H-imidazol-2-yl)
thiophene-2-carboxamide (10b). Mp 173–175°C; IR (KBr
3,263 (NH), 1,671 (C═O), 1,636 (C═C), 1,567 (C═N);
1H NMR (400 MHz, DMSO-d6): δ 7.17 (d, J = 3.7 Hz,
1H, C4’─H), 7.71–8.22 (m, 5H, Ar─H, C5─H), 8.29 (d,
J = 3.7 Hz, 1H, C3’─H), 9.84 (bs, 1H, NHCO), 11.65
(bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ
128.6, 130.8, 131.5, 134.2, 137.2, 138.6, 141.2, 141.9,
143.2, 145.8, 152.3, 165.4 ppm (C-2, C-4, C-5, C-50, C-
20, C-30, C-40, C═O, aromatic carbons). HRMS: m/z
371.7508 [M + Na]. Anal. Calcd. For C14H9ClN4O3S: C
48.21; H 2.60; N 16.06. Found: C 48.29; H 2.62; N
16.25%.
cmꢀ1): 3,264 (NH), 1,681 (C═O), 1,643 (C═C), 1,578
1
(C═N); H NMR (400 MHz, DMSO-d6): δ 2.53 (s, 3H,
Ar─CH3), 6.73 (d, J = 3.4 Hz, 1H, C4’─H), 7.15–7.59
(m, 5H, Ar─H, C5─H), 8.02 (d, J = 3.4 Hz, 1H, C3’─H),
9.74 (bs, 1H, NHCO), 11.42 (bs, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 22.6 (Ar─CH3), 125.3,
129.6, 130.1, 130.5, 131.7, 133.5, 136.8, 141.4, 142.4,
143.8, 153.2, 164.8 ppm (C-2, C-4, C-5, C-50, C-20, C-30,
C-40, C═O, aromatic carbons). HRMS: m/z 340.7819
[M + Na]. Anal. Calcd. for C15H12ClN3OS: C 56.69; H
3.81; N 13.22. Found: C 56.82; H 3.86; N 13.47%.
5-Chloro-N-(4-(4-methoxyphenyl)-1H-imidazol-2-yl)
thiophene-2-carboxamide (10c). Mp 181–182°C; IR (KBr
Acknowledgments. The authors, T. Sreenivasulu and U.
Nagarjuna, are thankful to the University Grants Commission
(UGC), New Delhi for the sanction of UGC-SRF fellowships.
The authors are also thankful to Prof Ch Apparao,
Department of Bio-Chemistry, S. V. University, Tirupati, for
providing necessary facilities to carry out the antioxidant
activity.
cmꢀ1): 3,260 (NH), 1,676 (C═O), 1,638 (C═C), 1,575
1
(C═N); H NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H,
Ar─OCH3), 6.67 (d, J = 3.9 Hz, 1H, C4’─H), 7.01–7.89
(m, 5H, Ar─H, C5─H), 7.92 (d, J = 3.9 Hz, 1H, C3’─H),
9.78 (bs, 1H, NHCO), 11.68 (bs, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 53.2 (Ar─OCH3),
125.6, 126.8, 127.9, 129.7, 130.6, 134.2, 137.3, 140.6,
142.8, 143.6, 154.2, 163.9 ppm (C-2, C-4, C-5, C-50,
C-20, C-30, C-40, C═O, aromatic carbons). HRMS: m/z
356.7791 [M + Na]. Anal. Calcd. for C15H12ClN3O2S:
C 53.98; H 3.62; N 12.59. Found: C 54.07; H 3.64; N
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