Synthesis and antioxidant activities of acetamidomethylsulfonyl bis heterocycles-oxazolyl/thiazolyl/imidazolyl-1,3,4-Oxadiazoles

Article abstract of DOI:10.1002/ardp.201300115

A new class of acetamidomethylsulfonyl bis heterocycles-oxazolyl-1,3,4- oxadiazoles, -thiazolyl-1,3,4-oxadiazoles, and -imidazolyl-1,3,4-oxadiazoles were synthesized from the synthetic intermediates, methyl 2-((4-aryloxazol-2- ylcarbamoyl)methylsulfonyl)acetate, methyl 2-((4-arylthiazol-2-ylcarbamoyl) methylsulfonyl)acetate, and methyl 2-((4-aryl-1H-imidazol-2-ylcarbamoyl) methylsulfonyl)acetate. All the title compounds were tested for their antioxidant activity. The oxadiazolylmethylsulfonyloxazolylacetamide displayed excellent radical-scavenging activity when compared with the standard ascorbic acid. A new class of acetamidomethylsulfonyl bis heterocycles-oxazolyl/ thiazolyl/imidazolyl-1,3,4-oxadiazoles were synthesized and tested for their antioxidant activity. The oxadiazolylmethylsulfonyloxazolylacetamide displayed excellent radical-scavenging activity when compared with the standard ascorbic acid.

Full text of DOI:10.1002/ardp.201300115

Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520
511
Full Paper
Synthesis and Antioxidant Activities of
Acetamidomethylsulfonyl Bis Heterocycles-Oxazolyl/Thiazolyl/
Imidazolyl-1,3,4-Oxadiazoles
Nabhubygari Mahaboob Basha, Gopala Lavanya, Adivireddy Padmaja, and
Venkatapuram Padmavathi
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
A new class of acetamidomethylsulfonyl bis heterocycles-oxazolyl-1,3,4-oxadiazoles, -thiazolyl-1,3,4-
oxadiazoles, and -imidazolyl-1,3,4-oxadiazoles were synthesized from the synthetic intermediates,
methyl 2-((4-aryloxazol-2-ylcarbamoyl)methylsulfonyl)acetate, methyl 2-((4-arylthiazol-2-ylcarbamoyl)-
methylsulfonyl)acetate, and methyl 2-((4-aryl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl)acetate. All
the title compounds were tested for their antioxidant activity. The oxadiazolylmethylsulfonylox-
azolylacetamide displayed excellent radical-scavenging activity when compared with the standard
ascorbic acid.
Keywords: Antioxidant activity / Imidazole / 1,3,4-Oxadiazole / Oxazole / Thiazole
Received: April 8, 2013; Revised: May 1, 2013; Accepted: May 6, 2013
DOI 10.1002/ardp.201300115
Introduction
endows its derivatives with broad and potent biological
functions such as anti-inflammatory [8], hypoglycemic [9],
anti-anxiety [10], and antidepressant activities [11]. Motivated
by the aforesaid findings and in continuation of our studies
towards the synthesis and bioassay of different bis heterocy-
clic derivatives [12–16], the present work is formulated.
Azoles are the principal core structures present in a variety of
natural products and have acquired significance due to a wide
variety of medicinal and biological properties associated with
them. Several oxazoles have been used as therapeutic agents.
Because of their structural relationship to procaine, oxazole
derivatives might be expected to have local anesthetic
properties [1]. The thiazole ring is a main structural motif
of many natural compounds such as vitamin B1 (thiamine),
penicillin, and carboxylase. Moreover, 2-aminothiazoles as
important precursors have been employed in the preparation
of different drugs required for the treatment of allergies,
hypertension, inflammation, schizophrenia, and bacterial
and HIV infections [2]. The imidazole nucleus forms the main
structure of some well-known components of the human
organism, viz. histidine, vitamin B12, histamine, and biotin.
Dacarbazine [3], zoledronic acid [4], tipifarnib [5, 6], and
azathioprine [7] are some of the potent anticancer agents
bearing an imidazole ring. Apart from these, the azole having
three heteroatoms, 1,3,4-oxadiazole (a privileged structure),
Results and discussion
Chemistry
In our earlier studies, we have identified compounds having
the 1,3,4-oxadiazole unit as excellent antioxidant agents
when compared with those having the 1,3,4-thiadiazole
and 1,2,4-triazole units [16, 17]. Our continued interest in
this direction induced us to report here the synthesis
and antioxidant activities of acetamidomethylsulfonyl bis
heterocycles-oxazolyl/thiazolyl/imidazolyl-1,3,4-oxadiazoles
(Scheme 1). These compounds were obtained by functionaliz-
ing the amino group in 4-aryloxazol-2-amine (1), 4-arylthiazol-
2-amine (2), and 4-aryl-1H-imidazol-2-amine (3). The reaction of
1–3 with chloroacetyl chloride produced 2-chloro-N-(4-arylox-
azol-2-yl)acetamide (4), 2-chloro-N-(4-arylthiazol-2-yl)acet-
amide (5), and 2-chloro-N-(4-aryl-1H-imidazol-2-yl)acetamide
(6). The reaction of 4–6 with thioglycolic acid afforded 2-((4-
aryloxazol-2-ylcarbamoyl)methylthio)acetic acid (7), 2-((4-
arylthiazol-2-ylcarbamoyl)methylthio)acetic acid (8), and 2-
Correspondence: Dr. Padmavathi Venkatapuram, Department of Chem-
istry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh,
India.
E-mail: vkpuram2001@yahoo.com
Fax: þ91-877-2261825
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

512
N. M. Basha et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520
Ar
i
Ar
Ar
O
N
N
O
O
N
ii
iii
Cl
S
NH2
N
H
X
N
H
OH
v
X
X
1 / 2 / 3
4 / 5 / 6
7 / 8 / 9
Ar
Ar
Ar
O
O
O
O
O
N
N
iv
O
O
O
O
S
S
N
H
OMe
N
OH
X
X
H
10 / 11 / 12
13 / 14 / 15
Ar
O
O
O
Cl
N
2
N N
N
vi
3'
2'
3
4'
5'
4
O
O
O
5
1
1'
S
NH2
S
N
H
N
H
N
H
X
O
X
16 / 17 / 18
19 / 20 / 21
(i) ClCOCH2Cl / Benzene
(ii) SHCH2CO2H / NaOH / MeOH
(iii) H2O2 / AcOH
(iv) MeOH / H2SO4
(v) NH2NH2.H2O / Pyridine / MeOH
(vi) 2-ClC6H4COOH / POCl3
X = O / S / NH
Ar = a) Ph
b) 4-Me.Ph
c) 4-Cl.Ph
Scheme 1. Synthesis of the bis heterocycles.
((4-aryl-1H-imidazol-2-ylcarbamoyl)methylthio)acetic acid (9).
The latter compounds were subjected to oxidation with
hydrogen peroxide in acetic acid to give 2-((4-aryloxazol-2-
ylcarbamoyl)methylsulfonyl)acetic acid (10), 2-((4-arylthiazol-
2-ylcarbamoyl)methylsulfonyl)acetic acid (11), and 2-((4-aryl-
1H-imidazol-2-ylcarbamoyl)methylsulfonyl)acetic acid (12).
The 1H NMR spectra of 10a, 11a, and 12a displayed two
singlet signals at d 4.32, 4.29, 4.30 and 4.37, 4.34, 4.36 ppm
due to methylene protons flanked between carbonyl and
sulfonyl and sulfonyl and acid functionalities, respectively.
Besides, two broad singlets were observed at d 11.01, 10.08,
10.09 and 12.17, 12.13, 12.15 ppm due to NH and OH.
Compound 12a displayed another broad singlet at d
12.61 ppm due to the NH of the imidazole ring. The signals
of NH and OH disappeared when D2O was added. Esterifica-
tion of compounds 10–12 with methanol in the presence of
sulfuric acid gave methyl 2-((4-aryloxazol-2-ylcarbamoyl)-
methylsulfonyl)acetate (13), methyl 2-((4-arylthiazol-2-ylcarba-
moyl)methylsulfonyl)acetate (14), and methyl 2-((4-aryl-1H-
imidazol-2-ylcarbamoyl)methylsulfonyl)acetate (15). The 1H
NMR spectra of 13a, 14a, and 15a displayed a singlet at d 3.85,
3.82, and 3.84 ppm due to methoxy protons in addition to the
signals of other protons. The acid hydrazides, 2-((4-aryloxazol-
2-ylcarbamoyl)methylsulfonyl)acetohydrazide (16), 2-((4-
arylthiazol-2-ylcarbamoyl)methylsulfonyl)acetohydrazide
(17), and 2-((4-aryl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl)-
acetohydrazide (18) were prepared by the treatment of 13–15
with hydrazine hydrate in pyridine. In the 1H NMR spectra of
16a, 17a, and 18a, the absence of a singlet corresponding to
methoxy protons and the presence of two broad singlets at d
8.50, 8.45, 8.49 and 3.52, 3.49, 3.50 ppm due to NH and NH2,
which disappeared on deuteration, indicated their formation.
The cyclocondensation of acid hydrazides 16–18 with 2-
chlorobenzoic acid in POCl3 resulted in acetamidomethylsul-
fonyl bis heterocycles-2-((50-(2-chlorophenyl)-10,30,40-oxadiazol-
20-yl)methylsulfonyl)-N-(4-aryloxazol-2-yl)acetamide (19), 2-((50-
(2-chlorophenyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-
arylthiazol-2-yl)acetamide (20), and 2-((50-(2-chlorophenyl)-
10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-aryl-1H-imidazol-2-
1
yl)acetamide (21). The H NMR spectra of 19a, 20a, and 21a
displayed two singlets at d 4.34, 4.31, 4.32 and 4.69, 4.65,
4.67 ppm due to methylene protons present between
carbonyl and sulfonyl and sulfonyl and the heterocyclic ring.
Moreover, a broad singlet observed at d 11.34, 11.03, and
11.26 ppm was assigned to NH. Besides, compound 21a
showed another broad singlet at d 12.48 ppm due to the NH of
the imidazole ring. The signals of NH disappeared when D2O
was added. The structures of all the compounds were further
established by IR and 13C NMR spectral data.
Biological results
Antioxidant activity
Compounds 19–21 were tested for antioxidant activity by the
2,20-diphenyl-1-picrylhydrazyl (DPPH) [18, 19], nitric oxide
(NO) [20, 21], and 2,20-azino-bis(3-ethylbenzothiazoline-6-
sulfonic acid) (ABTS) [22] methods. The results are shown in
Tables 1–3. Among all the tested compounds, acetamidome-
thylsulfonyl oxazolyl oxadiazoles (19) displayed excellent
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Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520 Acetamidomethylsulfonyl Bis Heterocycles-Oxazolyl/Thiazolyl/Imidazolyl-1,3,4-Oxadiazoles 513
Table 1. The in vitro antioxidant activities of 19–21 determined by
the DPPH method.
Table 3. The in vitro antioxidant activities of 19–21 determined by
the ABTS method.
Compound
Concentration (mg/mL)
Compound
Concentration (mg/mL)
50
75
100
50
75
100
19a
19b
19c
20a
20b
20c
21a
65.63 ꢀ 0.15
75.06 ꢀ 1.17
60.54 ꢀ 0.14
59.36 ꢀ 0.12
72.05 ꢀ 1.45
54.35 ꢀ 0.98
–
69.42 ꢀ 1.42
78.65 ꢀ 1.23
61.32 ꢀ 1.02
62.44 ꢀ 0.76
73.56 ꢀ 1.04
58.81 ꢀ 1.55
–
72.24 ꢀ 0.61
82.94 ꢀ 0.41
65.24 ꢀ 1.47
66.35 ꢀ 0.95
79.46 ꢀ 0.17
60.37 ꢀ 1.71
–
19a
19b
19c
20a
20b
20c
21a
23.31 ꢀ 0.86
25.51 ꢀ 1.57
20.15 ꢀ 0.85
17.32 ꢀ 0.96
20.05 ꢀ 0.61
15.98 ꢀ 0.76
–
24.56 ꢀ 1.05
26.37 ꢀ 1.24
22.10 ꢀ 1.41
18.94 ꢀ 0.19
21.72 ꢀ 1.13
17.01 ꢀ 0.66
–
25.96 ꢀ 0.91
28.35 ꢀ 1.32
23.97 ꢀ 1.02
20.07 ꢀ 1.64
24.32 ꢀ 0.33
18.87 ꢀ 1.14
–
21b
21c
45.36 ꢀ 1.33
–
49.62 ꢀ 1.16
–
54.51 ꢀ 0.86
–
21b
21c
15.35 ꢀ 1.04
–
16.71 ꢀ 1.56
–
18.04 ꢀ 0.11
–
Ascorbic acid
Blank
77.15 ꢀ 0.36
–
80.98 ꢀ 1.32
–
83.82 ꢀ 0.83
–
Ascorbic acid
Blank
28.80 ꢀ 0.44
–
29.20 ꢀ 1.31
–
29.70 ꢀ 0.99
–
–, Showed no scavenging activity.
–, Showed no scavenging activity.
Values are the means of three replicates ꢀ SD.
Values are the means of three replicates ꢀ SD.
Table 2. The in vitro antioxidant activities of 19–21 determined by
the nitric oxide method.
method, as shown in Table 4. It was noticed that, at these
10-min intervals, the values are very close, and the results
exemplify that the antioxidant activity is independent of
time.
Compound
Concentration (mg/mL)
50
75
100
Conclusion
19a
19b
19c
20a
20b
20c
21a
21b
70.34 ꢀ 0.16
84.58 ꢀ 1.02
66.24 ꢀ 0.93
64.45 ꢀ 1.18
80.72 ꢀ 1.27
59.35 ꢀ 0.67
–
72.26 ꢀ 0.63
88.64 ꢀ 0.86
68.72 ꢀ 1.43
67.32 ꢀ 0.64
83.54 ꢀ 0.97
62.26 ꢀ 1.01
–
75.37 ꢀ 0.45
91.25 ꢀ 1.32
70.37 ꢀ 0.91
69.06 ꢀ 0.06
87.71 ꢀ 0.21
64.30 ꢀ 0.42
–
A new class of acetamidomethylsulfonyl bis heterocycles-
oxazolyl-1,3,4-oxadiazoles, -thiazolyl-1,3,4-oxadiazoles, and
-imidazolyl-1,3,4-oxadiazoles were synthesized from the syn-
thetic intermediates, methyl 2-((4-aryloxazol-2-ylcarbamoyl)-
methylsulfonyl)acetate, methyl 2-((4-arylthiazol-2-ylcarba-
moyl)methylsulfonyl)acetate, and methyl 2-((4-aryl-1H-imida-
zol-2-ylcarbamoyl)methylsulfonyl)acetate. All the title
compounds were tested for their antioxidant activity. The
oxadiazolylmethylsulfonyloxazolylacetamide displayed excel-
lent radical-scavenging activity when compared with the
standard ascorbic acid.
49.62 ꢀ 1.32
–
52.34 ꢀ 0.84
–
57.37 ꢀ 1.14
–
21c
Ascorbic acid
Blank
86.02 ꢀ 0.13
–
89.46 ꢀ 0.87
–
91.53 ꢀ 1.11
–
–, Showed no scavenging activity.
Values are the means of three replicates ꢀ SD.
radical-scavenging activity in all three methods, when
compared with the standard ascorbic acid. Recently, we have Experimental
identified that isoxazolyl oxadiazoles displayed greater
activity than pyrazolyl oxadiazoles [14]. Further, it was
observed that there was no marked difference in activity
between the compounds having isoxazolyl oxadiazoles [14]
and oxazolyl oxadiazoles. The thiazolyl oxadiazole com-
pounds (20) also showed good radical-scavenging activity.
However, the imidazolyl oxadiazoles (21) exhibited the least
activity. With reference to the nature of the substituents on
the aromatic ring, the electron-donating 4-methyl group
enhanced the activity when compared with the unsubstituted
and chloro-substituted compounds. The free radical-scaveng-
ing activity of the compounds 19a, 19b, 19c, and 20b was
measured at different concentrations, monitored by the
change in absorbance at 10, 20, and 30 min in the DPPH
Chemistry
Melting points were determined in open capillaries on a Mel-
Temp apparatus and are uncorrected. The purity of the
Table 4. Antioxidant activities of compounds 19a–c and 20b at
10-min time intervals determined by the DPPH radical-scavenging
method.
Compound
10 min
20 min
30 min
19a
19b
19c
20b
72.01
82.33
64.98
79.25
72.18
82.65
64.15
79.32
72.24
82.94
65.24
79.46
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514
N. M. Basha et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520
compounds was checked by TLC (silica gel H, BDH, ethyl acetate/
hexane, 1:3). The IR spectra were recorded on a Thermo Nicolet IR
200 FT-IR spectrometer as KBr pellets and the wave numbers are
given in cmꢁ1. The 1H NMR spectra were recorded in DMSO-d6 on
a Bruker-400 spectrometer (400 MHz). The 13C NMR spectra were
recorded in DMSO-d6 on a Bruker spectrometer operating at
100 MHz. All chemical shifts are reported in d (ppm) using TMS as
internal standard. The mass spectra were recorded on Jeol JMS-D
300 and Finnigan Mat 1210 B instruments at 70 eV, with an
emission current of 100 mA. The microanalyses were performed
on a Perkin-Elmer 240C elemental analyzer. The antioxidant
activity measurement was carried out using a Shimadzu UV-2450
spectrophotometer. The compounds 4-aryloxazol-2-amine (1), 4-
arylthiazol-2-amine (2), 4-aryl-1H-imidazol-2-amine (3), 2-chloro-N-
(4-aryloxazol-2-yl)acetamide (4), 2-chloro-N-(4-arylthiazol-2-yl)acet-
amide (5), and 2-chloro-N-(4-aryl-1H-imidazol-2-yl)acetamide (6)
were prepared as per literature procedures [23–25].
(NH), 3350 (OH); 1H NMR (DMSO-d6) d (ppm): 3.43 (s, 2H, CO–CH2),
3.52 (s, 2H, S–CH2), 7.43–7.86 (m, 5H, Ar–H and C5–H), 10.97 (bs,
1H, NH), 12.20 (bs, 1H, COOH); 13C NMR (DMSO-d6) d (ppm): 42.0
(CO–CH2), 44.8 (S–CH2), 138.4 (C-5), 141.3 (C-4), 151.7 (C-2), 169.3
(NH–CO), 174.6 (COOH), 128.9, 130.5, 132.7, 135.9 (aromatic
carbons); MS (m/z): 326.76 [Mþ•]. Anal. calcd. for C13H11ClN2O4S: C
47.78, H 3.39, N 8.57; Found: C 47.86, H 3.32, N 8.65%.
2-((4-Phenylthiazol-2-ylcarbamoyl)methylthio)acetic
acid 8a
White solid in 65% (0.82 g) yield; m.p.: 149–151°C; IR (KBr) ymax
(cmꢁ1): 1576 (C N), 1630 (C C), 1689 (NH–CO), 1708 (COOH), 3242
–
–
–
–
(NH), 3343 (OH); 1H NMR (DMSO-d6) d (ppm): 3.39 (s, 2H, CO–CH2),
3.48 (s, 2H, S–CH2), 6.61 (s, 1H, C5–H), 7.32–7.69 (m, 5H, Ar–H),
10.08 (bs, 1H, NH), 12.15 (bs, 1H, COOH); 13C NMR (DMSO-d6) d
(ppm): 41.8 (CO–CH2), 43.6 (S–CH2), 104.3 (C-5), 148.3 (C-4), 162.8
(C-2), 167.1 (NH–CO), 173.0 (COOH), 127.1, 129.7, 131.8, 135.0
(aromatic carbons); MS (m/z): 308.37 [Mþ•]. Anal. calcd. for
C13H12N2O3S2: C 50.63, H 3.92, N 9.08; Found: C 50.74, H 3.97, N
9.14%.
General procedure for the synthesis of 2-((4-
aryloxazol-2-ylcarbamoyl)methylthio)acetic acid (7a–c)/
2-((4-arylthiazol-2-ylcarbamoyl)methylthio)acetic acid
(8a–c)/2-((4-aryl-1H-imidazol-2-ylcarbamoyl)methylthio)-
2-((4-p-Tolylthiazol-2-ylcarbamoyl)methylthio)acetic
acetic acid (9a–c)
acid 8b
To a solution of sodium hydroxide (0.40 g, 10 mmol) in methanol
(6 mL), mercaptoacetic acid (0.46 g, 5 mmol) and compound 4/5/6
(5 mmol) were added and refluxed for 4–6 h. The reaction
mixture was cooled and poured into crushed ice containing conc.
HCl. The separated solid was filtered, dried, and recrystallized
from water.
White solid in 63% (0.84 g) yield; m.p.: 173–175°C; IR (KBr) ymax
(cmꢁ1): 1569 (C N), 1627 (C C), 1685 (NH–CO), 1706 (COOH), 3236
–
–
–
–
(NH), 3340 (OH); 1H NMR (DMSO-d6) d (ppm): 2.34 (s, 3H, Ar–CH3),
3.38 (s, 2H, CO–CH2), 3.47 (s, 2H, S–CH2), 6.58 (s, 1H, C5–H),
7.15–7.61 (m, 4H, Ar-H), 10.06 (bs, 1H, NH), 12.09 (bs, 1H, COOH);
13C NMR (DMSO-d6) d (ppm): 24.5 (Ar–CH3), 41.8 (CO–CH2), 43.2
(S–CH2), 103.0 (C-5), 149.1 (C-4), 162.3 (C-2), 166.8 (NH–CO), 173.8
(COOH), 126.2, 128.1, 129.2, 131.8 (aromatic carbons); MS (m/z):
322.40 [Mþ•]. Anal. calcd. for C14H14N2O3S2: C 52.15, H 4.38, N
8.69; Found: C 52.07, H 4.44, N 8.60%.
2-((4-Phenyloxazol-2-ylcarbamoyl)methylthio)acetic
acid 7a
White solid in 65% (0.76 g) yield; m.p.: 145–147°C; IR (KBr) ymax
(cmꢁ1): 1578 (C N), 1628 (C C), 1690 (NH–CO), 1709 (COOH), 3240
–
–
–
–
(NH), 3344 (OH); 1H NMR (DMSO-d6) d (ppm): 3.42 (s, 2H, CO–CH2),
3.51 (s, 2H, S–CH2), 7.34–7.72 (m, 6H, Ar–H, and C5–H), 10.90 (bs,
1H, NH), 12.15 (bs, 1H, COOH); 13C NMR (DMSO-d6) d (ppm): 41.7
(CO–CH2), 44.2 (S–CH2), 137.9 (C-5), 140.4 (C-4), 151.3 (C-2), 169.1
(NH–CO), 174.3 (COOH), 127.6, 130.0, 132.1, 135.7 (aromatic
carbons); MS (m/z): 292.31 [Mþ•]. Anal. calcd. for C13H12N2O4S: C
53.41, H 4.13, N 9.58; Found: C 53.52, H 4.19, N 9.74%.
2-((4-(p-Chlorophenyl)thiazol-2-ylcarbamoyl)methylthio)-
acetic acid 8c
White solid in 66% (0.94 g) yield; m.p.: 182–184°C; IR (KBr) ymax
(cmꢁ1): 1584 (C N), 1632 (C C), 1690 (NH–CO), 1712 (COOH), 3254
–
–
–
–
(NH), 3349 (OH); 1H NMR (DMSO-d6) d (ppm): 3.41 (s, 2H, CO–CH2),
3.50 (s, 2H, S–CH2), 6.63 (s, 1H, C5–H), 7.21–7.80 (m, 4H, Ar–H),
11.02 (bs, 1H, NH), 12.17 (bs, 1H, COOH); 13C NMR (DMSO-d6) d
(ppm): 42.7 (CO–CH2), 44.3 (S–CH2), 104.7 (C-5), 149.4 (C-4), 163.7
(C-2), 168.1 (NH–CO), 173.3 (COOH), 128.4, 130.0, 132.2, 135.3
(aromatic carbons); MS (m/z): 342.82 [Mþ•]. Anal. calcd. for
C13H11ClN2O3S2: C 45.55, H 3.23, N 8.17; Found: C 45.67, H 3.28, N
8.27%.
2-((4-p-Tolyloxazol-2-ylcarbamoyl)methylthio)acetic
acid 7b
White solid in 67% (0.83 g) yield; m.p.: 162–164°C; IR (KBr) ymax
(cmꢁ1): 1571 (C N), 1621 (C C), 1688 (NH–CO), 1704 (COOH), 3235
–
–
–
–
(NH), 3342 (OH); 1H NMR (DMSO-d6) d (ppm): 2.39 (s, 3H, Ar–CH3),
3.40 (s, 2H, CO–CH2), 3.49 (s, 2H, S–CH2), 7.31–7.69 (m, 5H, Ar–H
and C5–H), 10.82 (bs, 1H, NH), 12.12 (bs, 1H, COOH); 13C NMR
(DMSO-d6) d (ppm): 25.3 (Ar–CH3), 41.2 (CO–CH2), 43.7 (S–CH2),
137.2 (C-5), 140.1 (C-4), 150.9 (C-2), 168.6 (NH–CO), 174.1 (COOH),
127.1, 129.6, 131.5, 135.2 (aromatic carbons); MS (m/z): 306.34
[Mþ•]. Anal. calcd. for C14H14N2O4S: C 54.88, H 4.60, N 9.14;
Found: C 54.96, H 4.65, N 9.26%.
2-((4-Phenyl-1H-imidazol-2-ylcarbamoyl)methylthio)acetic
acid 9a
White solid in 64% (0.75 g) yield; m.p.: 157–159°C; IR (KBr) ymax
(cmꢁ1): 1572 (C N), 1633 (C C), 1689 (NH–CO), 1705 (COOH), 3248
–
–
–
–
(NH), 3336 (OH); 1H NMR (DMSO-d6) d (ppm): 3.40 (s, 2H, CO–CH2),
3.49 (s, 2H, S–CH2), 7.31–7.72 (m, 6H, Ar–H and C5–H), 11.00 (bs,
1H, NH–CO), 12.15 (bs, 1H, COOH), 12.52 (bs, 1H, NH); 13C NMR
(DMSO-d6) d (ppm): 41.6 (CO–CH2), 43.9 (S–CH2), 122.9 (C-5), 137.1
(C-2), 141.4 (C-4), 168.6 (NH–CO), 173.7 (COOH), 128.3, 129.7,
131.7, 134.6 (aromatic carbons); MS (m/z): 291.33 [Mþ•]. Anal.
calcd. for C13H13N3O3S: C 53.60, H 4.50, N 14.42; Found: C 53.69, H
4.56, N 14.51%.
2-((4-(p-Chlorophenyl)oxazol-2-ylcarbamoyl)methylthio)-
acetic acid 7c
White solid in 64% (0.83 g) yield; m.p.: 169–171°C; IR (KBr) ymax
(cmꢁ1): 1585 (C N), 1633 (C C), 1693 (NH–CO), 1711 (COOH), 3249
–
–
–
–
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Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520 Acetamidomethylsulfonyl Bis Heterocycles-Oxazolyl/Thiazolyl/Imidazolyl-1,3,4-Oxadiazoles 515
2-((4-p-Tolyl-1H-imidazol-2-ylcarbamoyl)methylthio)acetic
7.30–7.71 (m, 5H, Ar–H, and C5–H), 10.07 (bs, 1H, NH), 12.13 (bs,
1H, COOH); 13C NMR (DMSO-d6) d (ppm): 25.6 (Ar–CH3), 53.3
(CO–CH2), 57.2 (SO2–CH2), 137.4 (C-5), 140.0 (C-4), 150.8 (C-2), 169.1
(NH–CO), 174.2 (COOH), 128.0, 129.5, 131.5, 135.1 (aromatic
carbons); MS (m/z): 338.34 [Mþ•]. Anal. calcd. for C14H14N2O6S: C
49.70, H 4.17, N 8.28; Found: C 49.80, H 4.22, N 8.17%.
acid 9b
White solid in 66% (0.82 g) yield; m.p.: 189–191°C; IR (KBr) ymax
(cmꢁ1): 1567 (C N), 1629 (C C), 1687 (NH–CO), 1708 (COOH), 3241
–
–
–
–
(NH), 3331 (OH); 1H NMR (DMSO-d6) d (ppm): 2.36 (s, 3H, Ar–CH3),
3.39 (s, 2H, CO–CH2), 3.48 (s, 2H, S–CH2), 7.28–7.70 (m, 5H, Ar–H,
and C5–H), 10.95 (bs, 1H, NH–CO), 12.10 (bs, 1H, COOH), 12.50 (bs,
1H, NH); 13C NMR (DMSO-d6) d (ppm) 24.9 (Ar–CH3), 41.1 (CO–CH2),
43.4 (S–CH2), 122.2 (C-5), 137.6 (C-2), 141.0 (C-4), 168.1 (NH–CO),
173.1 (COOH), 127.6, 129.0, 131.1, 133.9 (aromatic carbons); MS
(m/z): 305.36 [Mþ•]. Anal. calcd. for C14H15N3O3S: C 55.07, H 4.95, N
13.76; Found: C 55.16, H 4.90, N 13.85%.
2-((4-(p-Chlorophenyl)oxazol-2-ylcarbamoyl)-
methylsulfonyl)acetic acid 10c
White solid in 82% (2.67 g) yield; m.p.: 183–185°C; IR (KBr) ymax
(cmꢁ1): 1130, 1324 (SO ), 1591 (C N), 1636 (C C), 1692 (NH–CO),
–
–
–
–
2
1712 (COOH), 3257 (NH), 3358 (OH); 1H NMR (DMSO-d6) d (ppm):
4.33 (s, 2H, CO–CH2), 4.40 (s, 2H, SO2–CH2), 7.38–7.79 (m, 5H,
Ar–H, and C5–H), 11.03 (bs, 1H, NH), 12.21 (bs, 1H, OH); 13C NMR
(DMSO-d6) d (ppm): 54.7 (CO–CH2), 58.1 (SO2–CH2), 138.4 (C-5),
140.9 (C-4), 151.6 (C-2), 169.5 (NH–CO), 174.9 (COOH), 128.9, 130.7,
132.8, 136.1 (aromatic carbons); MS (m/z): 358.76 [Mþ•]. Anal.
calcd. for C13H11ClN2O6S: C 43.52, H 3.09, N 7.81; Found: C 43.63,
H 3.02, N 7.92%.
2-((4-(p-Chlorophenyl)-1H-imidazol-2-ylcarbamoyl)-
methylthio)acetic acid 9c
White solid in 67% (0.90 g) yield; m.p.: 201–203°C; IR (KBr) ymax
(cmꢁ1): 1581 (C N), 1635 (C C), 1694 (NH–CO), 1710 (COOH), 3250
–
–
–
–
(NH), 3339 (OH); 1H NMR (DMSO-d6) d (ppm): 3.42 (s, 2H, CO–CH2),
3.51 (s, 2H, S–CH2), 7.35–7.76 (m, 5H, Ar–H, and C5–H), 11.13 (bs,
1H, NH–CO), 12.18 (bs, 1H, COOH), 12.57 (bs, 1H, NH); 13C NMR
(DMSO-d6) d (ppm): 41.9 (CO–CH2), 44.2 (S–CH2), 123.3 (C-5), 138.8
(C-2), 141.9 (C-4), 168.8 (NH–CO), 174.0 (COOH), 128.6, 130.1,
132.1, 134.9 (aromatic carbons); MS (m/z): 325.77 [Mþ•]. Anal.
calcd. for C13H12ClN3O3S: C 47.93, H 3.71, N 12.90; Found: C 48.86,
H 3.62, N 13.02%.
2-((4-Phenylthiazol-2-ylcarbamoyl)methylsulfonyl)acetic
acid 11a
White solid in 83% (2.55 g) yield; m.p.: 171–173°C; IR (KBr) ymax
(cmꢁ1): 1126, 1317 (SO ), 1585 (C N), 1635 (C C), 1688 (NH–CO),
–
–
–
–
2
1708 (COOH), 3248 (NH), 3350 (OH); 1H NMR (DMSO-d6) d (ppm):
4.29 (s, 2H, CO–CH2), 4.34 (s, 2H, SO2–CH2), 6.65 (s, 1H, C5–H),
7.34–7.73 (m, 5H, Ar–H), 10.08 (bs, 1H, NH), 12.13 (bs, 1H, COOH);
13C NMR (DMSO-d6) d (ppm): 53.3 (CO–CH2), 57.0 (SO2–CH2), 104.6
(C-5), 146.9 (C-4), 163.0 (C-2), 167.8 (NH–CO), 174.1 (COOH), 128.3,
129.9, 131.9, 135.2 (aromatic carbons); MS (m/z): 340.37 [Mþ•].
Anal. calcd. for C13H12N2O5S2: C 45.87, H 3.55, N 8.23, Found: C
45.80, H 3.53, N 8.33%.
General procedure for the synthesis of 2-((4-aryloxazol-2-
ylcarbamoyl)methylsulfonyl)acetic acid (10a–c)/2-((4-
arylthiazol-2-ylcarbamoyl)methylsulfonyl)acetic acid
(11a–c)/2-((4-aryl-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetic acid (12a–c)
An ice-cold solution of compound 7/8/9 (10 mmol) in glacial acetic
acid (10 mL) was treated with 30% hydrogen peroxide (3 mL) in
portions. The contents were allowed to attain laboratory
temperature and then were refluxed for 2–3 h. The reaction
mixture was cooled, and acetic acid was removed in vacuo. The
residual portion was poured onto crushed ice, and the product
obtained was filtered, dried, and recrystallized from water.
2-((4-p-Tolylthiazol-2-ylcarbamoyl)methylsulfonyl)acetic
acid 11b
White solid in 82% (2.64 g) yield; m.p.: 184–186°C; IR (KBr) ymax
(cmꢁ1): 1123, 1315 (SO ), 1581 (C N), 1631 (C C), 1687 (NH–CO),
–
–
–
–
2
1704 (COOH), 3241 (NH), 3347 (OH); 1H NMR (DMSO-d6) d (ppm):
2.40 (s, 3H, Ar–CH3), 4.28 (s, 2H, CO–CH2), 4.33 (s, 2H, SO2–CH2),
6.63 (s, 1H, C5–H), 7.30–7.67 (m, 4H, Ar–H), 11.00 (bs, 1H, NH),
12.10 (bs, 1H, COOH); 13C NMR (DMSO-d6) d (ppm): 25.1 (Ar–CH3),
53.1 (CO–CH2), 56.7 (SO2–CH2), 104.2 (C-5), 146.5 (C-4), 162.8 (C-2),
167.4 (NH–CO), 173.8 (COOH), 127.9, 129.6, 131.4, 134.6 (aromatic
carbons); MS (m/z): 354.40 [Mþ•]. Anal. calcd. for C14H14N2O5S2: C
47.45, H 3.98, N 7.90; Found: C 47.54, H 4.05, N 8.02%.
2-((4-Phenyloxazol-2-ylcarbamoyl)methylsulfonyl)acetic
acid 10a
White solid in 82% (2.39 g) yield; m.p.: 162–164°C; IR (KBr) ymax
(cmꢁ1): 1121, 1320 (SO ), 1587 (C N), 1634 (C C), 1686 (NH–CO),
–
–
–
–
2
1709 (COOH), 3246 (NH), 3352 (OH); 1H NMR (DMSO-d6) d (ppm):
4.32 (s, 2H, CO–CH2), 4.37 (s, 2H, SO2–CH2), 7.36–7.75 (m, 6H, Ar–H
and C5–H), 11.01 (bs, 1H, NH), 12.17 (bs, 1H, COOH); 13C NMR
(DMSO-d6) d (ppm): 53.8 (CO–CH2), 57.6 (SO2–CH2), 137.9 (C-5),
140.4 (C-4), 151.3 (C-2), 169.3 (NH–CO), 174.7 (COOH), 128.6, 130.0,
132.1, 135.7 (aromatic carbons); MS (m/z): 324.31 [Mþ•]. Anal.
calcd. for C13H12N2O6S: C 48.14, H 3.37, N 8.64, Found: C 32.52, H
3.65, N 14.72%.
2-((4-(p-Chlorophenyl)thiazol-2-ylcarbamoyl)-
methylsulfonyl)acetic acid 11c
White solid in 80% (2.74 g) yield; m.p.: 193–195°C; IR (KBr) ymax
(cmꢁ1): 1131, 1321 (SO ), 1590 (C N), 1638 (C C), 1690 (NH–CO),
–
–
–
–
2
1710 (COOH), 3261 (NH), 3355 (OH); 1H NMR (DMSO-d6) d (ppm):
4.32 (s, 2H, CO–CH2), 4.38 (s, 2H, SO2–CH2), 6.69 (s, 1H, C5–H),
7.37–7.81 (m, 4H, Ar–H), 11.02 (bs, 1H, NH), 12.18 (bs, 1H, COOH);
13C NMR (DMSO-d6) d (ppm): 53.9 (CO–CH2), 56.2 (SO2–CH2), 105.1
(C-5), 147.3 (C-4), 163.7 (C-2), 168.2 (NH–CO), 174.4 (COOH), 128.5,
130.1, 132.2, 135.9 (aromatic carbons); MS (m/z): 374.82 [Mþ•].
Anal. calcd. for C13H11ClN2O5S2: C 41.66, H 2.96, N 7.47; Found: C
41.75, H 3.01, N 7.56%.
2-((4-p-Tolyloxazol-2-ylcarbamoyl)methylsulfonyl)acetic
acid 10b
White solid in 80% (2.45 g) yield; m.p.: 175–177°C; IR (KBr) ymax
(cmꢁ1): 1120, 1316 (SO ), 1582 (C N), 1630 (C C), 1690 (NH–CO),
–
–
–
–
2
1706 (COOH), 3240 (NH), 3348 (OH); 1H NMR (DMSO-d6) d (ppm):
2.43 (s, 3H, Ar–CH3), 4.29 (s, 2H, CO–CH2), 4.36 (s, 2H, SO2–CH2),
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516
N. M. Basha et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520
2-((4-Phenyl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl)-
Anal. calcd. for C14H14N2O6S: C 49.70, H 4.17, N 8.28; Found: C
49.81, H 4.22, N 8.31%.
acetic acid 12a
White solid in 81% (2.35 g) yield; m.p.: 169–171°C; IR (KBr) ymax
(cmꢁ1): 1128, 1320 (SO ), 1582 (C N), 1687 (C C), 1687 (NH–CO),
Methyl 2-((4-p-tolyloxazol-2-ylcarbamoyl)methylsulfonyl)-
–
–
–
–
2
1705 (COOH), 3249 (NH), 3340 (OH); 1H NMR (DMSO-d6) d (ppm):
4.30 (s, 2H, CO–CH2), 4.36 (s, 2H, SO2–CH2), 7.24–7.62 (m, 6H,
Ar–H, and C5–H), 10.09 (bs, 1H, NH–CO), 12.15 (bs, 1H, COOH),
12.61 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 54.4 (CO–CH2), 57.3
(SO2–CH2), 123.6 (C-5), 136.9 (C-2), 140.4 (C-4), 169.1 (NH–CO),
174.3 (COOH), 128.2, 129.6, 131.8, 135.4 (aromatic carbons); MS
(m/z): 323.33 [Mþ•]. Anal. calcd. for C13H13N3O5S: C 48.29, H 4.05, N
13.00, Found: C 48.37, H 3.98, N, 13.14%.
acetate 13b
White solid in 84% (2.84 g) yield; m.p.: 170–172°C; IR (KBr) ymax
(cmꢁ1): 1138, 1327 (SO ), 1575 (C N), 1626 (C C), 1689 (NH–CO),
–
–
–
–
2
1734 (COO), 3234 (NH); 1H NMR (DMSO-d6) d (ppm): 2.32 (s, 3H,
Ar–CH3), 3.84 (s, 3H, OCH3), 4.31 (s, 2H, CO–CH2), 4.39 (s, 2H,
SO2–CH2), 7.12–7.46 (m, 5H, Ar–H, and C5–H), 10.08 (bs, 1H, NH);
13C NMR (DMSO-d6) d (ppm): 24.5 (Ar–CH3), 52.3 (OCH3), 52.8
(SO2–CH2), 54.5 (CO–CH2), 138.2 (C-5), 139.5 (C-4), 150.6 (C-2), 163.5
(CO2Me), 169.3 (NH–CO), 122.6, 124.6, 128.7, 135.4 (aromatic
carbons); MS (m/z): 352.38 [Mþ•]. Anal. calcd. for C15H16N2O6S: C,
51.13, H 4.58, N 7.95; Found: C 51.23, H 4.63, N 8.08%.
2-((4-p-Tolyl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl)-
acetic acid 12b
White solid in 83% (2.53 g) yield; m.p.: 196–198°C; IR (KBr) ymax
(cmꢁ1): 1126, 1317 (SO ), 1577 (C N), 1632 (C C), 1685 (NH–CO),
Methyl 2-((4-(p-chlorophenyl)oxazol-2-ylcarbamoyl)-
–
–
–
–
2
1708 (COOH), 3244 (NH), 3338 (OH); 1H NMR (DMSO-d6) d (ppm):
2.38 (s,3H, Ar–CH3), 4.28 (s, 2H, CO–CH2), 4.37 (s, 2H, SO2–CH2),
7.30–7.70 (m, 5H, Ar–H, and C5–H), 10.17 (bs, 1H, NH–CO), 12.12
(bs, 1H, COOH), 12.55 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm):
25.7 (Ar–CH3), 54.1 (CO–CH2), 57.0 (SO2–CH2), 123.1 (C-5), 136.0
(C-2), 140.6 (C-4), 168.7 (NH–CO), 174.0 (COOH), 127.8, 129.2,
131.3, 135.0 (aromatic carbons); MS (m/z): 337.36 [Mþ•]. Anal.
calcd. for C14H15N3O5S: C 49.84, H 4.48, N 12.46; Found: C 49.72, H
4.52, N 12.56%.
methylsulfonyl)acetate 13c
White solid in 85% (3.04 g) yield; m.p.: 176–178°C; IR (KBr) ymax
(cmꢁ1): 1149, 1338 (SO ), 1581 (C N), 1638 (C C), 1694 (NH–CO),
–
–
–
–
2
1738 (COO), 3256 (NH); 1H NMR (DMSO-d6) d (ppm): 3.89 (s, 3H,
OCH3), 4.35 (s, 2H, CO–CH2), 4.43 (s, 2H, SO2–CH2), 7.28–7.62 (m,
5H, Ar–H, and C5–H), 11.01 (bs, 1H, NH); 13C NMR (DMSO-d6) d
(ppm): 53.0 (OCH3), 53.9 (SO2–CH2), 55.9 (CO–CH2), 139.0 (C-5),
140.2 (C-4), 151.3 (C-2), 163.7 (CO2Me), 169.8 (NH–CO), 128.8,
130.2, 131.4, 133.8 (aromatic carbons); MS (m/z): 372.78 [Mþ•].
Anal. calcd. for C14H13ClN2O6S: C 45.11, H 3.51, N 7.51; Found: C
45.05, H 3.46, N 7.59%.
2-((4-(p-Chlorophenyl)-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetic acid 12c
Methyl 2-((4-phenylthiazol-2-ylcarbamoyl)methylsulfonyl)-
White solid in 80% (2.60 g) yield; m.p.: 214–216°C; IR (KBr) ymax
(cmꢁ1): 1132, 1322 (SO ), 1588 (C N), 1639 (C C), 1691 (NH–CO),
acetate 14a
–
–
–
–
2
1711 (COOH), 3253 (NH), 3345 (OH); 1H NMR (DMSO-d6) d (ppm):
4.31 (s, 2H, CO–CH2), 4.39 (s, 2H, SO2–CH2), 7.36–7.74 (m, 5H,
Ar–H, and C5–H), 11.20 (bs, 1H, NH–CO), 12.19 (bs, 1H, COOH),
12.62 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 54.8 (CO–CH2), 57.5
(SO2–CH2), 123.8 (C-5), 137.2 (C-2), 140.7 (C-4), 169.5 (NH–CO),
174.6 (COOH), 128.8, 130.0, 132.1, 135.9 (aromatic carbons); MS
(m/z): 357.77 [Mþ•]. Anal. calcd. for C13H12ClN3O5S: C 43.64, H 3.38,
N 11.74; Found: C 43.71, H 3.31, N 11.86%.
White solid in 83% (2.82 g) yield; m.p.: 158–160°C; IR (KBr) ymax
(cmꢁ1): 1144, 1330 (SO ), 1576 (C N), 1632 (C C), 1691 (NH–CO),
–
–
–
–
2
1734 (COO), 3250 (NH); 1H NMR (DMSO-d6) d (ppm): 3.82 (s, 3H,
OCH3), 4.32 (s, 2H, CO–CH2), 4.40 (s, 2H, SO2–CH2), 6.64 (s, 1H,
C5–H), 7.14–7.48 (m, 5H, Ar–H), 11.22 (bs, 1H, NH); 13C NMR
(DMSO-d6) d (ppm): 52.1 (OCH3), 52.9 (SO2–CH2), 54.7 (CO–CH2),
104.6 (C-5), 147.4 (C-4), 162.3 (NH–CO), 163.5 (C-2), 168.4 (CO2Me),
122.8, 124.6, 128.0, 130.1 (aromatic carbons); MS (m/z): 354.40
[Mþ•]. Anal. calcd. for C14H14N2O5S2: C 47.45, H 3.98, N 7.90;
Found: C 47.53, H 4.03, N 8.01%.
General procedure for the synthesis of methyl 2-((4-
aryloxazol-2-ylcarbamoyl)methyl-sulfonyl)acetate (13a–c)/
methyl 2-((4-arylthiazol-2-ylcarbamoyl)methylsulfonyl)-
acetate (14a–c)/methyl 2-((4-aryl-1H-imidazol-2-
Methyl 2-((4-p-tolylthiazol-2-ylcarbamoyl)methylsulfonyl)-
acetate 14b
White solid in 84% (2.97 g) yield; m.p.: 173–175°C; IR (KBr) ymax
ylcarbamoyl)methylsulfonyl)acetate (15a–c)
(cmꢁ1): 1140, 1324 (SO ), 1574 (C N), 1631 (C C), 1687 (NH–CO),
–
–
–
–
2
A mixture of compound 10/11/12 (10 mmol), methanol (10 mL),
and conc. H2SO4 (1 mL) was refluxed for 9–11 h. The contents
were cooled and poured onto crushed ice. The solid separated was
filtered, dried, and recrystallized from methanol.
1730 (COO), 3235 (NH); 1H NMR (DMSO-d6) d (ppm): 2.31 (s, 3H,
Ar–CH3), 3.80 (s, 3H, OCH3), 4.30 (s, 2H, CO–CH2), 4.37 (s, 2H,
SO2–CH2), 6.61 (s, 1H, C5–H), 7.10–7.42 (m, 4H, Ar–H), 10.18 (bs, 1H,
NH); 13C NMR (DMSO-d6) d (ppm): 24.0 (Ar–CH3), 51.8 (OCH3), 52.6
(SO2–CH2), 54.4 (CO–CH2), 104.1 (C-5), 147.1 (C-4), 161.7 (NH–CO),
164.1 (C-2), 168.2 (CO2Me), 122.4, 125.6, 129.7, 130.0 (aromatic
carbons); MS (m/z): 368.44 [Mþ•]. Anal. calcd. for C15H16N2O5S2: C
48.90, H 4.38, N 7.60; Found: C 48.98, H 4.03, N 7.72%.
Methyl 2-((4-phenyloxazol-2-ylcarbamoyl)methylsulfonyl)-
acetate 13a
White solid in 82% (2.65 g) yield; m.p.: 155–157°C; IR (KBr) ymax
(cmꢁ1): 1146, 1331 (SO ), 1579 (C N), 1629 (C C), 1690 (NH–CO),
–
–
–
–
2
1736 (COO), 3248 (NH); 1H NMR (DMSO-d6) d (ppm): 3.85 (s, 3H,
OCH3), 4.33 (s, 2H, CO–CH2), 4.41 (s, 2H, SO2–CH2), 7.17–7.55 (m,
6H, Ar–H, and C5–H), 11.00 (bs, 1H, NH); 13C NMR (DMSO-d6) d
(ppm): 52.7 (OCH3), 53.1 (SO2–CH2), 55.6 (CO–CH2), 138.6 (C-5),
140.8 (C-4), 152.0 (C-2), 163.8 (CO2Me), 169.6 (NH–CO), 124.3,
126.4, 128.5, 130.8 (aromatic carbons); MS (m/z): 338.34 [Mþ•].
Methyl 2-((4-(p-chlorophenyl)thiazol-2-ylcarbamoyl)-
methylsulfonyl)acetate 14c
White solid in 81% (3.03 g) yield; m.p.: 186–188°C; IR (KBr) ymax
(cmꢁ1): 1145, 1333 (SO ), 1578 (C N), 1641 (C C), 1693 (NH–CO),
–
–
–
–
2
1735 (COO), 3255 (NH); 1H NMR (DMSO-d6) d (ppm): 3.86 (s, 3H,
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Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520 Acetamidomethylsulfonyl Bis Heterocycles-Oxazolyl/Thiazolyl/Imidazolyl-1,3,4-Oxadiazoles 517
OCH3), 4.33 (s, 2H, CO–CH2), 4.41 (s, 2H, SO2–CH2), 6.66 (s, 1H,
C5–H), 7.22–7.63 (m, 4H, Ar–H), 11.33 (bs, 1H, NH); 13C NMR
(DMSO-d6) d (ppm): 52.5 (OCH3), 53.2 (SO2–CH2), 55.2 (CO–CH2),
105.9 (C-5), 148.5 (C-4), 162.9 (NH–CO), 164.3 (C-2), 168.9 (CO2Me),
128.2, 129.1, 130.4, 132.8 (aromatic carbons); MS (m/z): 388.84
[Mþ•]. Anal. calcd. for C14H13ClN2O5S2: C 43.24, H 3.37, N 7.20;
Found: C 43.35, H 3.42, N 7.09%.
2-((4-Phenyloxazol-2-ylcarbamoyl)methylsulfonyl)-
acetohydrazide 16a
White solid in 78% (2.63 g) yield; m.p.: 171–173°C; IR (KBr) ymax
(cmꢁ1): 1131, 1333 (SO ), 1572 (C N), 1631 (C C), 1674 (CO–NH),
–
–
–
–
2
1687 (NHCO), 3255 (NH), 3366, 3443 (NH2); 1H NMR (DMSO-d6) d
(ppm): 3.52 (bs, 2H, NH2), 4.31 (s, 2H, CO–CH2), 4.36 (s, 2H,
SO2–CH2), 7.26–7.50 (m, 6H, Ar–H, and C5–H), 8.50 (bs, 1H,
CO–NH), 10.90 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 56.9
(CO–CH2), 58.2 (SO2–CH2), 138.7 (C-5), 140.7 (C-4), 151.8 (C-2), 171.4
(NH–CO), 173.2 (CO–NH), 123.3, 124.2, 128.9, 134.8 (aromatic
carbons); 338.35 [Mþ•], 187.34, 144.16, 103.17 (100%), 77.24; Anal.
calcd. for C13H14N4O5S: C 46.15, H 4.17, N 16.56; Found: C 46.08, H
4.24, N 16.68%.
Methyl 2-((4-phenyl-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetate 15a
White solid in 84% (2.71 g) yield; m.p.: 155–157°C; IR (KBr) ymax
(cmꢁ1): 1140, 1330 (SO ), 1575 (C N), 1634 (C C), 1688 (NH–CO),
–
–
–
–
2
1733 (COO), 3254 (NH); 1H NMR (DMSO-d6) d (ppm): 3.84 (s, 3H,
OCH3), 4.34 (s, 2H, CO–CH2), 4.39 (s, 2H, SO2–CH2), 7.20–7.56 (m,
6H, Ar–H, and C5–H), 10.87 (bs, 1H, NH–CO), 12.60 (bs, 1H, NH);
13C NMR (DMSO-d6) d (ppm): 52.4 (OCH3), 53.5 (SO2–CH2), 54.8
(CO–CH2), 123.0 (C-5), 137.3 (C-2), 140.8 (C-4), 163.4 (CO2Me), 169.3
(NH–CO), 124.2, 126.3, 128.2, 130.6 (aromatic carbons); MS (m/z):
337.36 [Mþ•]. Anal. calcd. for C14H15N3O5S: C 49.84, H 4.48, N
12.46; Found: C 49.96, H 4.55, N 12.60%.
2-((4-p-Tolyloxazol-2-ylcarbamoyl)methylsulfonyl)-
acetohydrazide 16b
White solid in 76% (2.67 g) yield; m.p.: 186–188°C; IR (KBr) ymax
(cmꢁ1): 1130, 1329 (SO ), 1569 (C N), 1629 (C C), 1671 (CO–NH),
–
–
–
–
2
1685 (NHCO), 3248 (NH), 3360, 3435 (NH2); 1H NMR (DMSO-d6) d
(ppm): 2.41 (s, 3H, Ar–CH3), 3.50 (bs, 2H, NH2), 4.30 (s, 2H, CO–CH2),
4.33 (s, 2H, SO2–CH2), 7.16–7.42 (m, 5H, Ar–H, and C5–H), 8.49 (bs,
1H, CO–NH), 10.87 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm):
24.9 (Ar–CH3), 56.6 (CO–CH2), 57.8 (SO2–CH2), 138.1 (C-5), 140.2 (C-
4), 151.4 (C-2), 171.0 (NH–CO), 172.9 (CO–NH), 122.4, 124.3, 128.5,
132.5 (aromatic carbons); MS (m/z): 352.38 [Mþ•], 201.08, 158.13,
117.19 (100%), 91.22; Anal. calcd. for C14H16N4O5S: C 47.72, H 4.58,
N 15.90; Found: C 47.81, H 4.63, N 15.84%.
Methyl 2-((4-p-tolyl-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetate 15b
White solid in 82% (2.76 g) yield; m.p.: 176–178°C; IR (KBr) ymax
(cmꢁ1): 1139, 1325 (SO ), 1573 (C N), 1632 (C C), 1686 (NH–CO),
–
–
–
–
2
1731 (COO), 3242 (NH); 1H NMR (DMSO-d6) d (ppm): 2.34 (s, 3H,
Ar–CH3), 3.82 (s, 3H, OCH3), 4.31 (s, 2H, CO–CH2), 4.39 (s, 2H,
SO2–CH2), 7.17–7.48 (m, 5H, Ar–H, and C5–H), 10.69 (bs, 1H,
NH–CO), 12.57 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 24.4
(Ar–CH3), 52.1 (OCH3), 53.0 (SO2–CH2), 54.5 (CO–CH2), 122.6 (C-5),
136.7 (C-2), 141.1 (C-4), 163.1 (CO2Me), 168.7 (NH–CO), 122.6,
125.3, 130.2, 134.6 (aromatic carbons); MS (m/z): 351.39 [Mþ•].
Anal. calcd. for C15H17N3O5S: C 51.27, H 4.87, N 11.96; Found: C
51.39, H 4.96, N 12.09%.
2-((4-(p-Chlorophenyl)oxazol-2-ylcarbamoyl)-
methylsulfonyl)acetohydrazide 16c
White solid in 75% (2.79 g) yield; m.p.: 195–197°C; IR (KBr) ymax
(cmꢁ1): 1138, 1340 (SO ), 1587 (C N), 1636 (C C), 1675 (CO–NH),
–
–
–
–
2
1692 (NHCO), 3256 (NH), 3366, 3443 (NH2); 1H NMR (DMSO-d6) d
(ppm): 3.53 (bs, 2H, NH2), 4.34 (s, 2H, CO–CH2), 4.37 (s, 2H,
SO2–CH2), 7.33–7.48 (m, 5H, Ar–H, and C5–H), 8.52 (bs, 1H,
CO–NH), 11.11 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 57.5
(CO–CH2), 58.6 (SO2–CH2), 138.8 (C-5), 140.5 (C-4), 152.0 (C-2), 171.6
(NH–CO), 173.5 (CO–NH), 126.3, 128.2, 131.8, 135.2 (aromatic
carbons); MS (m/z): 372.79 [Mþ•], 221.74, 178.59, 137.43, (100%),
111.27; Anal. calcd. for C13H13ClN4O5S: C 41.88, H 3.51, N 15.03;
Found: C 41.97, H 3.56, N 15.15%.
Methyl 2-((4-(p-chlorophenyl)-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetate 15c
White solid in 81% (2.89 g) yield; m.p.: 192–194°C; IR (KBr) ymax
(cmꢁ1): 1144, 1334 (SO ), 1576 (C N), 1643 (C C), 1691 (NH–CO),
–
–
–
–
2
1737 (COO), 3257 (NH); 1H NMR (DMSO-d6) d (ppm): 3.88 (s, 3H,
OCH3), 4.33 (s, 2H, CO–CH2), 4.42 (s, 2H, SO2–CH2), 7.30–7.66 (m,
5H, Ar–H, and C5–H), 10.23 (bs, 1H, NH–CO), 12.61 (bs, 1H, NH);
13C NMR (DMSO-d6) d (ppm): 52.8 (OCH3), 53.7 (SO2–CH2), 55.3
(CO–CH2), 123.2 (C-5), 137.5 (C-2), 141.3 (C-4), 163.9 (CO2Me), 169.0
(NH–CO), 128.6, 129.8, 130.6, 134.8 (aromatic carbons); MS (m/z):
371.80 [Mþ•]. Anal. calcd. for C14H14ClN3O5S: C 45.23, H 3.79, N
11.30; Found: C 45.32, H 3.71, N 11.43%.
2-((4-Phenylthiazol-2-ylcarbamoyl)methylsulfonyl)-
acetohydrazide 17a
White solid in 77% (2.72 g) yield; m.p.: 183–185°C; IR (KBr) ymax
(cmꢁ1): 1134, 1332 (SO ), 1570 (C N), 1634 (C C), 1677 (CO–NH),
–
–
–
–
2
1690 (NHCO), 3250 (NH), 3365, 3431 (NH2); 1H NMR (DMSO-d6) d
(ppm): 3.49 (bs, 2H, NH2), 4.30 (s, 2H, CO–CH2), 4.35 (s, 2H,
SO2–CH2), 6.63 (s, 1H, C5–H), 7.18–7.43 (m, 5H, Ar–H), 8.45 (bs, 1H,
CO–NH), 10.86 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 56.4
(CO–CH2), 57.5 (SO2–CH2), 104.7 (C-5), 147.1 (C-4), 163.8 (C-2), 170.1
(NH–CO), 171.2 (CO–NH), 125.3, 128.0, 129.9, 132.8 (aromatic
carbons); MS (m/z): 354.41 [Mþ•], 203.09, 160.25 (100%), 103.22,
77.18; Anal. calcd. for C13H14N4O4S2: C 44.06, H 3.98, N 15.81;
Found: C 44.17, H 4.03, N 15.91%.
General procedure for the synthesis of 2-((4-aryloxazol-2-
ylcarbamoyl)methylsulfonyl)acetohydrazide (16a–c)/2-((4-
arylthiazol-2-ylcarbamoyl)methylsulfonyl)acetohydrazide
(17a–c)/2-((4-aryl-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetohydrazide (18a–c)
Compound 13/14/15 (10 mmol), hydrazine hydrate (0.55 g,
11 mmol), pyridine (0.2 mL), and methanol (6 mL) were
refluxed for 5–7 h. The reaction mixture was cooled and the
solid separated was filtered, dried, and recrystallized from
methanol.
2-((4-p-Tolylthiazol-2-ylcarbamoyl)methylsulfonyl)-
acetohydrazide 17b
White solid in 76% (2.80 g) yield; m.p.: 192–194°C; IR (KBr) ymax
(cmꢁ1): 1132, 1326 (SO ), 1566 (C N), 1630 (C C), 1670 (CO–NH),
–
–
–
–
2
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www.archpharm.com

518
N. M. Basha et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520
1688 (NHCO), 3243 (NH), 3358, 3426 (NH2); 1H NMR (DMSO-d6) d
(ppm): 2.38 (s, 3H, Ar–CH3), 3.45 (bs, 2H, NH2), 4.28 (s, 2H,
CO–CH2), 4.31 (s, 2H, SO2–CH2), 6.60 (s, 1H, C5–H), 7.10–7.35 (m,
4H, Ar–H), 8.42 (bs, 1H, CO–NH), 10.22 (bs, 1H, NH–CO); 13C NMR
(DMSO-d6) d (ppm): 24.6 (Ar–CH3), 56.0 (CO–CH2), 57.1 (SO2–CH2),
104.5 (C-5), 147.8 (C-4), 163.4 (C-2), 169.9 (NH–CO), 170.9 (CO–NH),
124.4, 126.3, 130.5, 134.5 (aromatic carbons); MS (m/z): 368.44
[Mþ•], 217.32, 174.17 (100%), 117.21, 91.36; Anal. calcd. for
C14H16N4O4S2: C 45.64, H 4.38, N 15.21; Found: C 45.75, H 4.41, N
15.30%.
(ppm): 3.52 (bs, 2H, NH2), 4.32 (s, 2H, CO–CH2), 4.35 (s, 2H,
SO2–CH2), 7.36–7.53 (m, 5H, Ar–H, and C5–H), 8.51 (bs, 1H,
CO–NH), 10.92 (bs, 1H, NH–CO), 12.57 (bs, 1H, NH); 13C NMR
(DMSO-d6) d (ppm): 57.6 (CO–CH2), 58.8 (SO2–CH2), 123.8 (C-5),
137.9 (C-2), 142.0 (C-4), 170.9 (NH–CO), 171.5 (CO–NH), 126.3,
130.4, 132.8, 135.8 (aromatic carbons); MS (m/z): 371.80 [Mþ•],
220.58, 177.59, 137.32 (100%), 111.14; Anal. calcd. for
C13H14ClN5O4S: C 42.00, H 3.80, N 18.84; Found: C 42.09, H
3.86, N 18.72%.
General procedure for the synthesis of 2-((50-(o-
chlorophenyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-
(4-aryloxazol-2-yl)acetamide (19a–c)/2-((50-(o-
2-((4-(p-Chlorophenyl)thiazol-2-ylcarbamoyl)-
methylsulfonyl)acetohydrazide 17c
White solid in 74% (2.87 g) yield; m.p.: 201–203°C; IR (KBr) ymax
chlorophenyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-
(4-arylthiazol-2-yl)acetamide (20a–c)/2-((50-(o-chloro-
phenyl)-10,30,40-oxadiazol-20-yl)methylsulfonyl)-N-(4-aryl-
(cmꢁ1): 1139, 1336 (SO ), 1582 (C N), 1637 (C C), 1772 (CO–NH),
–
–
–
–
2
1691 (NHCO), 3252 (NH), 3372, 3438 (NH2); 1H NMR (DMSO-d6) d
(ppm): 3.51 (bs, 2H, NH2), 4.33 (s, 2H, CO–CH2), 4.34 (s, 2H,
SO2–CH2), 6.67 (s, 1H, C5–H), 7.26–7.44 (m, 4H, Ar–H), 8.50 (bs, 1H,
CO–NH), 11.07 (bs, 1H, NH–CO); 13C NMR (DMSO-d6) d (ppm): 56.5
(CO–CH2), 58.1 (SO2–CH2), 105.8 (C-5), 147.7 (C-4), 164.0 (C-2), 170.4
(NH–CO), 171.3 (CO–NH), 127.3, 130.2, 132.8, 134.6 (aromatic
carbons); MS (m/z): 388.85 [Mþ•], 237.71, 194.73 (100%), 137.28,
111.15; Anal. calcd. for C13H13ClN4O4S2: C 40.15, H 3.37, N 14.41;
Found: C 40.09, H 3.42, N 14.52%.
1H-imidazol-2-yl)acetamide (21a–c)
To an equimolar mixture of (10 mmol) acid hydrazide 16/17/18
and 2-chlorobenzoic acid (1.56 g, 10 mmol), POCl3 (7 mL) was
added and refluxed for 6–9 h. The excess POCl3 was removed
under reduced pressure and the residue was poured onto crushed
ice. The resulting precipitate was filtered, washed with
saturated sodium bicarbonate solution, and then with water. It
was dried and recrystallized from ethanol.
2-((4-Phenyl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl)-
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
acetohydrazide 18a
methylsulfonyl)-N-(4-phenyloxazol-2-yl)acetamide 19a
White solid in 69% (2.33 g) yield; m.p.: 127–129°C; IR (KBr) ymax
White solid in 72% (2.42 g) yield; m.p.: 177–179°C; IR (KBr) ymax
(cmꢁ1): 1134, 1333 (SO ), 1571 (C N), 1637 (C C), 1673 (CO–NH),
–
–
–
–
2
1685 (NHCO), 3254 (NH), 3364, 3440 (NH2); 1H NMR (DMSO-d6) d
(ppm): 3.50 (bs, 2H, NH2), 4.29 (s, 2H, CO–CH2), 4.33 (s, 2H,
SO2–CH2), 7.24–7.49 (m, 6H, Ar–H, and C5–H), 8.49 (bs, 1H,
CO–NH), 11.12 (bs, 1H, NH–CO), 12.42 (bs, 1H, NH); 13C NMR
(DMSO-d6) d (ppm): 56.8 (CO–CH2), 57.9 (SO2–CH2), 123.2 (C-5),
137.8 (C-2), 141.8 (C-4), 170.7 (NH–CO), 171.4 (CO–NH), 126.4,
128.8, 130.9, 133.8 (aromatic carbons); MS (m/z): 337.36 [Mþ•],
186.22, 143.19, 103.24 (100%), 77.15; Anal. calcd. for C13H15N5O4S:
C 46.28, H 4.48, N 20.76; Found: C 46.36, H 4.42, N 20.89%.
(cmꢁ1): 1129, 1317 (SO ), 1564 (C N), 1620 (C C), 1685 (C O),
–
–
–
–
–
–
2
3249 (NH); 1H NMR (DMSO-d6) d (ppm): 4.34 (s, 2H, CO–CH2), 4.69
(s, 2H, SO2–CH2), 7.46–7.72 (m, 10H, Ar–H, and C5–H), 11.34 (bs,
1H, NH); 13C NMR (DMSO-d6) d (ppm): 50.4 (SO2–CH2), 54.1
(CO–CH2), 137.4 (C-5), 140.8 (C-4), 150.2 (C-2), 158.7 (C-20), 165.7
(C-50), 170.4 (CO), 126.1, 126.8, 127.3, 128.1, 128.9, 129.2, 131.2,
132.4, 134.7, 135.6 (aromatic carbons); MS (m/z): 458.89 [Mþ•],
192.54, 187.23, 179.43, 144.24, 111.24 (100%), 103.17; Anal. calcd.
for C20H15ClN4O5S: C 52.34, H 3.29, N 12.20; Found: C 52.44, H
3.34, N 12.34%.
2-((4-p-Tolyl-1H-imidazol-2-ylcarbamoyl)methylsulfonyl)-
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
acetohydrazide 18b
methylsulfonyl)-N-(4-p-tolyloxazol-2-yl)acetamide 19b
White solid in 71% (2.50 g) yield; m.p.: 134–136°C; IR (KBr) ymax
White solid in 76% (2.67 g) yield; m.p.: 213–215°C; IR (KBr) ymax
(cmꢁ1): 1131, 1328 (SO ), 1564 (C N), 1631 (C C), 1671 (CO–NH),
–
–
–
–
2
1687 (NHCO), 3249 (NH), 3367, 3434 (NH2); 1H NMR (DMSO-d6) d
(ppm): 2.46 (s, 3H, Ar–CH3), 3.49 (bs, 2H, NH2), 4.31 (s, 2H,
CO–CH2), 4.36 (s, 2H, SO2–CH2), 7.21–7.43 (m, 5H, Ar–H, and
C5–H), 8.47 (bs, 1H, CO–NH), 10.74 (bs, 1H, NH–CO), 12.48 (bs, 1H,
NH); 13C NMR (DMSO-d6) d (ppm): 24.7 (Ar–CH3), 56.2 (CO–CH2),
58.6 (SO2–CH2), 122.0 (C-5), 136.4 (C-2), 140.8 (C-4), 170.2 (NH–CO),
171.2 (CO–NH), 122.4, 124.3, 127.5, 134.0 (aromatic carbons); MS
(m/z): 351.38 [Mþ•], 200.31, 157.24, 117.23 (100%), 91.23; Anal.
calcd. for C14H17N5O4S: C 47.85, H 4.88, N 19.93; Found: C 47.94, H
4.93, N 20.03%.
(cmꢁ1): 1125, 1311 (SO ), 1559 (C N), 1618 (C C), 1687 (C O),
–
–
–
–
–
–
2
3243 (NH); 1H NMR (DMSO-d6) d (ppm): 2.47 (s, 3H, Ar–CH3), 4.32 (s,
2H, CO–CH2), 4.67 (s, 2H, SO2–CH2), 7.42–7.62 (m, 9H, Ar–H, and
C5–H), 10.98 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 24.6
(Ar–CH3), 50.2 (SO2–CH2), 53.8 (CO–CH2), 138.0 (C-5), 140.4 (C-4),
150.5 (C-2), 157.2 (C-20), 164.8 (C-50), 169.8 (CO), 126.3, 126.7, 127.2,
127.5, 128.3, 128.6, 129.5, 131.6, 132.3, 135.0 (aromatic carbons);
MS (m/z): 472.91 [Mþ•], 201.33, 192.31, 179.45, 158.24, 117.24,
111.20 (100%); Anal. calcd. for C21H17ClN4O5S: C 53.33, H 3.62, N
11.84; Found: C 53.42, H 3.58, N 11.98%.
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-(p-chlorophenyl)-oxazol-2-yl)-
2-((4-(p-Chlorophenyl)-1H-imidazol-2-ylcarbamoyl)-
methylsulfonyl)acetohydrazide 18c
acetamide 19c
White solid in 78% (2.90 g) yield; m.p.: 227–229°C; IR (KBr) ymax
(cmꢁ1): 1137, 1337 (SO ), 1580 (C N), 1639 (C C), 1677 (CO–NH),
White solid in 72% (2.68 g) yield; m.p.: 150–152°C; IR (KBr) ymax
–
–
–
–
2
1694 (NHCO), 3255 (NH), 3378, 3447 (NH2); 1H NMR (DMSO-d6) d
(cmꢁ1): 1134, 1320 (SO ), 1568 (C N), 1629 (C C), 1692 (C O),
–
–
–
–
–
–
2
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520 Acetamidomethylsulfonyl Bis Heterocycles-Oxazolyl/Thiazolyl/Imidazolyl-1,3,4-Oxadiazoles 519
3262 (NH); 1H NMR (DMSO-d6) d (ppm): 4.35 (s, 2H, CO–CH2), 4.70
(s, 2H, SO2–CH2), 7.47–7.80 (m, 9H, Ar–H, and C5–H), 11.38 (bs, 1H,
NH); 13C NMR (DMSO-d6) d (ppm): 50.6 (SO2–CH2), 54.7 (CO–CH2),
138.3 (C-5), 140.2 (C-4), 151.3 (C-2), 158.2 (C-20), 166.7 (C-50), 171.8
(CO), 127.8, 128.0, 128.6, 128.9, 129.8, 130.2, 131.6, 132.0, 132.3,
135.9 (aromatic carbons); MS (m/z): 493.34 [Mþ•], 221.54, 192.18,
179.24, 178.33, 137.26, 111.16 (100%); Anal. calcd. for
(s, 2H, SO2–CH2), 7.42–7.83 (m, 10H, Ar–H, and C5–H), 11.26 (bs,
1H, NH–CO), 12.48 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 50.7
(SO2–CH2), 54.7 (CO–CH2), 123.5 (C-5), 137.3 (C-2), 140.4 (C-4), 154.8
(C-20), 165.5 (C-50), 169.9 (CO), 126.1, 126.8, 127.3, 128.1, 128.9,
129.2, 131.2, 132.4, 134.7, 135.6 (aromatic carbons); MS (m/z):
457.90 [Mþ•], 192.55, 186.17, 179.31, 143.54 (100%), 103.16,
111.55, 77.14; Anal. calcd. for C20H16ClN5O4S: C 52.46, H 3.52, N
15.29; Found: C 52.57, H 3.58, N 15.41%.
C20H14Cl2N4O5S: C 48.69, H 2.86, N 11.35; Found: C 48.60, H
2.82, N 11.23%.
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-p-tolyl-1H-imidazol-2-yl)acetamide
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-phenylthiazol-2-yl)-acetamide 20a
White solid in 70% (2.48 g) yield; m.p.: 141–143°C; IR (KBr) ymax
21b
White solid in 72% (2.52 g) yield; m.p.: 129–131°C; IR (KBr) ymax
(cmꢁ1): 1132, 1312 (SO ), 1563 (C N), 1624 (C C), 1688 (C O),
(cmꢁ1): 1131, 1313 (SO ), 1552 (C N), 1624 (C C), 1686 (C O), 3244
–
–
–
–
–
–
–
–
–
–
–
–
2
2
3251 (NH); 1H NMR (DMSO-d6) d (ppm): 4.31 (s, 2H, CO–CH2), 4.65
(s, 2H, SO2–CH2), 6.68 (s, 1H, C5–H), 7.36–7.76 (m, 9H, Ar–H), 11.03
(bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 49.6 (SO2–CH2), 53.6
(CO–CH2), 105.4 (C-5), 148.3 (C-4), 156.4 (C-20), 163.9 (C-2), 164.7
(C-50), 167.9 (CO), 126.1, 126.8, 127.3, 128.1, 128.9, 129.2, 131.2,
132.4, 134.7, 135.6 (aromatic carbons); MS (m/z): 474.95 [Mþ•],
203.20, 192.61, 179.24, 160.15, 111.05, 103.16 (100%), 77.19; Anal.
calcd. for C20H15ClN4O4S2: C 50.57, H 3.18, N 11.79; Found: C
50.66, H 3.12, N 11.91%.
1
(NH); H NMR (DMSO-d6) d (ppm): 2.49 (s, 3H, Ar–CH3), 4.31 (s, 2H,
CO–CH2), 4.65 (s, 2H, SO2–CH2), 7.48–7.66 (m, 9H, Ar–H, and C5–H),
11.18 (bs, 1H, NH–CO), 12.46 (bs, 1H, NH); 13C NMR (DMSO-d6) d
(ppm): 24.8 (Ar–CH3), 49.7 (SO2–CH2), 54.4 (CO–CH2), 123.0 (C-5),
137.1 (C-2), 140.2 (C-4), 153.7 (C-20), 165.3 (C-50), 168.3 (CO), 126.3,
126.7, 127.2, 127.5, 128.3, 128.6, 129.5, 131.6, 132.3, 135.0 (aromatic
carbons); MS (m/z): 471.92 [Mþ•], 200.19, 192.61, 179.28, 157.24
(100%), 117.26, 111.36, 91.34; Anal. calcd. for C21H18ClN5O4S: C
53.44, H 3.84, N 14.83; Found: C 53.57, H 3.81, N 14.95%.
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-(p-chlorophenyl)-1H-imidazol-2-yl)-
methylsulfonyl)-N-(4-p-tolylthiazol-2-yl)-acetamide 20b
White solid in 68% (2.50 g) yield; m.p.: 148–150°C; IR (KBr) ymax
acetamide 21c
(cmꢁ1): 1130, 1310 (SO ), 1557 (C N), 1623 (C C), 1685 (C O),
–
–
–
–
–
–
2
White solid in 70% (2.60 g) yield; m.p.: 159–161°C; IR (KBr) ymax
3244 (NH); 1H NMR (DMSO-d6) d (ppm): 2.42 (s, 3H, Ar–CH3), 4.30 (s,
2H, CO–CH2), 4.64 (s, 2H, SO2–CH2), 6.66 (s, 1H, C5–H), 7.33–7.71
(m, 8H, Ar–H), 11.30 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 24.5
(Ar–CH3), 50.3 (SO2–CH2), 53.2 (CO–CH2), 105.5 (C-5), 148.0 (C-4),
154.2 (C-20), 163.5 (C-2), 166.5 (C-50), 167.8 (CO), 126.3, 126.7, 127.2,
127.5, 128.3, 128.6, 129.5, 131.6, 132.3, 135.0 (aromatic carbons);
MS (m/z): 488.97 [Mþ•], 217.34, 192.51, 179.23, 174.17, 117.24
(100%), 111.55, 91.00; Anal. calcd. for C21H17ClN4O4S2: C 51.58, H
3.50, N 11.45; Found: C 51.69, H 3.57, N 11.58%.
(cmꢁ1): 1134, 1321 (SO ), 1566 (C N), 1631 (C C), 1693 (C O),
–
–
–
–
–
–
2
3268 (NH); 1H NMR (DMSO-d6) d (ppm): 4.34 (s, 2H, CO–CH2), 4.69
(s, 2H, SO2–CH2), 7.47–7.86 (m, 9H, Ar–H, and C5–H), 11.34 (bs, 1H,
NH–CO), 12.51 (bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 50.9
(SO2–CH2), 55.0 (CO–CH2), 123.6 (C-5), 138.0 (C-2), 141.2 (C-4), 155.4
(C-20), 166.7 (C-50), 171.2 (CO), 127.8, 128.0, 128.6, 128.9, 129.8,
130.2, 131.6, 132.0, 132.3, 135.9 (aromatic carbons); MS (m/z):
492.35 [Mþ•], 220.58, 192.54, 179.23, 177.53, (100%), 137.28,
111.28; Anal. calcd. for C20H15Cl2N5O4S: C 48.79, H 3.07, N 14.22;
Found: C 48.87, H 3.12, N 14.37%.
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-(p-chlorophenyl)-thiazol-2-yl)-
Biological assays
Antioxidant activity
The compounds 19–21 were tested for antioxidant activity by the
DPPH, NO, and ABTS methods.
acetamide 20c
White solid in 69% (2.68 g) yield; m.p.: 164–166°C; IR (KBr) ymax
(cmꢁ1): 1135, 1315 (SO ), 1567 (C N), 1633 (C C), 1690 (C O),
–
–
–
–
–
–
2
3264 (NH); 1H NMR (DMSO-d6) d (ppm): 4.33 (s, 2H, CO–CH2), 4.68
(s, 2H, SO2–CH2), 7.02 (s, 1H, C5–H), 7.41–7.78 (m, 8H, Ar–H), 11.37
(bs, 1H, NH); 13C NMR (DMSO-d6) d (ppm): 50.8 (SO2–CH2), 53.8
(CO–CH2), 106.0 (C-5), 148.6 (C-4), 155.6 (C-20), 164.3 (C-2), 164.8 (C-
50), 168.2 (CO), 127.8, 128.0, 128.6, 128.9, 129.8, 130.2, 131.6,
132.0, 132.3, 135.9 (aromatic carbons); MS (m/z): 509.40 [Mþ•],
237.58, 194.34, 192.47, 179.31, 137.29 (100%), 111.05; Anal. calcd.
for C20H14Cl2N4O4S2: C 47.15, H 2.76, N 10.99; Found: C 47.08, H
2.72, N 11.11%.
DPPH radical-scavenging activity
The hydrogen atom or electron donation ability of the
compounds was measured from the bleaching of the purple-
colored methanol solution of DPPH radicals. The spectrophoto-
metric assay uses the stable radical DPPH• as reagent. To 4 mL of
0.004% w/v methanol solution of DPPH, 1 mL of various
concentrations of the test compounds (50, 75, and 100 mg/mL)
in methanol was added. After a 30-min incubation period at room
temperature, the absorbance was read against the blank at
517 nm. Ascorbic acid was used as the standard. The percent of
inhibition (I%) of free-radical production from DPPH was
calculated by the following equation:
2-((50-(o-Chlorophenyl)-10,30,40-oxadiazol-20-yl)-
methylsulfonyl)-N-(4-phenyl-1H-imidazol-2-yl)acetamide
21a
ꢀ
ꢁ
White solid in 71% (2.39 g) yield; m.p.: 135–137°C; IR (KBr) ymax
ðAcontrol ꢁ Asample
Þ
(cmꢁ1): 1133, 1318 (SO ), 1561 (C N), 1628 (C C), 1689 (C O),
–
–
–
–
–
–
2
I% ¼
ꢂ 100
3253 (NH); 1H NMR (DMSO-d6) d (ppm): 4.32 (s, 2H, CO–CH2), 4.67
Ablank
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

520
N. M. Basha et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 511–520
where Acontrol is the absorbance of the control reaction
(containing methanolic DPPH and ascorbic acid), Asample is the
absorbance of the test compound (containing methanolic DPPH
and the test compound), and Ablank is the absorbance of the blank
(containing only methanolic DPPH). The tests were carried out in
triplicate.
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Nitric oxide-scavenging activity
The NO-scavenging activity was measured by the methods of
Green et al. [20] and Marcocci et al. [21], with slight modifications.
NO radicals were generated from sodium nitroprusside. Of
sodium nitroprusside, 1 mL (10 mM) and 1.5 mL of phosphate-
buffered saline (0.2 M, pH 7.4) were added to different concen-
trations (50, 75, and 100 mg/mL) of the test compounds and
incubated for 150 min at 25°C. After incubation, 1 mL of the
reaction mixture was treated with 1 mL Griess reagent (1%
sulfanilamide, 2% H3PO4, 0.1% naphthylethylenediamine dihy-
drochloride). The absorbance of the chromatophore was measured
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scavenging activity was calculated by the following equation
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Farmaco 2002, 57, 101–107.
ðAcontrol ꢁ Asample
Þ
[9] T. Ramalingum, P. B. Sattur, Eur. J. Med. Chem. 1990, 25, 541–
% of scavenging ¼
ꢂ 100
Ablank
544.
[10] M. Harfenist, D. J. Heuser, C. T. Joyner, J. F. Batchelor,
where Acontrol is the absorbance of the control reaction (containing
all reagents and ascorbic acid), Asample is the absorbance of the test
compound (containing all reagents and the test compound), and
Ablank is the absorbance of the blank (containing only reagents).
The tests were carried out in triplicate.
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ABTS radical-scavenging activity
A. Padmaja, Chem. Pharm. Bull. 2012, 60, 449–459.
The antioxidant activities of the test compounds and the standard
(ascorbic acid) were assessed on the basis of the radical-scavenging
effect of the stable ABTS free radical. The ABTS•þ solution was
prepared by mixing 0.02 mol ABTS salt with 0.01 mol potassium
persulfate in 25 mL distilled water. The solution was kept at room
temperature in the dark for 16 h before use. Then the ABTS•þ
solution was diluted with methanol in order to obtain an
absorbance between 0.7 and 0.9 at 734 nm, using the spectro-
photometer. Fresh ABTS•þ solutions were prepared for each
assay. To 50, 75, and 100 mg/mL of each test compound or
standard, 1 mL ABTS•þ solution was added and allowed to react
for 2 h in the dark. Then the absorbance was read at 734 nm,
using the spectrophotometer. The corresponding blank reading
was also taken and the results as percentage were expressed as the
ratio of the absorbance decrease at 734 nm to the absorbance of
the ABTS•þ solution in the absence of test compounds.
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The authors are grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial assistance under a major
research project. One of the authors, N.M.B., thanks the University Grants
Commission, New Delhi, for the sanction of a UGC-BSR fellowship.
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ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com