Synthesis and antioxidant activity of pyrazolyl-oxazolines/thiazolines and isoxazolyl-oxazolines/thiazolines

Article abstract of DOI:10.1007/s00044-013-0688-z

A new class of pyrazolyl/isoxazolyl-oxazolines and thiazolines were synthesized from E-arylsulfonylethenesulfonylacetic acid methyl ester and tested for antioxidant activity. Among the tested compounds, 14b exhibited excellent antioxidant activity when compared with the standard ascorbic acid.

Full text of DOI:10.1007/s00044-013-0688-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:1084–1098
DOI 10.1007/s00044-013-0688-z
ORIGINAL RESEARCH
Synthesis and antioxidant activity of pyrazolyl-oxazolines/
thiazolines and isoxazolyl-oxazolines/thiazolines
Adivireddy Padmaja
Suram Durgamma Bhumireddy Chinnachennaiahgari Venkatesh
Venkatapuram Padmavathi
•
Chittoor Rajasekhar
•
•
•
Received: 16 April 2013 / Accepted: 26 July 2013 / Published online: 24 August 2013
Ó Springer Science+Business Media New York 2013
Abstract A new class of pyrazolyl/isoxazolyl-oxazolines
and thiazolines were synthesized from E-arylsulfonylethe-
nesulfonylacetic acid methyl ester and tested for antioxi-
dant activity. Among the tested compounds, 14b exhibited
excellent antioxidant activity when compared with the
standard ascorbic acid.
(Penning et al., 1997), rimonabant (Deng and Mani,
2008) and valdecoxib (Dannhardt et al., 2000) contain
the pyrazole and isoxazole as their core molecular entity
(Katritzky et al., 2001; Elguero et al., 1996; Deng and
Mani, 2006). Besides, the marketed drugs of isoxazole
such as acetylsulfisoxazole, cycloserine, drazoxol, sulfi-
soxazole, and zonisamide show antimicrobial (Vyas
et al., 2007; Clark and McElligott, 1969), tuberculostatic
(Folkers and co-workers, 1955), anticonvulsant (Ozdemir
et al., 2007), neurotoxic (Kamei et al., 1978), and anti-
epileptic activities (Sackellares et al., 1985). Oxazoline
and thiazoline rings are important constituents of bio-
active natural products and pharmaceuticals (Wang and
Dervan, 2001; Sharma et al., 2001; Dyatkina et al.,
2002). The oxazole ring is a useful structural moiety
found in numerous biologically active molecules (Pad-
maja et al., 2011). Natural product hennoxazole A, first
isolated from the marine sponge, exhibit predominant
antiviral activity against herpes simplex type I (Ichiba
et al., 1991). The thiazole ring is an interesting building
block in a variety of natural products and bioactive
compounds useful as pharmaceuticals or agrochemical
agents (Rivkin et al., 2004; Ganesh et al., 2003; Plazzi
et al., 1995; Bai et al., 2008; Hu et al., 2009). In fact,
compounds with good antioxidant activity are supposed
to have good anti-inflammatory activity. In view of the
importance of different five-membered heterocycles we
have synthesized a variety of bioactive heterocycles and
studied their biological activity (Padmaja et al., 2011;
Muralikrishna et al., 2012; Mallikarjuna et al., 2013). In
continuation of our efforts in this direction the
present work, synthesis and antioxidant activity of sul-
Keywords Pyrazolyl-oxazoline/thiazoline ꢀ
Isoxazolyl-oxazoline/thiazoline ꢀ Nitrile imine ꢀ
Nitrile oxide ꢀ Antioxidant activity
Introduction
Azoles are one of the most prevalent heterocyclic com-
pounds that are frequently found in a variety of natural
products and pharmaceuticals. Pyrazoles and isoxazoles
have attracted much attention since they play vital role
in synthetic organic chemistry over the years and are
important bioactive compounds as anticancer (Shin
et al., 2005; Amer et al., 2007; Abdolhamid et al.,
2
008), antiviral (Sechi et al., 2005), anti-inflammatory
(
Rapposelli et al., 2004), antidiabetic (Cottineau et al.,
2
2
2
002), antibacterial and antifungal agents (Cali et al.,
004; Shinde et al., 2004; Al-Omran and El-Khair,
004). Several pharmaceutical drugs including celecoxib
A. Padmaja (&) ꢀ C. Rajasekhar ꢀ S. Durgamma ꢀ
B. C. Venkatesh ꢀ V. Padmavathi
fonylmethane-linked
pyrazolyl-oxazolines/thiazolines
Department of Chemistry, Sri Venkateswara University,
Tirupati 517 502, Andhra Pradesh, India
e-mail: adivireddyp@yahoo.co.in
and isoxazolyl-oxazolines/thiazolines is taken up Figs. 1,
2, 3.
1
23

Med Chem Res (2014) 23:1084–1098
1085
Fig. 1 The in vitro antioxidant
activity of 4–15 in DPPH
method
Fig. 2 The in vitro antioxidant
activity of 4–15 in nitric oxide
method
Results and discussion
olefin proton, H . However, the signal corresponding to
B
another olefin proton H appeared at much downfield region
A
Chemistry
and merged with aromatic protons. The coupling constant
values JAB & 14.1 and 14.3 Hz indicated that they possess
trans geometry. The 1,3-dipolar cycloaddition of diazo-
methane to 2 and 3 in the presence of triethylamine in ether at
The cyclocondensation of E-arylsulfonylethenesulfonyla-
cetic acid methyl ester (1) with 2-aminoethanol/2-ami-
noethanethiol in the presence of samarium (III) chloride
and n-BuLi produced 2-(E-arylsulfonylethenesulfonylm-
ethyl)-4,5-dihydrooxazole (2) and 2-(E-arylsulfonyl-ethe-
nesulfonylmethyl)-4,5-dihydrothiazole (3) (Scheme 1). The
0
0
0
0
-20 to -15 °C gave 2-(4 ,5 -dihydro-3 -arylsulfonyl-1 H-
pyrazol-4 -ylsulfonylmethyl)-4,5-dihydrooxazole (4) and
0
0
0
0
0
0
2-(4 ,5 -dihydro-3 -arylsulfonyl-1 H-pyrazol-4 -ylsulfonylm-
ethyl)-4,5-dihydrothiazole (5). In fact, the addition of diazo-
methane to 2 and 3 may produce regioisomers. However, only
one pure regioisomer was isolated under the applied reaction
conditions. This may be due to electron withdrawing effect of
1
H NMR spectra of 2a and 3a exhibited a singlet at d 4.24 and
4
.27 for SO CH , two triplets at d 3.62, 3.76 and d 4.65,
2
2
3
.37 ppm for C -H and C -H and a doublet at d 7.28, 7.37 for
4
5
123

1
086
Med Chem Res (2014) 23:1084–1098
Fig. 3 The in vitro antioxidant
activity of 4–15 in hydrogen
peroxide method
0
nyl-isoxazol-5 -ylsulfonylmethyl)-4,5-dihydrooxazole (14)
sulfonyl group (Padmavathi et al., 2002; Padmaja et al.,
0
0
0
2
011). A small amount of the other isomer if any, formed
and 2-(3 -aryl-4 -arylsulfonylisoxazol-5 -ylsulfonylmeth-
could not be detected by this process (Padmavathi et al.,
1
003). The H NMR spectra of 4a and 5a showed three
yl)-4,5-dihydrothiazole (15). The absence of doublets due
0
1
-H in the H NMR spectra of com-
2
to at C4
-H and C5
0
double doublets at d 4.63, 4.59; 4.36, 4.23 and d 3.95, 3.83
which were assigned to pyrazoline ring protons, H , H
pounds 10–15 confirmed that oxidation took place. The
structures of all the new compounds were further estab-
A
M
1
lished by IR, C NMR spectra and elemental analyses.
3
and H , respectively. The coupling constant values JAM
X
=
1
2.4 Hz, JAX = 6.3 Hz, and JMX = 11.5 Hz in 4a and
JAM = 12.0 Hz, JAX = 6.0 Hz, JMX = 10.8 Hz in 5a
indicated that H , H are cis, H , HX are trans and HM,
A
M
A
HX are geminal. On the other hand, the cycloaddition of
nitrile imines and nitrile oxides generated from araldehyde
phenylhydrazones and araldoximes in the presence of
Biological evaluation
Antioxidant activity
0
0
0
chloramine-T to 2 and 3 resulted in 2-(4 ,5 -dihydro-1 -
0
0
0
phenyl-3 -aryl-4 -arylsulfonylpyrazol-5 -ylsulfonylmethyl)
0 0 0 0
The results of antioxidant activity of the test compounds and
control drug are presented in Tables 1, 2, 3. The aim of this
study is to identify the potential heterocyclic compound for
antioxidant activity. In general, bis heterocycles having
pyrazole/isoxazole with oxazoline and thiazoline moieties
(10–15) exhibited greater activity than the compounds con-
taining pyrazoline/isoxazoline with oxazoline and thiazoline
(4–9). It was also observed that compounds having pyrazole/
isoxazole unit in combination with oxazoline (10, 12, 14)
displayed considerable antioxidant activity than the corre-
sponding thiazolines (11, 13, 15). Moreover, the presence of
electron-donating methyl substituent on aromatic ring
enhanced the activity when compared with unsubstituted and
chloro-substituted compounds. The compounds oxazolyl
pyrazoles and isoxazoles having methyl substituent 10b,
12b, and 14b showed high antioxidant activity than other
compounds. In fact, the compound 14b exhibited excellent
radical scavenging activity in all the three methods when
-
4,5-dihydrooxazole (6), 2-(4 ,5 -dihydro-1 -phenyl-3 -
0
0
aryl-4 -arylsulfonylpyrazol-5 -ylsulfonylmethyl)-4,
0 0 0 0
5
-dihydrothiazole
(7),
sulfonylisoxazol-5 -ylsulfonylmethyl)-4,5-dihydrooxazole
2-(4 ,5 -dihydro-3 -aryl-4 -aryl
0
0 0 0 0 0
(
8), and 2-(4 ,5 -dihydro-3 -aryl-4 -arylsulfonylisoxazol-5 -
ylsulfonylmethyl)-4,5-dihydrothiazole (9), respectively. In
1
the H NMR spectra of 6a, 7a, 8a, and 9a two doublets
were observed at d 5.28, 5.26, 5.25, 5.22 and at d 5.65,
0 0
.63, 5.68, 5.71 due to for C4 -H and C5 -H, respectively,
5
in addition to signals due to other protons. The reaction of
0
compounds 4–9 with chloranil in xylene afforded 2-(3 -
0
0
arylsulfonyl-1 H-pyrazol-4 -ylsulfonylmethyl)-4,5-dihydro-
0
0
0
oxazole (10), 2-(3 -arylsulfonyl-1 H-pyrazol-4 -ylsulfo-
0
0
0
nylmethyl)-4,5-dihydrothiazole (11), 2-(1 -phenyl-3 -aryl-4 -a-
0
rylsulfonylpyrazol-5 -ylsulfonylmethyl)-4,5-dihydrooxazole (12),
0 0 0 0
2
-(1 -phenyl-3 -aryl-4 -aryl-sulfonylpyrazol-5 -ylsulfo-
0
0
nylmethyl)-4,5-dihydrothiazole (13), 2-(3 -aryl-4 -arylsulfo-
1
23

Med Chem Res (2014) 23:1084–1098
1087
HA
O
O
O
O
Ar
S
S
OMe
O
HB
1
i
HA
N
O
O
Ar
S
S
X
O
O
HB
2
/ 3
ii
iii
iv
O
N3 4
N3 4
N3 4
O
O
O
O
O
O
O
O
O
O
O
H
5
5
A
2
5
2
2
S
S
1
S
S
1
S
S
1
Ar
Ar
X
Ar
X
X
4'
3
' 4'
5'
5'
4' 5'
2' 1'O
3
'
3'
N 2'
HM
2' 1'N
N
1
'
Ar'
Ar'
N
N
HX
Ph
H
8
/ 9
6
/ 7
4
/ 5
v
v
v
N
X
N
N
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
Ar
Ar
X
Ar
X
N
N
O
Ar'
Ar'
N
H
N
N
Ph
1
2 / 13
14 / 15
1
0 / 11
2
3
/ 4 / 6 / 8 /10 /12 / 14 X = O
/ 5 / 7 / 9 /11 / 13 / 15 X = S
(
(
(
(
(
i) NH CH CH XH / Sm(III)Cl / n-BuLi / Toluene
2 2 2 3
o
a: Ar = Ph,
b: Ar = 4-Me.Ph, Ar' = 4-OMe.Ph
c: Ar = 4-Cl.Ph, Ar' = 4-Cl.Ph
Ar' = Ph
ii) CH N / Et N / -20 to -15 C / 40-48 h
2
2
3
iii) Ar'-CH=NNHPh / Chloramine-T.3H O / MeOH
2
iv) Ar'-CH=NOH / Chloramine-T.3H O / MeOH
2
v) Chloranil / Xylene.
Scheme 1 Synthesis of pyrazolyl-oxazolines/thiazolines and isoxazolyl-oxazolines/thiazolines
compared with the standard ascorbic acid. The activity of
4b may be due to the presence of more oxygen atoms. On
ester utilizing samarium chemistry and 1,3-diploar cyclo-
addition methodology. All the new compounds were tested
for their antioxidant activity. Amongst all the compounds,
14b exhibited promising antioxidant activity.
1
the other hand, the compounds 5a, 7a, 9a, and 4c–15c were
inactive. Apart from this, the results also indicated that
radical scavenging activity in all the three methods increases
with increase in concentration.
Experimental protocols
Conclusion
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, 1:3). The IR spectra were recorded on a
Thermo Nicolet IR 200 FT-IR spectrometer as KBr pellets
A new class of sulfonylmethane-linked pyrazolyl-oxazo-
lines/thiazolines and isoxazolyl-oxazolines/thiazolines
were synthesized by functionalization of ester and olefin
moieties in E-arylsulfonylethenesulfonylacetic acid methyl
-
1
1
and the wave numbers were given in cm . The H NMR
123

1
088
Med Chem Res (2014) 23:1084–1098
Table 1 The in vitro
antioxidant activity of 4–15 in
DPPH method
Compounds
Concentration
50 (lg/ml)
75 (lg/ml)
100 (lg/ml)
IC50 (lmol/ml)
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
a
20.37 ± 1.09
22.54 ± 1.62
23.82 ± 1.35
0.587 ± 1.52
b
32.22 ± 1.60
35.65 ± 1.52
37.82 ± 1.41
0.355 ± 1.31
c
–
–
–
–
a
–
–
–
–
b
26.71 ± 1.65
28.54 ± 1.54
30.43 ± 1.32
0.424 ± 1.12
c
–
–
–
–
a
21.16 ± 1.21
23.53 ± 1.32
25.16 ± 1.54
0.389 ± 1.28
b
35.26 ± 0.95
37.31 ± 0.54
39.28 ± 1.08
0.229 ± 0.85
c
–
–
–
–
a
–
–
–
–
b
27.16 ± 0.54
29.23 ± 0.82
32.54 ± 1.09
0.269 ± 0.98
c
–
–
–
–
a
23.27 ± 1.08
25.18 ± 1.26
26.07 ± 1.43
0.455 ± 1.23
0.254 ± 1.54
–
b
36.54 ± 1.32
38.27 ± 1.45
41.13 ± 1.62
c
–
–
–
a
–
–
–
–
b
30.23 ± 1.44
31.21 ± 1.32
33.02 ± 1.48
0.306 ± 1.58
–
c
–
–
–
0a
0b
0c
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
53.61 ± 1.28
67.10 ± 1.55
–
57.43 ± 1.03
71.54 ± 0.85
–
61.22 ± 0.87
74.62 ± 0.38
–
0.229 ± 1.15
0.181 ± 0.76
–
38.86 ± 1.52
61.65 ± 1.34
–
41.31 ± 1.10
65.21 ± 1.09
–
43.53 ± 1.09
69.13 ± 0.33
–
0.309 ± 0.93
0.187 ± 0.98
–
58.50 ± 1.26
69.31 ± 1.20
–
62.82 ± 1.13
73.42 ± 0.73
–
64.61 ± 1.42
78.68 ± 0.85
–
0.152 ± 0.86
0.115 ± 0.72
–
42.81 ± 1.43
63.62 ± 0.56
–
46.67 ± 1.30
66.51 ± 1.32
–
49.36 ± 1.22
70.32 ± 1.22
–
0.193 ± 1.30
0.125 ± 0.35
–
60.72 ± 0.75
78.83 ± 0.12
–
64.43 ± 0.45
82.26 ± 0.87
–
67.57 ± 0.64
84.21 ± 0.23
–
0.171 ± 0.56
0.124 ± 0.21
–
47.80 ± 1.23
65.48 ± 0.62
–
49.54 ± 1.12
68.73 ± 0.43
–
52.86 ± 0.53
71.86 ± 0.75
–
0.210 ± 1.23
0.141 ± 0.84
–
(–) Showed no scavenging
activity. Values are the mean of
three replicates ± SD
Ascorbic acid
Blank
79.54 ± 0.45
–
84.63 ± 0.57
–
87.43 ± 0.63
–
0.079 ± 0.11
spectra were recorded in CDCl on a Bruker spectrospin
3
General procedure for the synthesis of 2-(E-
1
operating at 400 MHz. The C NMR spectra were run in
3
arylsulfonylethenesulfonylmethyl)-4,5-dihydrooxazole
(2a–c)/2-(E-arylsulfonylethenesulfonylmethyl)-4,5-
dihydrothiazole (3a–c)
CDCl on Bruker spectrospin operating at 100 MHz. All
3
chemical shifts are reported in d (ppm) using TMS as an
internal standard. The microanalyses were performed on a
Perkin-Elmer 240C elemental analyzer. The starting com-
pound E-arylsulfonylethenesulfonylacetic acid methyl ester
To a flask charged with anhydrous samarium (III) chloride
(1 mmol), dry toluene (10 ml) and aminoalcohol/ami-
noethanethiol (2 mmol) were added followed by n-butyl-
lithium (2.2 mmol) at 0 °C and stirred for 20 min at the same
(1) was prepared as per the literature procedure (Padmav-
athi et al., 2010).
1
23

Med Chem Res (2014) 23:1084–1098
1089
Table 2 The in vitro antioxidant activity of 4–15 in nitric oxide
method
Table 3 The in vitro antioxidant activity of 4–15 in hydrogen per-
oxide method
Compounds
Concentration
0 (lg/ml)
Compounds
Concentration
5
75 (lg/ml)
100 (lg/ml)
50 (lg/ml)
75 (lg/ml)
100 (lg/ml)
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
a
20.72 ± 1.27
21.44 ± 1.47
22.63 ± 1.38
4a
22.37 ± 1.51
23.28 ± 1.35
25.08 ± 1.82
b
32.54 ± 1.32
34.62 ± 1.54
35.89 ± 1.62
4b
32.16 ± 1.41
34.26 ± 1.54
35.62 ± 1.39
c
–
–
–
4c
–
–
–
a
–
–
–
5a
–
–
–
b
26.12 ± 1.12
28.08 ± 1.28
30.32 ± 1.33
5b
29.07 ± 1.65
31.87 ± 1.58
33.62 ± 1.44
c
–
–
–
5c
–
–
–
a
22.72 ± 1.72
24.55 ± 1.65
25.72 ± 1.56
6a
24.61 ± 1.87
25.65 ± 1.79
27.38 ± 1.63
b
35.08 ± 1.18
37.63 ± 1.54
38.54 ± 1.27
6b
34.18 ± 1.08
36.23 ± 1.16
39.08 ± 1.72
c
–
–
–
6c
–
–
–
a
–
–
–
7a
–
–
–
b
28.72 ± 1.65
29.67 ± 1.54
31.54 ± 1.44
7b
31.21 ± 1.62
32.63 ± 1.44
34.56 ± 1.29
c
–
–
–
7c
–
–
a
24.63 ± 0.98
26.54 ± 1.12
28.27 ± 1.28
8a
26.09 ± 1.18
28.53 ± 1.27
29.63 ± 1.32
b
37.62 ± 1.26
39.54 ± 1.32
42.46 ± 1.43
8b
37.25 ± 1.23
38.94 ± 1.37
40.72 ± 1.44
c
–
–
–
8c
–
–
–
a
–
–
–
9a
–
–
–
b
30.12 ± 1.02
31.23 ± 1.24
33.31 ± 1.38
9b
33.07 ± 0.98
35.13 ± 1.02
37.18 ± 1.28
c
–
–
–
9c
–
–
–
0a
0b
0c
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
48.26 ± 0.79
64.27 ± 1.43
–
52.41 ± 0.92
67.38 ± 1.29
–
54.78 ± 0.57
69.89 ± 1.34
–
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
15a
15b
15c
Ascorbic acid
Blank
53.23 ± 1.59
68.02 ± 1.45
–
54.85 ± 1.43
70.34 ± 1.33
–
58.74 ± 1.27
73.76 ± 1.29
–
39.53 ± 1.48
57.53 ± 1.54
–
42.24 ± 1.37
60.28 ± 1.39
–
46.46 ± 1.12
64.37 ± 1.45
–
42.36 ± 1.12
48.65 ± 1.26
–
46.53 ± 0.98
50.43 ± 1.35
–
50.22 ± 1.32
53.37 ± 1.22
–
51.89 ± 0.65
67.78 ± 1.43
–
53.12 ± 0.59
72.64 ± 1.62
–
56.59 ± 0.48
76.30 ± 1.29
–
55.61 ± 1.58
70.86 ± 0.97
–
57.23 ± 1.49
73.38 ± 0.85
–
60.45 ± 1.37
76.03 ± 0.54
–
42.91 ± 1.56
60.83 ± 1.25
–
44.86 ± 1.48
63.62 ± 1.11
–
48.65 ± 1.39
65.15 ± 1.32
–
47.25 ± 1.62
53.33 ± 1.08
–
51.46 ± 1.34
56.16 ± 1.35
–
53.84 ± 1.11
58.29 ± 1.46
–
54.35 ± 1.64
71.42 ± 0.47
–
56.84 ± 1.25
78.52 ± 0.35
–
61.63 ± 1.42
81.34 ± 0.23
–
58.73 ± 1.23
73.47 ± 0.56
–
61.54 ± 1.54
75.62 ± 0.44
–
63.68 ± 1.36
81.13 ± 0.28
–
45.53 ± 0.98
62.26 ± 0.65
–
47.82 ± 0.87
65.86 ± 0.78
–
52.34 ± 1.08
68.42 ± 0.85
–
50.86 ± 1.42
57.79 ± 1.12
–
52.43 ± 1.38
60.08 ± 1.34
–
55.37 ± 1.23
62.44 ± 1.23
–
Ascorbic acid
Blank
80.12 ± 0.57
–
83.56 ± 0.45
–
85.83 ± 0.32
–
79.56 ± 0.36
–
82.26 ± 0.25
–
86.84 ± 0.13
–
(–) Showed no scavenging activity. Values are the mean of three
replicates ± SD
(–) Showed no scavenging activity. Values are the mean of three
replicates ± SD
temperature. The reaction mixture was heated to reflux at
The filtrate was extracted with chloroform and washed with
water. Removal of the solvent under vacuum gave a residue
which was purified by column chromatography (silica gel,
60–120 mesh) using ethyl acetate–hexane (1:3) as eluent.
1
00 °C. Then, compound 1 (1 mmol) was added to the
contents and refluxion was continued further for 8–10 h. The
suspension was cooled to ambient temperature and filtered.
123

1
090
Med Chem Res (2014) 23:1084–1098
2
-(Phenylsulfonylethenesulfonylmethyl)-4,5-
136.9 (SO CH), 58.0 (SO CH ), 51.7 (C-4), 36.9 (C-5),
2
2
2
dihydrooxazole 2a
131.9, 130.2, 129.7, 128.2 (aromatic carbons); MS (m/z):
?
ꢀ
31.43 [M ]. Anal. Calcd. for C H NO S : C, 43.49; H,
12 13 4 3
3
-
1
m. p. 125–126 °C, yield 71 %; IR (KBr) (cm ): 1628
3.95; N, 4.23 %; Found: C, 43.54; H, 3.91; N, 4.28 %.
1
C=C), 1581 (C=N), 1334, 1128 (SO2); H NMR
(
(
400 MHz, CDCl ): d 7.32–7.83 (m, 6H, HA & Ar–H),
2-(p-Methylphenylsulfonylethenesulfonylmethyl)-4,5-
3
7
.28 (d, J = 14.1 Hz, 1H, H ), 4.65 (t, 2H, C -H,
B
dihydrothiazole 3b
5
J = 5.5 Hz), 4.24 (s, 2H, SO CH ), 3.62 (t, 2H, C -H,
4
2
2
1
3
-1
m. p. 125 °C, yield 78 %; IR (KBr) (cm ): 1635 (C=C),
1583 (C=N), 1343, 1136 (SO2); H NMR (400 MHz,
J = 5.5 Hz); C NMR (100 MHz, CDCl ): d 161.8 (C-2),
3
1
1
43.9 (CHSO ), 137.4 (SO CH), 59.4 (C-5), 57.6
2
2
(
SO CH ), 51.4 (C-4), 131.5, 130.7, 129.4, 127.4 (aromatic
2
CDCl ): d 7.44–7.76 (m, 5H, HA & Ar–H), 7.35 (d,
2
3
?
carbons); MS (m/z): 315.37 [M ]. Anal. Calcd. for
ꢀ
J = 14.4 Hz, 1H, H ), 4.34 (s, 2H, SO CH ), 3.69 (t, 2H,
B
2
2
C H NO S : C, 45.70; H, 4.15; N, 4.44 %; Found: C,
2
C -H, J = 7.0 Hz), 3.33 (t, 2H, C -H, J = 7.0 Hz), 2.21 (s,
4 5
1
2
13
5
1
3
4
5.79; H, 4.19; N, 4.50 %.
3H, Ar–CH3); C NMR (100 MHz, CDCl ): d 159.3 (C-
3
2), 142.9 (CHSO ), 136.2 (SO CH), 59.9 (SO CH ), 52.5
2 2 2 2
2
-(p-Methylphenylsulfonylethenesulfonylmethyl)-4,5-
(C-4), 37.3 (C-5), 21.6 (Ar–CH ), 131.2, 130.6, 129.9,
3
?
128.6; (aromatic carbons); MS (m/z): 345.46 [M ]. Anal.
ꢀ
dihydrooxazole 2b
Calcd. for C H NO S : C, 45.2; H, 4.38; N, 4.05 %;
1
3
15
4 3
-
1
m. p. 152–154 °C, yield 66 %; IR (KBr) (cm ): 1642
Found: C, 45.14; H, 4.35; N, 4.08 %.
1
C=C), 1595 (C=N), 1336, 1138 (SO2); H NMR
(
(
400 MHz, CDCl ): d 7.36–7.74 (m, 5H, H & Ar–H), 7.32
2-(p-Chlorophenylsulfonylethenesulfonylmethyl)-4,5-
3
A
(
d, J = 14.3 Hz, 1H, H ), 4.71 (t, 2H, C -H, J = 5.7 Hz),
B
dihydrothiazole 3c
5
4
.28 (s, 2H, SO CH ), 3.71 (t, 2H, C -H, J = 5.7 Hz), 2.23
2 2 4
13
-1
m. p. 133–135 °C, yield 70 %; IR (KBr) (cm ): 1632
(C=C), 1588 (C=N), 1345, 1129 (SO2); H NMR
(
s, 3H, Ar–CH3); C NMR (100 MHz, CDCl ): d 160.1
3
1
(
C-2), 142.6 (CHSO ), 138.7 (SO CH), 60.2 (C-5), 58.2
2
2
(
SO CH ), 51.9 (C-4), 22.1 (Ar–CH ), 132.4, 130.2, 129.9,
3
(400 MHz, CDCl ): d 7.49–7.79 (m, 5H, H & Ar–H), 7.47
2
2
3
A
?
28.6 (aromatic carbons); MS (m/z): 329.39 [M ]. Anal.
ꢀ
1
(d, J = 14.2 Hz, 1H, H ), 4.32 (s, 2H, SO CH ), 3.73 (t,
B 2 2
1
3
Calcd. for C H NO S : C, 47.40; H, 4.59; N, 4.25 %;
2
2H, C -H, J = 7.5 Hz), 3.39 (t, 2H, C -H, J = 7.5 Hz); C
4 5
1
3
15
5
Found: C, 47.32; H, 4.64; N, 4.29 %.
NMR (100 MHz, CDCl ): d 158.7 (C-2), 143.2 (CHSO ),
3
2
137.7 (SO CH), 59.2 (SO CH ), 51.9 (C-4), 36.8 (C-5),
2 2 2
2
-(p-Chlorophenylsulfonylethenesulfonylmethyl)-4,5-
131.6, 130.4, 129.7, 128.1; (aromatic carbons); MS (m/z):
?
365.88 [M ]. Anal. Calcd. for C H ClNO S : C, 39.39;
ꢀ
dihydrooxazole 2c
1
2
12
4 3
H, 3.31; N, 3.83 %; Found: C, 39.43; H, 3.28; N, 3.87 %.
-
1
m. p. 166–168 °C, yield 69 %; IR (KBr) (cm ): 1637
1
C=C), 1587 (C=N), 1332, 1134 (SO2); H NMR
0 0
General procedure for the synthesis of 2-(4 ,5 -dihydro-
(
0 0 0
0 0 0
dihydrooxazole (4a–c)/2-(4 ,5 -dihydro-3 -arylsulfonyl-
(
400 MHz, CDCl ): d 7.45–7.79 (m, 5H, H & Ar–H), 7.41
3 -arylsulfonyl-1 H-pyrazol-4 -ylsulfonylmethyl)-4,5-
3
A
(
d, J = 14.6 Hz, 1H, H ), 4.62 (t, 2H, C -H, J = 5.2 Hz),
B
5
1
3
0
0
4
.31 (s, 2H, SO CH ), 3.65 (t, 2H, C -H, J = 5.2 Hz);
2
C
1 H-pyrazol-4 -ylsulfonylmethyl)-4,5-dihydrothiazole
(5a–c)
2
4
NMR (100 MHz, CDCl ): d 159.6 (C-2), 143.1 (CHSO ),
3
2
1
1
3
38.1 (SO CH), 59.7 (C-5), 58.9 (SO CH ), 52.2 (C-4),
2 2 2
32.6, 131.8, 130.4, 129.2 (aromatic carbons); MS (m/z):
To a well-cooled solution of 2/3 (2.5 mmol) in dichloro-
methane (20 ml), an ethereal solution of diazomethane
(40 ml, 0.4 M) and triethylamine (0.1 ml) were added. The
reaction mixture was kept at -20 to -15 °C for 40–48 h.
Evaporation of the solvent in vacuo yielded a solid which
was purified by column chromatography (silica gel,
?
49.81 [M ]. Anal. Calcd. for C H ClNO S : C, 41.20;
ꢀ
1
2
12
5 2
H, 3.46; N, 4.00 %; Found: C 41.26, H 3.49, N 4.06 %.
2
-(Phenylsulfonylethenesulfonylmethyl)-4,5-
dihydrothiazole 3a
60–120 mesh) using ethyl acetate–hexane (1:2.5) as eluent.
-
1
m. p. 114–116 °C, yield 76 %; IR (KBr) (cm ): 1640
1
C=C), 1594 (C=N), 1339, 1130 (SO ),; H (400 MHz,
0
0
0
0
0
(
2-(4 ,5 -Dihydro-3 -phenylsulfonyl-1 H-pyrazol-4 -
2
CDCl ): d 7.39–7.73 (m, 6H, HA & Ar–H), 7.37 (d,
ylsulfonylmethyl)-4,5-dihydrooxazole 4a
3
J = 14.3 Hz, 1H, H ), 4.27 (s, 2H, SO CH ), 3.76 (t, 2H,
B
2
2
1
3
-1
m. p. 174–176 °C, yield 82 %; IR (KBr) (cm ): 3338
C -H, J = 7.3 Hz), 3.37 (t, 2H, C -H, J = 7.3 Hz);
4
C
5
1
(NH), 1585 (C=N), 1336, 1131 (SO ); H NMR (400 MHz,
NMR (100 MHz, CDCl ): d 157.7 (C-2), 143.6 (CHSO ),
3
2
2
1
23

Med Chem Res (2014) 23:1084–1098
1091
CDCl ): d 7.38–7.52 (m, 5H, Ar–H), 8.89 (brs, 1H, NH),
4.59 (dd, 1H, H , J = 12.0 Hz, JAX = 6.0 Hz), 4.23
AM
3
A
4
.77 (t, 2H, C -H, J = 5.8 Hz), 4.63 (dd, 1H, H ,
5
(dd, 1H, H , J
M
= 12.0 Hz, JMX = 10.8 Hz), 4.12 (s,
AM
A
JAM = 12.4 Hz, JAX = 6.3 Hz), 4.36 (dd, 1H, HM,
JAM = 12.4 Hz, JMX = 11.5 Hz), 4.13 (s, 2H, SO CH ),
2H, SO CH ), 3.83 (dd, 1H, H , JAX = 6.0 Hz,
2 2 X
JMX = 10.8 Hz), 3.72 (t, 2H, C -H, J = 7.5 Hz), 3.43 (t,
4
2
2
1
3
3
2
1
.95 (dd, 1H, H , J = 6.3 Hz, J
X
= 11.5 Hz), 3.82 (t,
2H, C -H, J = 7.5 Hz); C NMR (100 MHz, CDCl ): d
AX
MX
5
3
1
3
0 0
161.4 (C-2), 149.5 (C-3 ), 59.6 (C-5 ), 54.1 (SO CH ), 49.4
2 2
H, C -H, J = 5.8 Hz); C NMR (100 MHz, CDCl ): d
4
3
0
0
0
63.7 (C-2), 152.3 (C-3 ), 60.4 (C-5 ), 56.2 (C-5), 54.7
0
(C-4 ), 52.7 (C-4), 36.7 (C-5), 135.3, 134.8, 128.8, 127.6;
?ꢀ
(
SO CH ), 53.3 (C-4), 51.6 (C-4 ), 135.4, 132.6, 129.7,
2
?
28.5; (aromatic carbons); MS (m/z): 357.41 [M ]. Anal.
(aromatic carbons); MS (m/z): 373.47 [M ]. Anal. Calcd.
2
ꢀ
1
for C H N O S : C, 41.81; H, 4.05; N, 11.25 %; Found:
3 15 3 4 3
1
Calcd. for C H N O S : C, 43.69; H, 4.23; N, 11.76 %;
13 15 3 5 2
C, 41.87; H, 4.07; N, 11.21 %.
Found: C, 43.74; H, 4.25; N, 11.84 %.
0
0
0
0
2
-(4 ,5 -Dihydro-3 -(p-methylphenyl)sulfonyl-1 H-pyrazol-
0
0
0
0
0
2
4
-(4 ,5 -Dihydro-3 -(p-methylphenyl)sulfonyl-1 H-pyrazol-
0
4 -ylsulfonylmethyl)-4,5-dihydrothiazole 5b
-ylsulfonylmethyl)-4,5-dihydrooxazole 4b
-
1
m. p. 173–175 °C, yield 75 %; IR (KBr) (cm ): 3331 (NH),
1587 (C=N), 1330, 1128 (SO2); H NMR (400 MHz,
-
1
1
m. p. 158–160 °C, yield 80 %; IR (KBr) (cm ): 3348
1
NH), 1570 (C=N), 1323, 1125 (SO ); H NMR (400 MHz,
(
CDCl ): d 8.78 (brs, 1H, NH), 7.13-7.37 (m, 4H, Ar–H), 4.54
2
3
CDCl ): d 8.83 (brs, 1H, NH), 7.32–7.48 (m, 4H, Ar–H),
(dd, 1H, H , J
A
= 11.8 Hz, JAX = 5.6 Hz), 4.20 (dd,1H,
AM
3
4
.73 (t, 2H, C -H, J = 5.5 Hz), 4.58 (dd, 1H, H ,
5
H , J
M
= 11.8 Hz, JMX = 10.5 Hz), 4.08 (s, 2H,
AM
A
JAM = 12.2 Hz, JAX = 6.0 Hz), 4.28 (dd, 1H, HM,
JAM = 12.2 Hz, JMX = 10.8 Hz), 4.11 (s, 2H, SO CH ),
SO CH ),
2
3.79
(dd,
1H,
H ,
X
JAX = 5.6 Hz,
2
JMX = 10.5 Hz), 3.66 (t, 2H, C -H, J = 7.2 Hz), 3.40 (t, 2H,
4
2
2
1
3
3
.91 (dd, 1H, H , J = 6.0 Hz, JMX = 10.8 Hz), 3.76 (t,
AX
C -H, J = 7.2 Hz), 2.36 (s, 3H, Ar–CH ),; C NMR
5 3
X
1
3
H, C -H, J = 5.5 Hz), 2.38 (s, 3H, Ar–CH ); C NMR
0
0
2
(100 MHz, CDCl ): d 161.0 (C-2), 149.6 (C-3 ), 59.1 (C-5 ),
53.7 (SO CH ), 52.4 (C-4), 48.9 (C-4 ), 35.5 (C-5), 22.9 (Ar–
2
4
3
3
0
0
(
100 MHz, CDCl ): d 162.7 (C-2), 151.6 (C-3 ), 59.8 (C-
3
2
0
0
5
), 55.8 (C-5), 54.3 (SO CH ), 52.6 (C-4), 51.9 (C-4 ),
2
CH ), 135.7, 132.8, 129.6, 128.5 (aromatic carbons); MS (m/
3
ꢀ
z): 387.50 [M ]. Anal. Calcd. for C H N O S : C, 43.39;
14 17 3 4 3
2
?
2
3.1 (Ar–CH ), 134.9, 131.8, 129.6, 128.2; (aromatic car-
3
?
bons); MS (m/z): 371.43 [M ]. Anal. Calcd. for
ꢀ
H, 4.42; N, 10.84 %; Found: C, 43.46; H, 4.44; N, 10.93 %.
C H N O S : C, 45.27; H, 4.61; N, 11.31 %; Found: C,
14 17 3 5 2
0
0
0
0
4
5.35; H, 4.60; N, 11.41 %.
2-(4 ,5 -Dihydro-3 -(p-chlorophenyl)sulfonyl-1 H-pyrazol-
0
4
-ylsulfonylmethyl)-4,5-dihydrothiazole 5c
0
0
0
0
2
4
-(4 ,5 -Dihydro-3 -(p-chlorophenyl)sulfonyl-1 H-pyrazol-
0
-1
m. p. 192–194 °C, yield 77 %; IR (KBr) (cm ): 3343
-ylsulfonylmethyl)-4,5-dihydrooxazole 4c
1
NH), 1572 (C=N), 1343, 1142 (SO ); H NMR (400 MHz,
(
2
-
1
m. p. 185–187 °C, yield 78 %; IR (KBr) (cm ): 3341
CDCl ): d 8.83 (brs, 1H, NH), 7.26–7.48 (m, 4H, Ar–H),
4.61 (dd, 1H, H , J
A
3
1
NH), 1573 (C=N), 1342, 1142 (SO ); H NMR (400 MHz,
(
= 12.2 Hz, JAX = 6.1 Hz), 4.25
AM
2
CDCl ): d 8.92 (brs, 1H, NH), 7.41–7.65 (m, 4H, Ar–H),
(dd, 1H, H , J
M
= 12.2 Hz, JMX = 11.0 Hz), 4.16 (s,
AM
3
4
.79 (t, 2H, C -H, J = 5.9 Hz), 4.65 (dd, 1H, H ,
5
2H, SO CH ), 3.84 (dd, 1H, H , JAX = 6.1 Hz,
2 2 X
A
JAM = 12.6 Hz, JAX = 6.5 Hz), 4.39 (dd, 1H, HM,
JAM = 12.6 Hz, JMX = 11.8 Hz), 4.17 (s, 2H, SO CH ),
JMX = 11.0 Hz), 3.77 (t, 2H, C -H, J = 7.7 Hz), 3.47 (t,
4
1
3
2H, C -H, J = 7.7 Hz); C NMR (100 MHz, CDCl ): d
2
2
5
3
0 0
161.5 (C-2), 150.4 (C-3 ), 60.2 (C-5 ), 54.5 (SO CH ), 53.2
2 2
3
2
1
.97 (dd, 1H, H , J = 6.5 Hz, J
X
= 11.8 Hz), 3.85 (t,
AX
MX
1
3
0
H, C -H, J = 5.9 Hz); C NMR (100 MHz, CDCl ): d
(C-4), 49.7 (C-4 ), 37.1 (C-5), 136.9, 134.6, 131.6, 129.2
?ꢀ
4
3
0
0
64.4 (C-2), 153.2 (C-3 ), 60.9 (C-5 ), 56.5 (C-5), 55.2
0
(aromatic carbons); MS (m/z): 407.92 [M ]. Anal. Calcd.
(
SO CH ), 53.9 (C-4), 52.1 (C-4 ), 135.9, 132.5, 128.9,
2
?
27.6; (aromatic carbons); MS (m/z): 391.85 [M ]. Anal.
for C H ClN O S : C, 38.28; H, 3.46; N, 10.30 %;
13 14 3 4 3
2
ꢀ
1
Found: C, 38.24; H, 3.50; N, 10.37 %.
Calcd. for C H ClN O S : C, 39.85; H, 3.60; N,
3 5 2
1
3
14
0
0
1
0.72 %; Found: C, 39.80; H, 3.63; N, 10.79 %.
General procedure for the synthesis of 2-(4 ,5 -dihydro-
0
0
0
0
1
-phenyl-3 -aryl-4 -arylsulfonylpyrazol-5 -
0 0 0 0 0
-(4 ,5 -Dihydro-3 -phenylsulfonyl-1 H-pyrazol-4 -
0
0
0
2
ylsulfonylmethyl)-4,5-dihydrooxazole (6a–c)/2-(4 ,5 -
0
0
0
ylsulfonylmethyl)-4,5-dihydrothiazole 5a
dihydro-1 -phenyl-3 -aryl-4 -arylsulfonylpyrazol-5 -
ylsulfonylmethyl)-4,5-dihydrothiazole (7a–c)
-
1
m. p. 178–180 °C, yield 73 %; IR (KBr) (cm ): 3335
1
NH), 1594 (C=N), 1322, 1134 (SO ); H NMR (400 MHz,
(
The compound 2/3 (1 mmol), araldehyde phenylhydrazone
(1.2 mmol), chloramine-T (1.2 mmol) and methanol
2
CDCl ): d 7.18–7.37 (m, 5H, Ar–H), 8.75 (brs, 1H, NH),
3
123

1
092
Med Chem Res (2014) 23:1084–1098
0
0
0
(
20 ml) were refluxed for 18–20 h using a water bath. The
2), 158.1 (C-3 ), 88.9 (C-5 ), 65.8 (C-4 ), 60.1 (C-5), 58.7
(SO CH ), 52.3 (C-4), 134.3, 133.7, 132.8, 131.6, 130.7,
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
2
130.1, 129.8, 128.3, 127.6, 125.8, 124.2, 123.5 (aromatic
?
carbons); MS (m/z): 578.49 [M ]. Anal. Calcd. for
ꢀ
C H Cl N O S : C, 51.91; H, 3.66; N, 7.26 %; Found: C,
25 21 2 3 5 2
2
4
removed under reduced pressure and the resultant solid was
purified by column chromatography (silica gel, 60–120
mesh) using ethyl acetate–hexane (1:2.5) as eluent.
51.96; H, 3.65; N, 7.34 %.
0
0
0
0
0
2-(4 ,5 -Dihydro-1 ,3 -diphenyl-4 -(phenylsulfonyl)pyrazol-
0
5
-ylsulfonylmethyl)-4,5-dihydrothiazole 7a
0
0
0
0
0
2
5
-(4 ,5 -Dihydro-1 ,3 -diphenyl-4 -(phenylsulfonyl)pyrazol-
0
-1
m. p. 195–197 °C, yield 71 %; IR (KBr) (cm ): 1595
-ylsulfonylmethyl)-4,5-dihydrooxazole 6a
1
(
C=N), 1333, 1124 (SO ); H NMR (400 MHz, CDCl ): d
2
3
-
1
m. p. 186–188 °C, IR yield 74 %; (KBr) (cm ): 1582
7.28–7.74 (15H, Ar & Ar’–H), 5.63 (d, 1H, C5
J = 8.1 Hz), 5.26 (d, 1H, C4 -H, J = 8.1 Hz), 4.31 (s, 2H,
SO CH ), 3.72 (t, 2H, C -H, J = 7.3 Hz), 3.35 (t, 2H, C -
0
-H,
1
(
C=N), 1330, 1128 (SO ); H NMR (400 MHz, CDCl ): d
0
2
3
7
.39–7.92 (15H, Ar & Ar’–H), 5.65 (d, 1H, C5
-H, J = 7.9 Hz), 4.71 (t, 2H,
C -H, J = 5.4 Hz), 4.27 (s, 2H, SO CH ), 3.63 (t, 2H, C -
0
-H,
2
2
4
5
1
3
J = 7.9 Hz), 5.28 (d, 1H, C4
0
H, J = 7.3 Hz); C NMR (100 MHz, CDCl ): d 159.8 (C-
3
0
0
0
2), 155.4 (C-3 ), 87.9 (C-5 ), 63.8 (C-4 ), 58.9 (SO CH ),
2
5
2
2
4
2
1
3
H, J = 5.4 Hz); C NMR (100 MHz, CDCl ): d 163.9 (C-
), 157.8 (C-3 ), 88.5 (C-5 ), 65.3 (C-4 ), 59.8 (C-5), 57.9
51.6 (C-4), 38.2 (C-5), 135.8, 133.4, 132.9, 132.0, 131.8,
130.1, 129.8, 129.2, 128.3, 127.9, 126.3, 125.8 (aromatic
?
carbons); MS (m/z): 525.66 [M ]. Anal. Calcd. for
3
0
0
0
2
ꢀ
(
SO CH ), 51.8 (C-4), 135.8, 135.2, 134.8, 133.5, 132.3,
2
2
1
31.8, 131.3, 129.5, 128.8, 128.1, 127.4, 126.2 (aromatic
C H N O S : C, 57.12; H, 4.41; N, 7.99 %; Found: C,
25 23 3 4 3
?
carbons); MS (m/z): 509.60 [M ]. Anal. Calcd. for
ꢀ
57.19; H, 4.43; N, 7.95 %.
C H N O S : C, 58.92; H, 4.55; N, 8.25 %; Found: C,
25 23 3 5 2
0
0
0
0
0
5
9.00; H, 4.52; N, 8.20 %.
2-(4 ,5 -Dihydro-1 -phenyl-3 -(p-methoxyphenyl)-4 -(p-
0
methylphenylsulfonyl)pyrazol-5 -ylsulfonylmethyl)-4,5-
0
0
0
0
0
2
-(4 ,5 -Dihydro-1 -phenyl-3 -(p-methoxyphenyl)-4 -(p-
0
dihydrothiazole 7b
methylphenylsulfonyl)pyrazol-5 -ylsulfonylmethyl)-4,5-
-
1
dihydrooxazole 6b
m. p. 192–194 °C, yield 72 %; IR (KBr) (cm ): 1586
1
(
C=N), 1334, 1126 (SO ); H NMR (400 MHz, CDCl ): d
2
3
-
1
m. p. 177–179 °C, yield 76 %; IR (KBr) (cm ): 1579
7.31–7.83 (13H, Ar & Ar’–H), 5.58 (d, 1H, C5
J = 7.4 Hz), 5.23 (d, 1H, C4 -H, J = 7.4 Hz), 4.28 (s, 2H,
SO CH ), 3.87 (s, 3H, Ar–OCH ), 3.69 (t, 2H, C -H,
0
-H,
1
(
C=N), 1332, 1120 (SO ); H NMR (400 MHz, CDCl ): d
0
2
3
7
.24–7.87 (13H, Ar & Ar’–H), 5.68 (d, 1H, C5
-H, J = 7.6 Hz), 4.71 (t, 2H,
C -H, J = 5.6 Hz), 4.25 (s, 2H, SO CH ), 3.84 (s, 3H,Ar–
0
-H,
2
2
3
4
J = 7.6 Hz), 5.23 (d, 1H, C4
0
J = 7.0 Hz), 3.32 (t, 2H, C -H, J = 7.0 Hz), 2.31 (s, 3H,
5
1
3
Ar–CH3); C NMR (100 MHz, CDCl ): d 159.3 (C-2),
0 0 0
154.8 (C-3 ), 86.8 (C-5 ), 63.5 (C-4 ), 58.2 (SO CH ), 56.1
2 2
5
2
2
3
OCH ), 3.65 (t, 2H, C -H, J = 5.6 Hz), 2.28 (s, 3H, Ar–
3
4
1
3
CH3); C NMR (100 MHz, CDCl ): d 163.4 (C-2), 157.6
(Ar–OCH ), 51.2 (C-4), 37.8 (C-5), 22.5 (Ar–CH ), 135.7,
3 3
3
0
0
0
(
C-3 ), 88.4 (C-5 ), 65.0 (C-4 ), 59.5 (C-5), 58.3 (SO CH ),
2
134.3, 133.8, 132.6, 131.2, 130.3, 129.4, 128.5, 127.8,
2
5
1
1
5.8 (Ar–OCH ), 52.1 (C-4), 22.3 (Ar–CH ), 135.6, 134.2,
3
126.4, 125.2, 124.5 (aromatic carbons); MS (m/z): 569.72
3
?
ꢀ
[M ]. Anal. Calcd. for C H N O S : C, 56.92; H, 4.78;
27 27 3 5 3
33.4, 132.6, 131.7, 129.7, 128.9, 128.2, 127.3, 126.3,
?
25.7, 125.5 (aromatic carbons); MS (m/z): 553.65 [M ].
ꢀ
N, 7.38 %; Found: C, 56.97; H, 4.81; N, 7.44 %.
Anal. Calcd. for C H N O S : C, 58.57; H, 4.92; N,
27 27 3 6 2
0
0
0
0
0
7
.59 %; Found: C, 58.50; H, 4.95; N, 7.65 %.
2-(4 ,5 -Dihydro-1 -phenyl-3 -(p-chlorophenyl)-4 -(p-
0
chlorophenylsulfonyl)pyrazol-5 -ylsulfonylmethyl)-4,5-
0
0
0
0
0
2
-(4 ,5 -Dihydro-1 -phenyl-3 -(p-chlorophenyl)-4 -(p-
0
dihydrothiazole 7c
chlorophenylsulfonyl)pyrazol-5 -ylsulfonylmethyl)-4,5-
-
1
dihydrooxazole 6c
m. p. 205–207 °C, yield 75 %; IR (KBr) (cm ): 1597
1
(
C=N), 1331, 1135 (SO ); H NMR (400 MHz, CDCl ): d
2
3
-
1
m. p. 190–191 °C, yield 78 %; IR (KBr) (cm ): 1587
7.35–7.81 (13H, Ar & Ar’–H), 5.68 (d, 1H, C5
J = 8.3 Hz), 5.29 (d, 1H, C4 -H, J = 8.3 Hz), 4.35 (s, 2H,
SO CH ), 3.74 (t, 2H, C -H, J = 7.5 Hz), 3.38 (t, 2H, C -
0
-H,
1
(
C=N), 1338, 1133 (SO ); H NMR (400 MHz, CDCl ): d
0
2
3
7
.40–7.95 (13H, Ar & Ar’–H), 5.69 (d, 1H, C5
-H, J = 8.0 Hz), 4.72 (t, 2H,
C -H, J = 5.8 Hz), 4.31 (s, 2H, SO CH ), 3.68 (t, 2H, C -
0
-H,
2
2
4
5
1
3
J = 8.0 Hz), 5.30 (d, 1H, C4
0
H, J = 7.5 Hz); C NMR (100 MHz, CDCl ): d 160.1 (C-
2), 155.9 (C-3 ), 88.3 (C-5 ), 63.9 (C-4 ), 59.2 (SO CH ),
2
3
0
0
0
5
2
2
4
2
1
3
H, J = 5.8 Hz); C NMR (100 MHz, CDCl ): d 164.2 (C-
51.9 (C-4), 38.7 (C-5), 135.9, 135.1, 134.9, 133.7, 132.5,
3
1
23

Med Chem Res (2014) 23:1084–1098
1093
1
31.6, 130.2, 129.5, 128.3, 127.6, 126.4, 125.7 (aromatic
C H N O S : C, 52.71; H, 4.63; N, 5.85 %;Found: C,
21 22 2 7 2
?
carbons); MS (m/z): 594.55 [M ]. Anal. Calcd. for
ꢀ
52.78; H, 4.66; N, 5.91 %.
C H Cl N O S : C, 50.50; H, 3.56; N, 7.07 %; Found: C,
2 3 4 3
2
5
21
0
0
0
0
5
0.58; H, 3.55; N, 7.15 %.
2-(4 ,5 -Dihydro-3 -(p-chlorophenyl)-4 -(p-
0
chlorophenylsulfonyl)isoxazol-5 -ylsulfonyl-methyl)-4,5-
0
0
General procedure for the synthesis of 2-(4 ,5 -dihydro-
dihydrooxazole 8c
0
0
0
3
4
-aryl-4 -arylsulfonylisoxazol-5 -ylsulfonylmethyl)-
0
0
0
0
-1
m. p. 185–187 °C, yield 76 %; IR (KBr) (cm ): 1578
(C=N), 1347, 1140 (SO ); H NMR (400 MHz, CDCl ): d
,5-dihydrooxazole (8a–c)/2-(4 ,5 -dihydro-3 -aryl-4 -
0
1
arylsulfonylisoxazol-5 -ylsulfonylmethyl)-4,5-
2
3
dihydrothiazole (9a–c)
7.23–7.82 (8H, Ar & Ar’–H), 5.74 (d, 1H, C5
J = 8.1 Hz), 5.31 (d, 1H, C4 -H, J = 8.1 Hz), 4.67 (t, 2H,
C -H, J = 5.7 Hz), 4.34 (s, 2H, SO CH ), 3.71 (t, 2H, C -
0
-H,
0
A mixture of 2/3 (1 mmol), araldoxime (1.2 mmol), chlo-
ramine-T (1.2 mmol) and methanol (20 ml) was refluxed
for 15–17 h on a water bath. 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 ). Evaporation of the solvent under vacuum affor-
5
2
2
4
1
3
H, J = 5.7 Hz); C NMR (100 MHz, CDCl ): d 164.5 (C-
2), 155.8 (C-3 ), 86.2 (C-5 ), 66.4 (C-4 ), 60.7 (C-5), 59.8
3
0
0
0
(SO CH ), 54.1 (C-4), 135.5, 134.9, 134.3, 133.4, 132.3,
2
2
130.5, 128.9, 128.0 (aromatic carbons); MS (m/z): 503.38
?
[M ]. Anal. Calcd. for C H Cl N O S : C, 45.33; H,
ꢀ
1
9
16
2 2 6 2
3.20; N, 5.57 %; Found: C, 45.29; H, 3.18; N, 5.52 %.
2
4
ded a solid which was purified by passing through a col-
umn of silica gel (60–120 mesh) using ethyl acetate–
hexane (1:3) as eluent.
0
0
0
0
0
2-(4 ,5 -Dihydro-3 -phenyl-4 -phenylsulfonylisoxazol-5 -
ylsulfonylmethyl)-4,5-dihydro-thiazole 9a
0
0
0
0
0
-1
m. p. 177–179 °C, yield 78 %; IR (KBr) (cm ): 1580
2
-(4 ,5 -Dihydro-3 -phenyl-4 -phenylsulfonylisoxazol-5 -
1
ylsulfonylmethyl)-4,5-dihydrooxazole 8a
(C=N), 1331, 1130 (SO ); H NMR (400 MHz, CDCl ): d
2
3
7
.18–7.69 (10H, Ar & Ar’–H), 5.71 (d, 1H, C5
J = 8.2 Hz), 5.22 (d, 1H, C4 -H, J = 8.2 Hz), 4.32 (s,
2H, SO CH ), 3.73 (t, 2H, C -H, J = 7.4 Hz), 3.36 (t,
0
-H,
-
1
m. p. 172–174 °C, yield 77 %; IR (KBr) (cm ): 1573
0
1
(
C=N), 1338, 1148 (SO ); H NMR (400 MHz, CDCl ): d
2
3
2
2
4
1
3
7
.18–7.69 (10H, Ar & Ar’–H), 5.68 (d, 1H, C5
-H, J = 8.0 Hz), 4.63 (t, 2H,
C -H, J = 5.3 Hz), 4.25 (s, 2H, SO CH ), 3.65 (t, 2H, C -
0
-H,
2H, C -H, J = 7.4 Hz); C NMR (100 MHz, CDCl ): d
163.8 (C-2), 155.3 (C-3 ), 84.8 (C-5 ), 65.2 (C-4 ), 59.1
5
3
0
0
0
J = 8.0 Hz), 5.25 (d, 1H, C4
0
(SO CH ), 52.9 (C-4), 38.4 (C-5), 135.8, 135.3, 134.1,
2
5
2
2
4
2
1
3
H, J = 5.3 Hz); C NMR (100 MHz, CDCl ): d 163.9 (C-
), 155.2 (C-3 ), 85.8 (C-5 ), 66.3 (C-4 ), 60.5 (C-5), 59.3
133.5, 132.8, 131.6 130.8, 128.4 (aromatic carbons); MS
?ꢀ
3
0
0
0
2
(m/z): 450.55 [M ]. Anal. Calcd. for C H N O S : C,
19 18 2 5 3
(
SO CH ), 53.8 (C-4), 134.5, 133.7, 132.6, 131.4, 130.3,
2
50.65; H, 4.03; N, 6.22 %; Found: C, 50.71; H, 4.04; N
6.18 %.
2
1
29.8, 129.2, 127.1 (aromatic carbons); MS (m/z): 434.49
?
ꢀ
M ]. Anal. Calcd. for C H N O S : C, 52.52; H, 4.18;
19 18 2 6 2
[
0
0
0
0
N, 6.45 %; Found: C, 52.46; H, 4.20; N, 6.53 %.
2-(4 ,5 -Dihydro-3 -(p-methoxyphenyl)-4 -(p-
0
methylphenylsulfonyl)isoxazol-5 -yl-sulfonylmethyl)-4,5-
0
0
0
0
2
-(4 ,5 -Dihydro-3 -(p-methoxyphenyl)-4 -(p-
0
dihydrothiazole 9b
methylphenylsulfonyl)isoxazol-5 -ylsulfonylmethyl)-4,5-
-
1
dihydrooxazole 8b
m. p. 181–183 °C, yield 71 %; IR (KBr) (cm ): 1576
1
(
C=N), 1334, 1136 (SO ); H NMR (400 MHz, CDCl ): d
2
3
-
1
m. p. 165–167 °C, yield 74 %; IR (KBr) (cm ): 1571
7.14–7.59 (8H, Ar & Ar’–H), 5.64 (d, 1H, C5
J = 7.9 Hz), 5.21 (d, 1H, C4 -H, J = 7.9 Hz), 4.28 (s, 2H,
SO CH ), 3.89 (s, 3H, Ar–OCH ), 3.65 (t, 2H, C -H,
0
-H,
1
(
C=N), 1342, 1132 (SO ); H NMR (400 MHz, CDCl ): d
0
2
3
7
.21–7.65 (8H, Ar & Ar’–H), 5.67 (d, 1H, C5
-H, J = 7.7 Hz), 4.64 (t, 2H,
C -H, J = 5.5 Hz), 4.26 (s, 2H, SO CH ), 3.82 (s, 3H, Ar-
0
-H,
2
2
3
4
J = 7.7 Hz), 5.18 (d, 1H, C4
0
J = 7.2 Hz), 3.34 (t, 2H, C -H, J = 7.2 Hz), 2.32 (s, 3H,
5
1
3
Ar–CH3); C NMR (100 MHz, CDCl ): d 163.6 (C-2),
0 0 0
154.8 (C-3 ), 84.7 (C-5 ), 65.1 (C-4 ), 58.6 (SO CH ), 56.5
2 2
5
2
2
3
OCH ), 3.68 (t, 2H, C -H, J = 5.5 Hz), 2.25 (s, 3H, Ar–
3
4
1
3
CH3); C NMR (100 MHz, CDCl ): d 22.9 (Ar–CH ),
(Ar–OCH ), 52.6 (C-4), 38.2 (C-5), 22.7 (Ar–CH ), 135.2,
3 3
3
3
5
1
1
2.7 (C-4), 57.2 (Ar–OCH ), 58.9 (SO CH ), 162.7 (C-2),
2
134.2, 133.6, 131.3, 130.7, 129.8, 129.2, 128.5 (aromatic
?ꢀ
3
2
0
0
0
54.8 (C-3 ), 85.5 (C-5 ), 65.9 (C-4 ), 60.1 (C-5), 135.1,
34.2, 132.0, 131.6, 130.8, 129.7, 129.1, 128.3 (aromatic
carbons); MS (m/z): 494.60 [M ]. Anal. Calcd. for
C H N O S : C, 51.00; H, 4.48; N, 5.66 %; Found: C,
21 22 2 6 3
?
ꢀ
carbons); MS (m/z): 478.54 [M ]. Anal. Calcd. for
51.08; H, 4.50; N, 5.73 %.
123

1
094
Med Chem Res (2014) 23:1084–1098
0
0
0
0
0
0
0
2
-(4 ,5 -Dihydro-3 -(p-chlorophenyl)-4 -(p-
0
2-(3 -(p-Methylphenyl)sulfonyl-1 H-pyrazol-4 -
chlorophenylsulfonyl)isoxazol-5 -ylsulfonyl-methyl)-4,5-
ylsulfonylmethyl)-4,5-dihydrooxazole 10b
dihydrothiazole 9c
-
1
m. p. 180–182 °C, yield 79 %; IR (KBr) (cm ): 1578
-
1
1
(C=N), 1338, 1127 (SO ), 3329 (NH); H NMR (400 MHz,
m. p. 196–198 °C, yield 80 %; IR (KBr) (cm ): 1585
2
1
(
C=N), 1342, 1129 (SO ); H NMR (400 MHz, CDCl ): d
CDCl ): d 8.87 (brs, 1H, NH), 7.19–7.92 (m, 5H, C -H &
0
5
2
3
3
7
.21–7.73 (8H, Ar & Ar’–H), 5.72 (d, 1H, C5
-H, J = 8.3 Hz), 4.33 (s,
H, SO CH ), 3.76 (t, 2H, C -H, J = 7.6 Hz), 3.39 (t,
0
-H,
Ar–H), 4.78 (t, 2H, C -H, J = 5.4 Hz), 4.05 (s, 2H,
5
J = 8.3 Hz), 5.26 (d, 1H, C4
0
SO CH ), 3.73 (t, 2H, C -H, J = 5.4 Hz), 2.36 (s, 3H, Ar-
4
2
2
1
3
2
2
1
CH3); C NMR (100 MHz, CDCl ): d 159.9 (C-2), 139.5
2
2
4
3
1
3
0 0 0
(C-5 ), 151.1 (C-3 ), 135.8 (C-4 ), 56.1 (SO CH ), 54.7 (C-
2 2
H, C -H, J = 7.6 Hz); C NMR (100 MHz, CDCl ): d
64.1 (C-2), 155.8 (C-3 ), 65.7 (C-4 ), 85.1 (C-5 ), 59.4
5
3
0
0
0
5), 53.0 (C-4), 23.8 (Ar-CH ), 133.5, 131.2, 129.7, 128.6
3
?
(aromatic carbons); MS (m/z): 369.42 [M ]. Anal. Calcd.
ꢀ
(
SO CH ), 53.3 (C-4), 38.8 (C-5), 135.4, 134.3, 133.9,
2
2
1
33.1, 132.9, 132.6, 131.2, 129.6; (aromatic carbons); MS
for C H N O S : C, 45.52; H, 4.09; N, 11.37 %; Found:
4 15 3 5 2
1
?
m/z): 519.44 [M ]. Anal. Calcd. for C H Cl N O S :
ꢀ
(
C, 45.58; H, 4.07; N, 11.47 %.
1
9
16
2 2 5 3
C, 43.93; H, 3.10; N, 5.39 %; Found: C, 44.00; H, 3.09;
N, 5.44 %.
0
0
0
2-(3 -(p-Chlorophenyl)sulfonyl-1 H-pyrazol-4 -
ylsulfonylmethyl)-4,5-dihydrooxazole 10c
0
General procedure for the synthesis of 2-(3 -
0
0
-1
m. p. 200–202 °C, yield 81 %; IR (KBr) (cm ): 3344
arylsulfonyl-1 H-pyrazol-4 -ylsulfonyl-methyl)-4,5-
0
0
1
(NH), 1583 (C=N), 1343, 1139 (SO ); H NMR (400 MHz,
dihydrooxazole (10a–c)/2-(3 -arylsulfonyl-1 H-pyrazol-
0
2
0
4
-ylsulfonylmethyl)-4,5-dihydrothiazole (11a–c)/2-(1 -
0
CDCl ): d 8.95 (brs, 1H, NH), 7.31–8.05 (m, 5H, C -H &
0
3
5
0
0
phenyl-3 -aryl-4 -arylsulfonylpyrazol-5 -
Ar–H), 4.82 (t, 2H, C -H, J = 5.8 Hz), 4.12 (s, 2H,
5
0
13
SO CH ), 3.83 (t, 2H, C -H, J = 5.8 Hz); C NMR
ylsulfonylmethyl)-4,5-dihydrooxazole (12a–c)/2-(1 -
0
2
2
4
0
0
0
phenyl-3 -aryl-4 -arylsulfonylpyrazol-5 -
ylsulfonylmethyl)-4,5-dihydrothiazole (13a–c)/2-(3 -
(100 MHz, CDCl ): d 163.9 (C-2), 151.5 (C-3 ), 141.2 (C-
3
0
0
0
5 ), 136.5 (C-4 ), 56.5 (SO CH ), 55.2 (C-5), 53.8 (C-4),
2
2
0
0
aryl-4 -arylsulfonylisoxazol-5 -ylsulfonylmethyl)-4,5-
0
134.7, 132.0, 131.3, 129.2 (aromatic carbons); MS (m/z):
?ꢀ
0
dihydro-oxazole (14a–c)/2-(3 -aryl-4 -
0
389.83 [M ]. Anal. Calcd. for C H ClN O S : C, 40.05;
1
3
12
3 5 2
arylsulfonylisoxazol-5 -ylsulfonylmethyl)-4,5-
H, 3.10; N, 10.78 %; Found: C, 40.10; H, 3.13; N, 10.86 %.
dihydrothiazole (15a–c)
0
0
0
2
-(3 -Phenylsulfonyl-1 H-pyrazol-4 -ylsulfonylmethyl)-4,5-
A solution of 4/5/6/7/8/9 (1 mmol) in xylene (10 ml) and
chloranil (1.2 mmol) was refluxed for 24–28 h. The reac-
tion mixture was treated with a 5 % sodium hydroxide
solution. The organic extract was separated, repeatedly
washed with water and dried (an. Na SO ). Removal of the
dihydrothiazole 11a
-
1
m. p. 197–199 °C, yield 73 %; IR (KBr) (cm ): 3327
1
(NH), 1560 (C=N), 1323, 1130 (SO ); H NMR (400 MHz,
2
CDCl ): d 8.84 (brs, 1H, NH), 7.29–8.05 (m, 6H, C -H &
0
5
2
4
3
solvent in vacuo yielded a solid which was purified by
recrystallization from 2-propanol.
Ar–H), 4.10 (s, 2H, SO CH ), 3.74 (t, 2H, C -H,
2 2 4
1
J = 7.8 Hz), 3.51 (t, 2H, C -H, J = 7.8 Hz); C NMR
3
5
0
(
100 MHz, CDCl ): d 157.6 (C-2), 149.9 (C-3 ), 139.1 (C-
3
0
0
0
0 0
5 ), 135.7 (C-4 ), 55.1 (SO CH ), 52.8 (C-4), 36.2 (C-5),
2 2
2
-(3 -Phenylsulfonyl-1 H-pyrazol-4 -ylsulfonylmethyl)-4,5-
dihydrooxazole 10a
133.8, 132.7, 129.3, 127.8 (aromatic carbons); MS (m/z):
?
ꢀ
71.46 [M ]. Anal. Calcd. for C H N O S : C, 42.03;
13 13 3 4 3
3
-
1
m. p. 189–192 °C, yield 82 %; IR (KBr) (cm ): 3336
H, 3.53; N, 11.31 %; Found: C, 42.10; H, 3.54; N,
11.40 %.
1
NH), 1565 (C=N), 1327, 1131 (SO ); H NMR (400 MHz,
(
2
CDCl ): d 8.91 (brs, 1H, NH), 7.29–7.95 (m, 6H, C -H &
0
5
3
0
0
0
Ar–H), 4.81 (t, 2H, C -H, J = 5.6 Hz), 4.08 (s, 2H,
5
2-(3 -(p-Methylphenyl)sulfonyl-1 H-pyrazol-4 -
1
SO CH ), 3.81 (t, 2H, C -H, J = 5.6 Hz); C NMR
3
ylsulfonylmethyl)-4,5-dihydrothiazole 11b
2
2
4
0
(
100 MHz, CDCl ): d 160.8 (C-2), 151.2 (C-3 ), 140.6 (C-
3
0
0
-1
m. p. 186–188 °C, yield 70 %; IR (KBr) (cm ): 3335
5
1
3
), 136.1 (C-4 ), 56.2 (SO CH ), 55.0 (C-5), 53.6 (C-4),
2
2
1
(NH), 1574 (C=N), 1331, 1125 (SO ); H NMR (400 MHz,
34.6, 132.8, 129.9, 128.5 (aromatic carbons); MS (m/z):
ꢀ
2
?
55.39 [M ]. Anal. Calcd. for C H N O S : C, 43.93;
CDCl ): d 8.78 (brs, 1H, NH), 7.27–8.21 (m, 5H, C -H &
0
5
1
3
13
3
5
2
3
H, 3.69; N, 11.82 %; Found: C, 43.90; H, 3.72; N,
1.94 %.
Ar–H), 4.09 (s, 2H, SO CH ), 3.73 (t, 2H, C -H,
2 2 4
1
J = 7.6 Hz), 3.47 (t, 2H, C -H, J = 7.6 Hz), 2.30 (s, 3H,
5
1
23

Med Chem Res (2014) 23:1084–1098
1095
1
3
0
0
0
Ar-CH3); C NMR (100 MHz, CDCl ): d 157.3 (C-2),
2-(1 -Phenyl-3 -(p-chlorophenyl)-4 -(p-
0
3
0
0
0
1
5
1
49.6 (C-3 ), 139.0 (C-5 ), 135.3 (C-4 ), 54.7 (SO CH ),
2
chlorophenylsulfonyl)pyrazol-5 -yl-sulfonyl-methyl)-4,5-
2
2.1 (C-4), 35.9 (C-5), 22.1 (Ar-CH ), 133.6, 130.7, 128.5,
3
?
27.6 (aromatic carbons); MS (m/z): 385.48 [M ]. Anal.
dihydrooxazole 12c
ꢀ
-
1
Calcd. for C H N O S : C, 43.62; H, 3.92; N, 10.90 %;
14 15 3 4 3
m. p. 208–210 °C, yield 69 %; IR (KBr) (cm ): 1637
(C=C), 1581 (C=N), 1339, 1147 (SO ); H NMR
2
1
Found: C, 43.69; H, 3.95; N, 10.85 %.
(
400 MHz, CDCl ): d 7.21–7.83 (13H, Ar & Ar’-H), 4.69
3
0
0
0
2
-(3 -(p-Chlorophenyl)sulfonyl-1 H-pyrazol-4 -
(t, 2H, C
5
-H, J = 5.6 Hz), 4.31 (s, 2H, SO
2
CH
2
), 3.78 (t,
): d
61.6 (C-2), 158.7 (C-3 ), 149.9 (C-4 ), 137.1 (C-5 ), 61.3
(C-5), 59.4 (SO CH ), 53.2 (C-4), 135.6, 134.2, 133.7,
133.0, 132.3, 130.4, 130.1, 129.7, 128.5, 127.4, 126.1,
1
3
ylsulfonylmethyl)-4,5-dihydrothiazole 11c
2H, C -H, J = 5.6 Hz); C NMR (100 MHz, CDCl
4 3
0
0
0
1
-
1
m. p. 211–213 °C, yield 78 %; IR (KBr) (cm ): 3348
2
2
1
NH), 1582 (C=N), 1338, 1148 (SO ); H NMR (400 MHz,
(
2
?
ꢀ
CDCl ): d 8.91 (brs, 1H, NH), 7.31–8.15 (m, 5H, C
Ar–H), 4.11 (s, 2H, SO CH ), 3.85 (t, 2H, C -H,
2
3
J = 8.0 Hz), 3.55 (t, 2H, C -H, J = 8.0 Hz); C NMR
0
-H &
5
125.6 (aromatic carbons). MS (m/z): 576.47 [M ]. Anal.
Calcd. for C25 : C, 52.09; H, 3.32; N, 7.29 %;
Found: C, 52.03; H, 3.34; N, 7.36 %.
3
H19Cl N O S
2 3 5 2
2
4
1
5
0
(
100 MHz, CDCl ): d 158.1 (C-2), 150.7 (C-3 ), 139.6 (C-
3
0
0
0
0
0
0
5
1
4
), 135.9 (C-4 ), 55.3 (SO CH ), 53.1 (C-4), 36.5 (C-5),
2
2-(1 ,3 -Diphenyl-4 -(phenylsulfonyl)pyrazol-5 -
2
32.9, 132.1, 129.7, 128.1 (aromatic carbons); MS (m/z):
ylsulfonylmethyl)-4,5-dihydrothiazole 13a
?
05.90 [M ]. Anal. Calcd. for C H ClN O S : C, 38.47;
ꢀ
1
3
12
3 4 3
-
1
H, 2.98; N, 10.35 %; Found: C, 38.43; H, 2.96; N,
m. p. 199–202 °C, yield 66 %; IR (KBr) (cm ): 1628 (C=C),
1
1
0.42 %.
1572 (C=N), 1341, 1133 (SO
); H NMR (400 MHz, CDCl ):
2 3
d 7.28-7.83 (15H, Ar & Ar’-H), 4.32 (s, 2H, SO CH ), 3.76 (t,
2
2
0
0
0
0
13
-H, J = 7.5 Hz); C
2
-(1 ,3 -Diphenyl-4 -(phenylsulfonyl)pyrazol-5 -
2H, C -H, J = 7.5 Hz), 3.52 (t, 2H, C
4
5
0
ylsulfonylmethyl)-4,5-dihydrooxazole 12a
NMR (100 MHz, CDCl
0 0
C-4 ), 135.1 (C-5 ), 58.7 (SO CH ), 51.9 (C-4), 38.4 (C-5),
2 2
3
): d 161.5 (C-2), 157.2 (C-3 ), 148.2
(
-
1
m. p. 190–192 °C, yield 67 %; IR (KBr) (cm ): 1635
134.5, 133.5, 132.4, 131.8, 130.7, 130.3, 129.8, 128.5, 127.3,
1
C=C), 1573 (C=N), 1337, 1135 (SO2); H NMR
(
126.7, 125.9, 125.2 (aromatic carbons); MS (m/z): 523.65
?
ꢀ
(
400 MHz, CDCl ): d 7.18–7.79 (15H, Ar & Ar’-H), 4.67
[M ]. Anal. Calcd. for C25
H N O S : C, 57.34; H, 4.04; N,
21 3 4 3
3
(
t, 2H, C -H, J = 5.5 Hz), 4.28 (s, 2H, SO CH ), 3.72 (t,
5
8.02 %; Found: C, 57.40; H, 4.03; N, 8.09 %.
2
2
1
3
2
H, C -H, J = 5.5 Hz); C NMR (100 MHz, CDCl ): d
4
3
0
0
0
0
0
0
1
62.3 (C-2), 158.1 (C-3 ), 148.9 (C-4 ), 136.0 (C-5 ), 60.6
2-(1 -Phenyl-3 -(p-methoxyphenyl)-4 -(p-
0
(
C-5), 59.3 (SO CH ), 52.8 (C-4), 134.3, 133.9, 133.1,
2
methylphenylsulfonyl)pyrazol-5 -ylsulfonyl-methyl)-4,5-
2
1
1
32.5, 131.6, 130.7, 129.5, 128.7, 127.2, 126.3, 125.8,
dihydrothiazole 13b
?
25.0 (aromatic carbons); MS (m/z): 507.58 [M ]. Anal.
ꢀ
-
1
Calcd. for C H N O S : C, 59.16; H, 4.17; N, 8.28 %;
25 21 3 5 2
m. p. 185–187 °C, yield 68 %; IR (KBr) (cm ): 1631
1
Found: C, 59.23; H, 4.18; N, 8.33 %.
(C=C), 1576 (C=N), 1337, 1141 (SO ); H NMR
2
(
400 MHz, CDCl ): d 7.25–7.78 (13H, Ar & Ar’-H), 4.29
3
0
0
0
2
-(1 -Phenyl-3 -(p-methoxyphenyl)-4 -(p-
0
(s, 2H, SO
2
CH
2
), 3.85 (s, 3H, Ar–OCH ), 3.73 (t, 2H, C -
3 4
methylphenylsulfonyl)pyrazol-5 -yl-sulfonyl-methyl)-4,5-
H, J = 7.2 Hz), 3.47 (t, 2H, C
5
-H, J = 7.2 Hz), 2.35 (s,
); C NMR (100 MHz, CDCl ): d 160.7 (C-
), 156.9 (C-3 ), 148.3 (C-4 ), 134.8 (C-5 ), 58.5 (SO CH ),
1
3
dihydrooxazole 12b
3H, Ar–CH
3
3
0
0
0
2
2
2
-
1
m. p. 203–205 °C, yield 65 %; IR (KBr) (cm ): 1628
56.1 (Ar–OCH ), 51.3 (C-4), 37.8 (C-5), 22.7 (Ar–CH ),
3 3
1
C=C), 1575 (C=N), 1332, 1142 (SO2); H NMR
(
134.0, 133.2, 132.8, 132.3, 131.7, 130.5, 129.6 129.0,
(
400 MHz, CDCl ): d 7.15–7.69 (13H, Ar & Ar’-H), 4.66
128.8, 127.2, 126.6, 125.8 (aromatic carbons); MS (m/z):
3
?
567.70 [M ]. Anal. Calcd. for C27
ꢀ
(
t, 2H, C -H, J = 5.2 Hz), 4.24 (s, 2H, SO CH ), 3.81 (s,
5
H N O S : C, 57.12;
25 3 5 3
2
2
3
H,Ar-OCH ), 3.70 (t, 2H, C -H, J = 5.2 Hz), 2.29 (s, 3H,
3 4
H, 4.44; N, 7.40 %; Found: C, 57.90; H, 4.46; N, 7.34 %.
1
3
Ar-CH3); C NMR (100 MHz, CDCl ): d 161.8 (C-2),
1
3
0
0
0
0
0
0
57.8 (C-3 ), 148.6 (C-4 ), 135.7 (C-5 ), 60.2 (C-5), 59.1
2-(1 -Phenyl-3 -(p-chlorophenyl)-4 -(p-
0
(
SO CH ), 56.5 (Ar–OCH ), 52.5 (C-4), 22.8 (Ar–CH ),
3
chlorophenylsulfonyl)pyrazol-5 -ylsulfonyl-methyl)-4,5-
2
2
3
1
1
5
34.1, 133.5, 133.1, 132.6, 132.0, 131.5, 129.3, 128.6,
dihydrothiazole 13c
27.8, 127.0, 126.2, 125.3 (aromatic carbons); MS (m/z):
?
51.63 [M ]. Anal. Calcd. for C H N O S : C, 58.79;
ꢀ
-1
m. p. 216–218 °C, yield 70 %; IR (KBr) (cm ): 1634
(C=C), 1583 (C=N), 1343, 1147 (SO
2
7 25 3 6 2
1
); H NMR
H, 4.57; N, 7.62 %; Found: C, 58.84; H, 4.55; N, 7.58 %.
2
123

1
096
Med Chem Res (2014) 23:1084–1098
(
400 MHz, CDCl ): d 7.31–7.87 (13H, Ar & Ar’–H), 4.37
130.7, 129.8, 128.1, 127.8 (aromatic carbons); MS (m/z):
3
?
ꢀ
501.36 [M ]. Anal. Calcd. for C H Cl N O S : C,
19 14 2 2 6 2
(
s, 2H, SO CH ), 3.82 (t, 2H, C -H, J = 7.7 Hz), 3.55 (t,
2
2
4
1
3
2
H, C -H, J = 7.7 Hz); C NMR (100 MHz, CDCl ): d
45.52; H, 2.81; N, 5.59 %; Found: C, 45.57; H, 2.80; N,
5.55 %.
5
3
0
0
0
1
62.4 (C-2), 158.4 (C-3 ), 149.2 (C-4 ), 136.2 (C-5 ), 59.1
(
SO CH ), 52.1 (C-4), 38.5 (C-5), 135.3, 134.3, 133.7,
2 2
1
1
32.6, 131.5, 130.2, 129.7, 128.6, 127.4, 126.9, 126.2,
0
0
0
2
-(3 -Phenyl-4 -phenylsulfonylisoxazol-5 -
?
25.3 (aromatic carbons); MS (m/z): 592.54 [M ]. Anal.
ꢀ
ylsulfonylmethyl)-4,5-dihydrothiazole 15a
Calcd. for C H Cl N O S : C, 50.67; H, 3.23; N, 7.09 %;
2
5
19
2 3 4 3
Found: C, 50.62; H, 3.20; N, 7.18 %.
-1
m. p. 201–203 °C, yield 63 %; IR (KBr) (cm ): 1627
1
C=C), 1587 (C=N), 1345, 1124 (SO2); H NMR
(
0
0
0
2
-(3 -Phenyl-4 -phenylsulfonylisoxazol-5 -
(
400 MHz, CDCl ): d 7.29–7.78 (10H, Ar & Ar’–H), 4.24
3
ylsulfonylmethyl)-4,5-dihydrooxazole 14a
(
s, 2H, SO CH ), 3.73 (t, 2H, C -H, J = 7.2 Hz), 3.38 (t,
2
2
4
1
3
2
H, C -H, J = 7.2 Hz); C NMR (100 MHz, CDCl ): d
5
3
-
1
m. p. 211–213 °C, yield 62 %; IR (KBr) (cm ): 1626
0
0
0
1
61.2 (C-2), 157.4 (C-3 ), 148.2 (C-4 ), 135.3 (C-5 ), 59.1
1
C=C), 1589 (C=N), 1336, 1127 (SO2); H NMR
(
(SO CH ), 52.5 (C-4), 38.3 (C-5), 134.7, 134.1, 133.8,
2 2
(
400 MHz, CDCl ): d 7.34–7.82 (10H, Ar & Ar’–H), 4.64
3
1
32.3, 131.4, 130.8, 129.4, 128.2 (aromatic carbons); MS
?ꢀ
(
t, 2H, C -H, J = 5.7 Hz), 4.31 (s, 2H, SO CH ), 3.76 (t,
5
2
2
(
m/z): 448.54 [M ]. Anal. Calcd. for C H N O S : C,
9 16 2 5 3
1
1
3
2
H, C -H, J = 5.7 Hz); C NMR (100 MHz, CDCl ): d
4
3
5
6
0.88; H, 3.60; N, 6.25 %; Found: C, 50.84; H, 3.63; N,
.32 %.
0
0
0
1
61.2 (C-2), 157.8 (C-3 ), 148.8 (C-4 ), 135.8 (C-5 ), 61.8
(
C-5), 59.4 (SO CH ), 52.7 (C-4), 133.4, 132.6, 131.2,
2 2
1
30.7, 129.4, 128.7, 127.6, 126.3 (aromatic carbons); MS
0 0
2-(3 -(p-Methoxyphenyl)-4 -(p-
?
ꢀ
m/z): 432.47 [M ]. Anal. Calcd. for C H N O S : C,
19 16 2 6 2
(
0
methylphenylsulfonyl)isoxazol-5 -ylsulfonylmethyl)-4,5-
5
6
2.77; H, 3.73; N, 6.48 %; Found: C, 52.86; H, 3.71; N,
.58 %.
dihydrothiazole 15b
-
1
0 0
-(3 -(p-Methoxyphenyl)-4 -(p-
m. p. 215–217 °C, yield 61 %; IR (KBr) cm ): 1633
2
1
0
(C=C), 1581 (C=N), 1342, 1127 (SO ); H NMR
2
methylphenylsulfonyl)isoxazol-5 -ylsulfonyl-methyl)-4,5-
(
400 MHz, CDCl ): d 7.22–7.83 (8H, Ar & Ar’-H), 4.21 (s,
H, SO CH ), 3.88 (s, 3H, Ar–OCH ), 3.72 (t, 2H, C -H,
4
3
dihydrooxazole 14b
2
2
2
3
-
1
J = 7.0 Hz), 3.32 (t, 2H, C -H, J = 7.0 Hz), 2.34 (s, 3H,
5
m. p. 194–196 °C, yield 60 %; IR (KBr) (cm ): 1622
1
3
1
C=C), 1585 (C = N), 1329, 1138 (SO2); H NMR
Ar–CH3); C NMR (100 MHz, CDCl ): d 160.2 (C-2),
3
(
0 0 0
56.4 (C-3 ), 147.9 (C-4 ), 135.4 (C-5 ), 59.5 (SO CH ),
2 2
1
5
1
(
400 MHz, CDCl ): d 7.28–7.79 (8H, Ar & Ar’-H), 4.61 (t,
H, C -H, J = 5.5 Hz), 4.27 (s, 2H, SO CH ), 3.91 (s, 3H,
5 2 2
3
6.7 (Ar–OCH ), 52.3 (C-4), 38.0 (C-5), 22.5 (Ar–CH ),
3
3
2
34.7, 133.3, 132.6, 131.9, 131.3, 130.4, 129.8, 129.3
Ar–OCH ), 3.69 (t, 2H, C -H, J = 5.5 Hz), 2.32 (s, 3H,
3
4
?
ꢀ
1
3
(aromatic carbons); MS (m/z): 492.59 [M ]. Anal. Calcd.
for C21 : C, 51.20; H, 4.09; N, 5.69 %; Found:
C, 51.28; H, 4.10; N, 5.76 %.
Ar–CH3); C NMR (100 MHz, CDCl ): d 161.3 (C-2),
57.1 (C-3 ), 147.9 (C-4 ), 135.4 (C-5 ), 61.5 (C-5), 59.8
3
0
0
0
H N O S
20 2 6 3
1
(
SO CH ), 57.2 (Ar–OCH ), 52.6 (C-4), 23.1 (Ar–CH ),
2
2
3
3
1
34.2, 133.6, 132.4, 131.3, 130.5, 129.3, 128.8, 127.5
?
aromatic carbons); MS (m/z): 476.52 [M ]. Anal. Calcd.
ꢀ
0 0
2-(3 -(p-Chlorophenyl)-4 -(p-
(
0
for C H N O S : C, 52.93; H, 4.23; N, 5.88 %; Found:
1 20 2 7 2
chlorophenylsulfonyl)isoxazol-5 -ylsulfonylmethyl)-4,5-
2
C, 53.00; H, 4.26; N, 5.96 %.
dihydrothiazole 15c
0
0
-1
m. p. 234–236 °C, yield 67 %; IR (KBr) (cm ): 1628
(C=C), 1594 (C=N), 1346, 1123 (SO2); H NMR
2
-(3 -(p-Chlorophenyl)-4 -(p-
0
1
chlorophenylsulfonyl)isoxazol-5 -ylsulfonylmethyl)-4,5-
dihydrooxazole 14c
(400 MHz, CDCl ): d 7.29–7.85 (8H, Ar & Ar’-H), 4.35 (s,
3
2
H, SO CH ), 3.86 (t, 2H, C -H, J = 7.4 Hz), 3.45 (t, 2H,
2 2 4
13
-
1
m. p. 207–209 °C, yield 65 %; IR (KBr) (cm ): 1629
C -H, J = 7.4 Hz); C NMR (100 MHz, CDCl ): d 161.8
(C-2), 157.8 (C-3 ), 148.5 (C-4 ), 135.6 (C-5 ), 59.8
5
3
1
C=C), 1592 (C=N), 1341, 1135 (SO2); H NMR
0
0
0
(
(
400 MHz, CDCl ): d 7.36–7.85 (8H, Ar & Ar’-H), 4.68 (t,
(SO CH ), 52.7 (C-4), 38.6 (C-5), 134.3, 133.4, 132.5,
2
3
2
2
H, C -H, J = 5.9 Hz), 4.32 (s, 2H, SO CH ), 3.78 (t, 2H,
5
131.6, 130.6, 129.7, 126.3, 125.8 (aromatic carbons); MS
?ꢀ
2
2
1
3
C -H, J = 5.9 Hz); C NMR (100 MHz, CDCl ): d 162.7
(m/z): 517.43 [M ]. Anal. Calcd. for C H Cl N O S ; C,
19 14 2 2 5 3
4
3
0
0
0
(
C-2), 157.9 (C-3 ), 149.7 (C-4 ), 136.8 (C-5 ), 62.1 (C-5),
44.10; H, 2.73; N 5.41 %; Found: C, 44.16; H, 2.75; N,
5.45 %.
5
9.9 (SO CH ), 52.9 (C-4), 133.7, 133.1, 132.3, 131.4,
2
2
1
23

Med Chem Res (2014) 23:1084–1098
Antioxidant activity
1097
Hydrogen peroxide (H O ) scavenging activity
2
2
The compounds 4–15 were evaluated for antioxidant
property by DPPH (Burits and Bucar, 2000; Cuendet et al.,
The H O scavenging ability of the test compound was
2 2
determined according to the method of Ruch et al. A solution
of H O (40 mm) was prepared in phosphate buffer (pH 7.4).
1
1
997), nitric oxide (Green et al., 1982; Marcocci et al.,
994), and H O (Ruch et al., 1989) methods.
2
2
50, 75, and 100 lg/ml concentrations of the test compounds
in 3.4 ml-phosphate buffer were added to H O solution
2
2
2
2
DPPH radical scavenging activity
(0.6 ml, 40 mm). The absorbance value of the reaction
mixture was recorded at 230 nm. The per cent of scavenging
of H O was calculated by the following equation
The hydrogen atom or electron donation ability of the
compounds was measured from the bleaching of the purple
colored methanol solution of 2,2,-diphenyl-1-picrylhy-
drazyl (DPPH). This property makes it suitable for spec-
trophotometric studies. 1 ml of various concentrations of
the test compounds (50, 75, and 100 lg/ml) in methanol
were added to 4 ml of 0.004 % (w/v) methanol solution of
DPPH. After a 30 min incubation period at room temper-
ature, the absorbance was read against blank at 517 nm.
The percent of inhibition (I %) of free radical production
from DPPH was calculated by the following equation
2
2
ÂÀ
Á
Ã
%
of scavenging ¼ Acontrol ꢁ Asample =Ablank ꢂ 100
where Acontrol was the absorbance of the control reaction
(containing all reagents and ascorbic acid), Asample was the
absorbance of the test compound (containing all reagents
and test compound), and Ablank was the absorbance of the
blank (containing only reagents). Tests were carried out in
triplicate.
Acknowledgments One of the aurhors (A. Padmaja) is grateful to
University Grants Commission (UGC), New Delhi, for financial
assistance under a major research project. 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 of the compounds.
ÂÀ
Á
Ã
I % ¼ Acontrol ꢁ Asample =Ablank ꢂ 100
where A
was the absorbance of the control reaction
control
(
containing methanolic DPPH and ascorbic acid), Asample
was the absorbance of the test compound (containing
methanolic DPPH and test compound) and Ablank was the
absorbance of the blank (containing only methanolic
DPPH). Tests were carried out in triplicate.
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