Synthesis and antioxidant activity of bis unsaturated sulfones, bis pyrroles, and bis pyrazoles

Article abstract of DOI:10.1007/s11164-015-1930-8

The Michael acceptor 1,4-bis-(E)-2-(arylsulfonylvinyl)benzene was exploited to prepare a new series of bis heterocycles-(1,4-phenylene)bis(arylsulfonylpyrrole) and (1,4-phenylene)bis(arylsulfonyl pyrazole). All of the compounds were tested for antioxidant activity. Amongst the tested compounds, 1,4-bis-(E)-2-(arylsulfonylvinyl)benzene (5) was found to be the best potential antioxidant agent.

Full text of DOI:10.1007/s11164-015-1930-8

Res Chem Intermed
DOI 10.1007/s11164-015-1930-8
Synthesis and antioxidant activity of bis unsaturated
sulfones, bis pyrroles, and bis pyrazoles
•
G. Lavanya T. Bhanu Prakash G. Sravya
•
•
•
V. Padmavathi A. Padmaja
Received: 11 October 2014 / Accepted: 13 January 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The Michael acceptor 1,4-bis-(E)-2-(arylsulfonylvinyl)benzene was
exploited to prepare a new series of bis heterocycles-(1,4-phenylene)bis(arylsul-
fonylpyrrole) and (1,4-phenylene)bis(arylsulfonyl pyrazole). All of the compounds
were tested for antioxidant activity. Amongst the tested compounds, 1,4-bis-(E)-2-
(arylsulfonylvinyl)benzene (5) was found to be the best potential antioxidant agent.
Keywords Bis unsaturated sulfones ꢀ Bis pyrroles ꢀ Bis pyrazolines ꢀ
Bis pyrazoles ꢀ Antioxidant activity
Introduction
a,b-Unsaturated sulfones are valuable intermediates in a variety of synthetic
transformations and are useful as building blocks in the synthesis of biologically
active heterocycles [1–3], cytotoxic, antimicrobial, analgesic, and antipyretic. The
synthetic utility of the 1,3-dipolar cycloaddition reaction stems from its wide scope
and from the relevance of numerous targets achievable by this chemistry [4],
especially heterocycles. In particular, nitrogen-containing heterocycles have
attracted widespread attention in the field of synthetic organic chemistry as well
as in medicinal chemistry [5]. Among them, pyrroles, pyrazoles, and their
derivatives are present in a plethora of natural and synthetic compounds that are
of considerable importance. Pyrroles possesses antibacterial, antifungal, antiviral,
anti-inflammatory, antitumor, and antioxidant activities [6–11]. The recent success
of pyrazole-based COX-2 inhibitors has highlighted the importance of these
heterocycles in medicinal chemistry [12]. Pyrazole and its derivatives show a
variety of pharmaceutical activities such as antimicrobial [13, 14], antiviral [15, 16],
G. Lavanya ꢀ T. B. Prakash ꢀ G. Sravya ꢀ V. Padmavathi ꢀ A. Padmaja (&)
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
e-mail: adivireddyp@yahoo.co.in
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G. Lavanya et al.
anxiolytic [17, 18], anti-inflammatory, [19] and antioxidant [1]. In fact, pyrazole
moiety makes the core structure of various drugs, namely difenamizole [20, 21],
celecoxib [22], and tepoxalin [23]. Motivated by these findings and in continuation
of our studies towards the synthesis and bioassay of different bis heterocycles [24–
27], the present work is formulated.
Experimental
Apparatus and analysis
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
IR200 FT-IR spectrometer as KBr pellets and the wave numbers were given in
cm-1. The 1H NMR spectra were recorded in DMSO-d6 on a Brucker-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 an internal standard. The mass spectra were recorded on
Agilent 1200 series LC-MC/Agilent 6310 Ion trap electron spray ionization mode.
The elemental analyses were carried out on a Perkin-Elmer 240C elemental
analyzer. The antioxidant property was carried out by using Shimadzu UV-2450
spectrophotometer. The starting compound arylsulfonylacetic acid (3) was prepared
according to literature procedure [28].
General procedure for the synthesis of 1, 4-bis((E)-2-
(arylsulfonyl)vinyl)benzene (5)
To a solution of arylsulfonylacetic acid (1) (1 mmol) in glacial acetic acid (10 ml),
terephthaldehyde (2) (0.5 mmol) followed by a catalytic amount of benzylamine
(0.20 ml) were added and refluxed for 6–8 h. The reaction mixture was cooled,
treated with dry ether (50 ml), and left overnight in a refrigerator. Any product that
formed was filtered off. The filtrate was diluted with ether and washed successively
with a saturated solution of sodium bicarbonate, sodium bisulfate, dilute
hydrochloric acid, and water. The organic layer was dried over anhydrous
Na2SO4. In many cases, a solid product was obtained on removal of ether under
reduced pressure. However, in some instances, a syrupy substance was obtained,
which was solidified on treatment with 2-propanol. The crude product was
recrystallized from 2-propanol.
Spectral data for compounds (5a–e)
1,4-Bis ((E)-2-(phenylsulfonyl)vinyl)benzene (5a) White solid; Mp. 236–238 °C.
1
IR (KBr) (cm–1): 1,625 (C=C), 1,299, 1,134 (SO2); H NMR (400 MHz, DMSO-
d6): d 7.19 (d, 2H, C–HB, J = 15.3 Hz), 7.46–7.77 (m, 14H, Ar–H), 7.63 (d, 2H, C–
HA, J = 15.3 Hz) ppm; 13C NMR (100 MHz, DMSO-d6): d 113.2 (C–HB), 135.2
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Synthesis and antioxidant activity
(C–HA), 125.7, 126.3, 129.7, 132.5, 134.1, 136.3, 138.3 ppm (aromatic carbons).
MS: (m/z) 411.51 [M ? H]?. Anal. Calcd. for C22H18O4S2:C, 64.37; H, 4.42 %.
Found: C, 64.45; H, 4.45 %.
1,4-Bis((E)-2-(p-methylphenylsulfonyl)vinyl)benzene (5b) White solid; Mp.
220–222 °C. IR (KBr) (cm–1): 1,620 (C=C), 1,297, 1,128 (SO2); 1H NMR
(400 MHz, DMSO-d6): d 2.38 (s, 6H, Ar–CH3), 7.16 (d, 2H, C–HB, J = 15.2 Hz),
7.50–7.79 (m, 12H, Ar–H), 7.60 (d, 2H, C–HA, J = 15.2 Hz) ppm; 13C NMR
(100 MHz, DMSO-d6): d 24.8 (Ar–CH3), 112.9 (C–HB), 133.7 (C–HA), 126.5,
128.8, 130.3, 131.8, 134.2, 137.5, 142.6 ppm (aromatic carbons). MS: (m/z) 439.56
[M ? H]?. Anal. Calcd. for C22H22O4S2:C, 65.73; H, 5.06 %. Found: C, 65.83; H,
5.05 %.
1,4-Bis((E)-2-(p-chlorophenylsulfonyl)vinyl)benzene (5c) White solid; Mp.
243–245 °C. IR (KBr) (cm–1): 1,630 (C=C), 1,302, 1,146 (SO2); 1H NMR
(400 MHz, DMSO-d6): d 7.23 (d, 2H, C–HB, J = 15.4 Hz), 7.66 (d, 2H, C–HA,
J = 15.4 Hz), 7.71–7.93 (m, 12H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): d
113.5 (C–HB), 135.9 (C–HA), 126.2, 128.5, 133.8, 135.1, 136.9, 138.7, 139.4 ppm
(aromatic carbons). MS: (m/z) 480.41 [M ? H]?. Anal. Calcd. for C22H16Cl2O4-
S2:C, 55.12; H, 3.36 %. Found: C, 55.18; H, 3.38 %.
1,4-Bis((E)-2-(p-methoxyphenylsulfonyl)vinyl)benzene (5d) White solid; Mp.
272–274 °C. IR (KBr) (cm–1): 1,628 (C=C), 1,295, 1,139 (SO2); 1H NMR
(400 MHz, DMSO-d6): d 3.85 (s, 6H, Ar–OCH3), 7.18 (d, 2H, C–HB, J = 15.6 Hz),
7.54–7.82 (m, 12H, Ar–H), 7.62 (d, 2H, C–HA, J = 15.6 Hz) ppm; 13C NMR
(100 MHz, DMSO-d6): d 54.6 (Ar–OCH3), 112.5 (C–HB), 133.2 (C–HA), 126.1,
126.5, 129.5, 129.7, 131.4, 136.2, 138.1 ppm (aromatic carbons). MS: (m/z) 471.56
[M ? H]?. Anal. Calcd. for C24H22O6S2:C, 61.26; H, 4.71 %. Found: C, 61.32; H,
4.74 %.
1,4-Bis((E)-2-(p-hydroxyphenylsulfonyl)vinyl)benzene (5e) White solid; Mp.
266–268 °C. IR (KBr) (cm–1): 1,632 (C=C), 1,306, 1,141 (SO2); 1H NMR
(400 MHz, DMSO-d6): d 5.27 (s, 2H, Ar–OH), 7.14 (d, 2H, C–HB, J = 15.1 Hz),
7.52–7.81 (m, 12H, Ar–H), 7.58 (d, 2H, C–HA, J = 15.1 Hz) ppm; 13C NMR
(100 MHz, DMSO-d6): d 111.7 (C–HB), 132.4 (C–HA), 125.6, 126.7, 131.2, 133.8,
134.2, 136.1, 139.3 ppm (aromatic carbons). MS: (m/z) 445.52 [M ? H]?. Anal.
Calcd. for C22H20O6S2:C, 59.53; H, 4.56 %. Found: C, 59.44; H, 4.53 %.
General procedure for the synthesis of 1,4-(bis(3-arylsulfonyl)-1H-pyrrol-4-
yl)benzene (6)
To a suspension of sodium hydride (0.05 g) in dry ether (10 ml), compound 5
(1 mmol) and tosylmethyl isocyanide (2 mmol) in Et2O–DMSO (2:1) (15 ml) was
added while stirring at room temperature and stirring was continued for 5–7 h. The
reaction mixture was diluted with water and extracted with ether. The ethereal layer
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G. Lavanya et al.
was dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo.
The resultant residue was purified by column chromatography (silica gel, 60–120
mesh) using hexane, and ethyl acetate (3:1) as eluent.
Spectral data for compounds (6a–e)
1,4-(Bis(3-phenylsulfonyl)-1H-pyrrol-4-yl)benzene (6a) Pale yellow solid; Mp.
230–232 °C. IR (KBr) (cm–1): 3,245 (NH), 1,325, 1,136 (SO2); 1H NMR (400 MHz,
DMSO-d6): d 6.81–7.55 (m, 18H, C2–H, C5–H and Ar–H), 11.53 (bs, 2H, NH) ppm;
13C NMR (100 MHz, DMSO-d6): d 110.2 (C-3), 116.9 (C-5), 122.4 (C-2), 126.6 (C-
4), 128.4, 129.9, 132.1, 134.6, 136.3, 141.7 ppm (aromatic carbons). MS: (m/z)
489.58 [M ? H]?. Anal. Calcd. for C26H20N2O4S2:C, 63.92; H, 4.13; N, 5.73 %.
Found: C, 64.05; H, 4.18; N, 5.93 %.
1,4-(Bis(3-(p-methylphenylsulfonyl)-1H-pyrrol-4-yl)benzene (6b) Pale yellow
1
solid; Mp. 238–240 °C. IR (KBr) (cm–1): 3,241 (NH), 1,334, 1,138 (SO2); H
NMR (400 MHz, DMSO-d6): d 2.38 (s, 6H, Ar–CH3), 6.90–7.52 (m, 16H, C2–H,
C5–H and Ar–H), 11.76 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d 24.3
(Ar–CH3), 113.5 (C-3), 117.8 (C-5), 123.7 (C-2), 127.9 (C-4), 128.2, 132.3, 135.6,
137.4, 138.7, 143.2 ppm (aromatic carbons). MS: (m/z) 517.63 [M ? H]?. Anal.
Calcd. for C28H24N2O4S2:C, 65.09; H, 4.68; N, 5.42 %. Found: C, 65.25; H, 4.75;
N, 5.64 %.
1,4-(Bis(3-(p-chlorophenylsulfonyl)-1H-pyrrol-4-yl)benzene (6c) Pale yellow
1
solid; Mp. 277–279 °C. IR (KBr) (cm–1): 3,256 (NH), 1,340, 1,145 (SO2); H
NMR (400 MHz, DMSO-d6): d 7.08–7.62 (m, 16H, C2–H, C5–H and Ar–H), 12.02
(bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d 114.8 (C–3), 119.2 (C–5),
125.6 (C–2), 129.4 (C-4), 127.2, 129.8, 134.5, 137.3, 139.4, 140.3 ppm (aromatic
carbons). MS: (m/z) 558.47 [M ? H]?. Anal. Calcd. for C26H18Cl2N2O4S2: C,
56.02; H, 3.25; N, 5.03 %. Found: C, 56.14; H, 3.21; N, 5.21 %.
1,4-(Bis(3-(p-methoxyphenylsulfonyl)-1H-pyrrol-4-yl)benzene (6d) Pale yellow
1
solid; Mp. 268–271 °C. IR (KBr) (cm–1): 3,251 (NH), 1,336, 1,130 (SO2); H
NMR (400 MHz, DMSO-d6): d 3.87 (s, 6H, Ar–OCH3), 7.05–7.57 (m, 16H, Ar–H,
C5–H and C2–H),11.83 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d 54.8
(Ar–OCH3), 114.3 (C–3), 118.5 (C–5), 124.7 (C–2), 128.4 (C–4), 115.1, 128.3,
129.5, 133.2, 136.8, 165.0 ppm (aromatic carbons). MS: (m/z) 549.63 [M ? H]?.
Anal. Calcd. for C28H24N2O6S2:C, 61.30; H, 4.41; N, 5.11 %. Found: C, 61.20; H,
4.44; N, 5.26 %.
1,4-(Bis(3-(p-hydroxyphenylsulfonyl)-1H-pyrrol-4-yl)benzene (6e) Pale yellow
solid; Mp. 241-243 °C. IR (KBr) (cm–1): 3,249 (NH), 1,332, 1,126 (SO2); 1H
NMR (400 MHz, DMSO-d6): d 5.29 (s, 2H, Ar–OH), 6.89–7.64 (m, 16H, Ar–H,
C5–H and C2–H), 11.68 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d
112.7 (C–3), 117.6 (C–5), 122.1 (C–2), 127.5 (C–4), 116.8, 128.5, 129.7, 134.3,
123

Synthesis and antioxidant activity
136.9, 163.2 ppm (aromatic carbons). MS: (m/z) 521.58 [M ? H]?. Anal. Calcd. for
C26H20N2O6S2:C, 59.99; H, 3.87; N, 5.38 %. Found: C, 60.17; H, 3.97; N, 5.62 %.
General procedure for the synthesis of 1,4-(bis(3-arylsulfonyl)-4,5-dihydro-(1H-
pyrazol-4-yl))benzene (7)
A well-cooled ethereal solution of diazomethane (40 ml, 4 mmol) and a catalytic
amount of triethylamine (2 ml) were added to a solution of compound 5 (1 mmol) in
dichloromethane (10 ml). The reaction mixture was kept at -20 to -15 °C for
48–56 h. The solvent was removed under reduced pressure. The resultant solid was
purified by column chromatography (silica gel, 60–120 mesh) using ethyl acetate,
and hexane (1:4) as eluent.
Spectral data for new compounds (7a–e)
1,4-(Bis(3-phenylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzene(7a) Yellow solid;
Mp. 232–234 °C. IR (KBr) (cm–1): 3,253 (NH), 1,565 (C=N), 1,326, 1,132 (SO2);
1H NMR (400 MHz, DMSO-d6): 3.32 (dd, 2H, HX, JAX = 5.8 Hz, JMX = 10.9 -
Hz), 3.87 (dd, 2H, HM, JAM = 12.5 Hz), 4.35 (dd, 2H, HA), 6.63 (bs, 2H, NH),
7.12–7.98 (m, 14H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): d 35.7 (C–4),
56.8 (C–5), 157.1 (C–3), 127.9, 130.6, 132.4, 134.7, 136.0, 141.2 ppm (aromatic
carbons). MS: (m/z) 495.59 [M ? H]?. Anal. Calcd. for C24H22N4O4S2:C, 58.28; H,
4.48; N, 11.33 %. Found: C, 58.39; H, 4.50; N, 11.49 %.
1,4-(Bis(3-(p-methylphenylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzene (7b) Yel-
low solid; Mp. 244–246 °C. IR (KBr) (cm–1): 3,265 (NH), 1,578 (C=N), 1,338,
1,146 (SO2); 1H NMR (400 MHz, DMSO-d6): d 2.32 (s, 6H, Ar–CH3), 3.43 (dd, 2H,
HX, JAX = 6.2 Hz, JMX = 11.1 Hz), 3.97 (dd, 2H, HM, JAM = 12.7 Hz), 4.45 (dd,
2H, HA), 6.72 (bs, 2H, NH), 6.98–7.85 (m, 12H, Ar–H) ppm; 13C NMR (100 MHz,
DMSO-d6): d 22.7 (Ar–CH3), 35.3 (C–4), 57.6 (C–5), 158.2 (C–3), 128.1, 135.4,
132.7, 137.2, 138.0, 143.8 ppm (aromatic carbons). MS: (m/z) 523.64 [M ? H]?.
Anal. Calcd. for C26H26N2O4S2:C, 59.75; H, 5.01; N, 10.72 %. Found: C, 59.83; H,
5.00; N, 10.85 %.
1,4-(Bis(3-(p-chlorophenylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzene (7c) Yel-
low solid; Mp. 283–285 °C. IR (KBr) (cm–1): 3,268 (NH), 1,584 (C=N), 1,345,
1
1,139 (SO2); H NMR (400 MHz, DMSO-d6): d 3.50 (dd, 2H, HX, JAX = 6.4 Hz,
JMX = 11.6 Hz), 4.08 (dd, 2H, HM, JAM = 12.8 Hz), 4.52 (dd, 2H, HA), 6.78 (bs,
2H, NH), 7.04–7.95 (m, 12H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-d6): d 37.4
(C–4), 58.5 (C–5), 159.3 (C–3), 126.8, 129.2, 133.6, 137.1,139.5, 140.7 ppm
(aromatic carbons). MS: (m/z) 564.48 [M ? H]?. Anal. Calcd. for C24H20Cl2N4-
O4S2:C, 51.16; H, 3.58; N, 9.94 %. Found: C, 51.02; H, 3.62; N, 10.14 %.
1,4-(Bis(3-(p-methoxyphenylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzene
(7d) Yellow solid; Mp. 278–280 °C. IR (KBr) (cm–1): 3,256 (NH), 1,570 (C=N),
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G. Lavanya et al.
1,339, 1,125 (SO2); 1H NMR (400 MHz, DMSO-d6): d 3.45 (dd, 2H, HX,
JAX = 6.3 Hz, JMX = 11.4 Hz), 3.81 (s, 6H, Ar–OCH3), 4.02 (dd, 2H, HM,
JAM = 12.7 Hz), 4.48 (dd, 2H, HA), 6.74 (bs, 2H, NH), 7.01–7.89 (m, 12H, Ar–H)
ppm; 13C NMR (100 MHz, DMSO-d6): d 36.8 (C–4), 54.3 (Ar–OCH3), 58.2 (C–5),
158.6 (C–3), 114.7, 127.3, 128.0, 133.5, 136.2, 164.6 ppm (aromatic carbons). MS:
(m/z) 555.64 [M ? H]?. Anal. Calcd. for C26H26N4O6S2:C, 56.30; H, 4.72; N,
10.10 %. Found: C, 56.37; H, 4.74; N, 10.22 %.
1,4-(Bis(3-(p-hydroxyphenylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzene (7e) Yel-
low solid; Mp. 258–260 °C. IR (KBr) (cm–1): 3,252 (NH), 1,572 (C=N), 1,331,
1
1,134 (SO2); H NMR (400 MHz, DMSO-d6): d 3.38 (dd, 2H, HX, JAX = 6.0 Hz,
JMX = 10.9 Hz), 3.93 (dd, 2H, HM, JAM = 11.7 Hz), 4.41 (dd, 2H, HA), 5.23 (s,
2H, Ar–OH), 6.68 (bs, 2H, NH), 6.95–7.82 (m, 12H, Ar–H) ppm; 13C NMR
(100 MHz, DMSO-d6): d 35.9 (C–4), 57.4 (C–5), 157.5 (C–3), 115.8, 126.5, 129.1,
133.4, 136.0, 162.9 ppm (aromatic carbons). MS: (m/z) 527.58 [M ? H]?. Anal.
Calcd. for C24H22N4O6S2:C, 54.74; H, 4.21; N, 10.64 %. Found: C, 54.90; H, 4.24;
N, 10.89 %.
General procedure for the synthesis of 1,4-(bis(3-phenylsulfonyl)-1H-pyrazol-4-
yl)benzene (8)
A mixture of compound 7 (1 mmol), chloranil (2.4 mmol) and xylene (20 ml) was
refluxed for 23–26 h. Then, it was treated with 5 % sodium hydroxide solution. The
organic extract was separated, washed with water, and dried (an. Na2SO4). The
solvent was removed on a rotary evaporator. The resultant solid was recrystallized
from 2-propanol.
Spectral data for compounds (8a–e)
1,4-(Bis(3-phenylsulfonyl)-1H-pyrazol-4-yl)benzene (8a) White solid; Mp.
1
257–259 °C. IR (KBr) (cm–1): 3,257 (NH), 1,560 (C=N), 1,327, 1,137 (SO2); H
NMR (400 MHz, DMSO-d6): d 6.61 (s, 2H, C5–H), 7.32–8.01 (m, 14H, Ar–H),
10.62 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d 127.5 (C–4), 131.3
(C–3), 135.0 (C–5), 128.6, 129.4, 133.5, 134.8, 136.5, 141.3 ppm (aromatic
carbons). MS: (m/z) 491.55 [M ? H]?. Anal. Calcd. for C24H18N4O4S2:C, 58.76; H,
3.70; N, 11.42 %. Found: C, 58.87; H, 3.76; N, 11.20 %.
1,4-(Bis(3-(p-methylphenylsulfonyl)-1H-pyrazol-4-yl)benzene (8b) White solid;
Mp. 246–248 °C. IR (KBr) (cm–1): 3,261 (NH), 1,575 (C=N), 1,335, 1,140
1
(SO2); H NMR (400 MHz, DMSO-d6): d 2.41 (s, 6H, Ar–CH3), 6.68 (s, 2H, C5–
H),7.43–8.07 (m, 12H, Ar–H), 10.73 (bs, 2H, NH) ppm; 13C NMR (100 MHz,
DMSO-d6): d 23.4 (Ar–CH3), 128.4 (C–4), 132.6 (C–3), 136.2 (C–5), 128.8, 132.6,
135.1, 137.8, 138.6, 143.0 ppm (aromatic carbons). MS: (m/z) 519.61 [M ? H]?.
Anal. Calcd. for C26H22N4O4S2:C, 60.21; H, 4.28; N, 10.28 %. Found: C, 60.38; H,
4.38; N, 10.53 %.
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Synthesis and antioxidant activity
1,4-(Bis(3-(p-chlorophenylsulfonyl)-1H-pyrazol-4-yl)benzene (8c) White solid;
Mp. 281–283 °C. IR (KBr) (cm–1): 3,254 (NH), 1,582 (C=N), 1,343, 1,143
1
(SO2); H NMR (400 MHz, DMSO-d6): d 6.83 (s, 2H, C5–H), 7.51-8.14 (m, 12H,
Ar–H), 10.85 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d 129.8 (C–4),
133.5 (C–3), 137.3 (C–5), 127.5, 129.3, 134.2, 137.6, 139.1, 140.6 ppm (aromatic
carbons). MS: (m/z) 560.44 [M ? H]?. Anal. Calcd. for C24H16Cl2N4O4S2:C,
51.53; H, 2.88; N, 10.01 %. Found: C, 51.46; H, 2.86; N, 10.15 %.
1,4-(Bis(3-(p-methoxyphenylsulfonyl)-1H-pyrazol-4-yl)benzene (8d) White solid;
Mp. 275–277 °C. IR (KBr) (cm–1): 3,258 (NH), 1,580 (C=N), 1,339, 1,136 (SO2);
1H NMR (400 MHz, DMSO-d6): d 3.89 (s, 6H, Ar–OCH3), 6.76 (s, 2H, C5–H),
7.48–8.12 (m, 12H, Ar–H), 10.79 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-
d6): d 55.6 (Ar–OCH3), 129.2 (C–4), 132.7 (C–3), 136.9 (C–5), 115.4, 128.7, 129.6,
133.9, 137.6, 165.2 ppm (aromatic carbons). MS: (m/z) 551.61 [M ? H]?. Anal.
Calcd. for C26H22N4O6S2:C, 56.72; H, 4.03; N, 10.18 %. Found: C, 56.87; H, 4.10;
N, 10.46 %.
1,4-(Bis(3-(p-hydroxyphenylsulfonyl)-1H-pyrazol-4-yl)benzene (8e) White solid;
Mp. 249–251 °C. IR (KBr) (cm–1): 3,260 (NH), 1,578 (C=N), 1,330, 1,131 (SO2);
1H NMR (400 MHz, DMSO-d6): d 5.32 (s, 2H, Ar–OH), 6.65 (s, 2H, C5–H),
7.39–8.05 (m, 12H, Ar–H), 10.64 (bs, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-
d6): d 127.7 (C–4), 131.9 (C–3), 135.4 (C–5), 116.5, 128.9, 129.6, 134.4, 136.7,
163.4 ppm (aromatic carbons). MS: (m/z) 523.55 [M ? H]?. Anal. Calcd. for
C24H18N4O6S2:C, 55.16; H, 3.47; N, 10.72 %. Found: C, 55.25; H, 3.50; N,
10.89 %.
Results and discussion
The synthetic scheme involves the preparation of bis heterocycles viz., 1,4-(bis(3-
arylsulfonyl)-1H-pyrrol-4-yl)benzene (6), 1,4-(bis(3-arylsulfonyl)-4,5-dihydro-(1H-
pyrazol-4-yl))benzene (7) and 1,4-(bis(3-arylsulfonyl)-1H-pyrazol-4-yl)benzene (8)
from the Michael acceptor 1,4-bis-(E)-2-(arylsulfonylvinyl)benzene (5). The
compound 5 was prepared by the Knoevenagel condensation of arylsulfonylacetic
acid (3) with terephthaldehyde (4) in the presence of benzylamine in AcOH. The
arylsulfonylacetic acid (3) was in turn obtained by the reaction of thiophenol (1)
with 2-chloroacetic acid followed by oxidation of the resultant arylthioacetic acid
(2) with hydrogen peroxide in glacial acetic acid (Scheme 1). The 1H NMR
spectrum of 5a exhibited two doublets at d 7.19 and 7.63 ppm due to olefin protons,
HB and HA. The downfield signal was assigned to HA. The coupling constant value
JAB = 15.3 Hz indicated that they possess trans geometry.
1,3-Dipolar cycloaddition of dipolar reagents to dipolarophiles is one of the facile
techniques for the preparation of five-membered heterocycles. The olefin functional
group moiety present in the synthetic intermediate 5 was exploited to synthesize
five-membered heterocycles- pyrroles and pyrazoles. The reaction of compound 5
123

G. Lavanya et al.
O
O
O
Ar
O
S
ii
i
S
Ar
OH
Ar SH
+ OHC
CHO
OH
3
1
4
2
iii
HB
H
A O
O
Ar
Ar
O
S
S
O
H
A
HB
5
a) C H
Ar =
6
5
(i) ClCH2COOH / MeOH / NaOH
(ii) H2O2 / AcOH
(iii) BnNH2 / AcOH
.
b) 4-CH3 C6H4
c) 4-Cl.C6H4
d) 4-OCH3. C6H4
e) 4-OH.C6H4
Scheme 1 Synthesis of 1,4-bis-(arylsulfonylvinyl)benzenes
HB
O
Ar
O
O
O
Ar
H
A O
S
S
Ar
O
O
Ar
3 4
2
3
4
1
N
H
i
S
S
2
5
5
1
O
N
H
H
6
A
HB
5
ii
H
HA
O
O
Ar
A
O
O
Ar
O
Ar
O
O
O
S
S
S
S
Ar
3
4
5
4
3
iii
2
N
5
2
1
1
N
HM
H
N
N
MH
N
X H
N
H
N
H
N
H
HX
8
7
a) C H
b) 4-CH3 C6H4
c) 4-Cl.C6H4
d) 4-OCH3 C6H4
e) 4-OH.C6H4
Ar =
6
5
(i) TosMIC / NaH / Et2O + DMSO
.
(ii) CH2N2 / Et3N / Et2O -20 to -15oC
(iii) Chloranil / xylene
.
Scheme 2 Synthesis of (1,4-phenylene)bis(arylsulfonylpyrroles and pyrazoles)
with tosylmethyl isocyanide (TosMIC) [3] in the presence of sodium hydride in a
solvent mixture of DMSO and ether yielded 1,4-(bis(3-arylsulfonyl)-1H-pyrrol-4-
1
yl)benzene (6) (Scheme 2). In the H NMR spectrum of compound 6a, the singlets
due to C2-H and C5-H of pyrrole ring appeared at downfield region and merged with
aromatic protons. Compound 6a also showed a broad signal at 11.53 ppm belonging
123

Synthesis and antioxidant activity
to NH of pyrrole ring. This signal disappeared upon addition of D2O. On the other
hand, the 1,3-dipolar cycloaddition of ethereal diazomethane (CH2N2) [29] to
compound 5 in the presence of Et3N at -20 to -15 °C produced 1,4-(bis(3-
arylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzene (7). The 1H NMR spectrum of
compound 7a displayed an AMX splitting pattern for methine and methylene
protons of pyrazoline ring. The three double doublets observed at d 4.35, 3.87,
3.32 ppm were assigned to HA, HM, and HX, respectively. The coupling constant
values JAM = 11.4, JMX = 10.6 and JAX = 5.8 Hz indicated that HA, HM are cis,
HA, HX are trans and HM, HX are geminal. In addition to these, a broad singlet was
observed at d 6.63 ppm due to NH, which disappeared on deuteration.
The treatment of compound 7 with chloranil in xylene resulted in aromatized
compound, 1,4-(bis(3-arylsulfonyl)-1H-pyrazol-4-yl)benzene (8) (Scheme 2). The
absence of an AMX splitting pattern due to pyrazoline ring protons in the 1H NMR
spectrum of 8a confirmed its formation. The structures of the compounds were
further confirmed by IR, 13C NMR, mass spectra and microanalyses.
Experimental procedure for antioxidant activity
2,2,-Diphenyl-1-picrylhydrazyl (DPPH) method
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-
picrylhydrazyl (DPPH) [30, 31]. This property makes it suitable for spectropho-
tometric studies. One milliliter 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 temperature, 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
Â
Ã
I % ¼ ðAcontrol ꢁ AsampleÞ=Ablank ꢂ 100
where Acontrol was the absorbance of the control reaction (containing methanolic
DPPH and ascorbic acid), Asample was the absorbance of the test compound (con-
taining methanolic DPPH and test compound) and Ablank was the absorbance of the
blank (containing only methanolic DPPH). Tests were carried out in triplicate.
The IC50 was calculated by the following equation
IC50 in lgmlꢁ1 ¼ 50 ꢂ 100=% Inhibition
50 lM ¼ % of the IC50=M:Wt: of the compound:
Nitric oxide (NO) method
Nitric oxide scavenging activity was measured by slightly modified methods of
Green et al. and Marcocci et al. [32, 33]. Nitric oxide radicals (NO) were generated
from sodium nitroprusside. One milliliter of sodium nitroprusside (10 mm) and
123

G. Lavanya et al.
1.5 ml of phosphate buffer saline (0.2 M, pH 7.4) were added to different
concentrations (50, 75, and 100 lg/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 of Griess reagent (1 % sulfanilamide, 2 % H3PO4 and 0.1 % naphthylethylene-
diamine dihydrochloride). The absorbance of the chromophore was measured at
546 nm. Ascorbic acid was used as the standard. Nitric oxide scavenging activity
was calculated by the following equation
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.
Hydrogen peroxide (H2O2) method
The H2O2 scavenging ability of the test compound was determined according to the
method of Ruch et al. [34]. A solution of H2O2 (40 mm) was prepared in phosphate
Table 1 The in vitro
Compound
Concentration (lg/ml)
antioxidant activity of
compounds 5a–e to 8a–e in
DPPH method
50
75
100
5a
59.23 0.40
67.40 0.25
47.90 0.66
69.23 0.23
68.61 0.24
50.11 0.60
55.66 0.48
45.46 0.71
63.50 0.35
62.11 0.38
42.13 0.79
43.85 0.75
41.78 0.86
49.54 0.63
48.73 0.62
52.92 0.54
57.54 0.44
46.53 0.69
65.14 0.29
63.84 0.32
61.44 0.37
–
61.36 0.31
69.54 0.21
49.51 0.62
71.35 0.17
70.41 0.15
51.53 0.56
57.90 0.43
46.93 0.67
66.69 0.27
64.69 0.32
44.95 0.65
46.12 0.68
44.18 0.61
50.13 0.59
49.86 0.62
56.10 0.47
59.55 0.42
47.03 0.68
67.32 0.25
66.75 0.28
64.66 0.29
–
63.98 0.33
71.43 0.17
52.65 0.54
72.86 0.16
71.92 0.18
55.16 0.48
58.04 0.41
48.82 0.64
68.93 0.26
66.04 0.29
48.20 0.67
49.46 0.62
47.85 0.66
51.97 0.56
52.10 0.54
57.23 0.42
61.52 0.35
51.18 0.55
69.41 0.22
69.71 0.25
66.05 0.26
–
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
– showed no scavenging
activity. Values were the means
of three replicates SD
Ascorbic acid
Blank
123

Synthesis and antioxidant activity
buffer (pH 7.4); 50-, 75-, and 100-lg/ml concentrations of the test compounds in
3.4 ml phosphate buffer were added to H2O2 solution (0.6 ml, 40 mm). The
absorbance value of the reaction mixture was recorded at 230 nm. The percent of
scavenging of H2O2 was calculated by the following equation
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.
Antioxidant activity
The compounds 5a–e to 8a–e were tested for antioxidant properties by DPPH, NO,
and H2O2 methods at three different concentrations 50, 75, and 100 lg ml-1. The
observed data on the antioxidant activity of the compounds and control drug are
shown in Tables 1, 2, 3, 4. Amongst all the tested compounds, 1,4-bis((E)-2-(p-
methoxyphenylsulfonyl)vinyl)benzene (5d) was found to be the most potential
Table 2 The IC50 of the
compounds 5a–e to 8a–e in
DPPH method
Compound
Concentration
50 (lmol ml-1
)
5a
0.1028 0.0018
0.0845 0.0020
0.1088 0.0011
0.0767 0.0019
0.0819 0.0020
0.1021 0.0012
0.0869 0.0013
0.0986 0.0008
0.0717 0.0016
0.0773 0.0016
0.1199 0.0010
0.1090 0.0011
0.1061 0.0009
0.0909 0.0010
0.0974 0.0010
0.0963 0.0013
0.0837 0.0013
0.0960 0.0009
0.0696 0.0015
0.0749 0.0015
0.2310 0.0065
–
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
– showed no scavenging
activity. Values were the means
of three replicates SD
Ascorbic acid
Blank
123

G. Lavanya et al.
antioxidant agent. This may be due to effective conjugation. On the other hand, 1,4-
(bis(3-arylsulfonyl)-1H-pyrrol-4-yl)benzenes 6a–e and 1,4-(bis(3-arylsulfonyl)-1H-
pyrazol-4-yl)benzenes 8a–e exhibited better antioxidant activity than 1,4-(bis(3-
arylsulfonyl)-4,5-dihydro-(1H-pyrazol-4-yl))benzenes 7a–e. It was also inferred that
those having methyl, methoxy, and hydroxy substituents on the aromatic ring
showed higher activity than the other substituents, which may due to ?I effect and
?M effect. This was evidenced that the compounds 5b, 5d, 5e, 8d, and 8e showed
excellent radical scavenging activity in all the three methods evaluated when
compared with the standard ascorbic acid. Furthermore, it was perceived that the
compounds, 5a, 6b, 6d, 6e, and 8b exhibited good activity whereas 7a–e displayed
the least activity. Among the aromatized compounds, 8a–e displayed slightly higher
activity than 6a–e. In general, it was noticed that electron-donating groups enhances
the activity. The IC50 value of the standard drug ascorbic acid in DPPH method was
found to be 40.69 lg ml-1 at 50 lg ml-1 whereas IC50 values of the compounds
5b, 5d, 5e, 8d, and 8e were found to be 37.09, 36.11, 36.43, 38.37, and
39.16 lg ml-1, respectively (Table 2). It was also observed that radical scavenging
activity increases with growing in concentration in all the three methods.
Table 3 The in vitro
Compound
Concentration (lg/ml)
antioxidant activity of
compounds 5a–e to 8a–e in NO
method
50
75
100
5a
67.04 0.25
76.71 0.11
60.93 0.31
79.54 0.08
77.12 0.10
62.71 0.29
65.73 0.27
58.15 0.34
68.16 0.14
67.78 0.24
49.12 0.63
53.80 0.49
45.26 0.65
57.53 0.43
54.34 0.48
64.15 0.28
66.48 0.26
60.13 0.32
74.58 0.12
72.63 0.15
69.21 0.21
–
68.24 0.24
77.34 0.10
62.13 0.39
80.45 0.06
78.76 0.09
63.14 0.30
66.47 0.26
60.09 0.32
72.61 0.14
69.82 0.23
50.97 0.42
55.82 0.37
47.12 0.66
59.56 0.33
56.71 0.36
65.36 0.27
67.52 0.25
61.68 0.34
75.89 0.13
73.92 0.15
72.60 0.16
–
71.69 0.17
79.74 0.06
64.61 0.30
84.53 0.04
80.15 0.07
66.83 0.28
70.02 0.19
61.89 0.32
74.05 0.12
72.94 0.16
51.72 0.54
55.64 0.58
48.38 0.62
60.25 0.40
58.92 0.42
67.58 0.25
70.74 0.18
63.86 0.31
77.38 0.10
75.63 0.13
74.51 0.15
–
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
– showed no scavenging
activity. Values were the means
of three replicates SD
Ascorbic acid
Blank
123

Synthesis and antioxidant activity
Table 4 The in vitro
antioxidant activity of
compounds 5a–e to 8a–e in
H2O2 method
Compound
Concentration (lg/ml)
50
75
100
5a
65.41 0.29
74.60 0.13
59.63 0.39
77.75 0.10
75.45 0.13
60.09 0.38
63.90 0.32
57.54 0.42
68.47 0.24
66.81 0.27
50.44 0.53
51.56 0.49
48.12 0.56
54.18 0.45
53.71 0.48
62.54 0.34
64.76 0.30
58.16 0.41
74.15 0.12
71.52 0.17
67.86 0.25
–
66.68 0.26
76.96 0.10
61.34 0.37
78.08 0.09
77.54 0.10
62.21 0.36
64.15 0.31
59.13 0.40
71.96 0.17
68.75 0.26
51.27 0.52
53.96 0.51
60.34 0.53
56.26 0.47
55.81 0.45
63.74 0.32
65.02 0.30
59.54 0.39
76.05 0.11
73.78 0.16
69.13 0.19
–
68.56 0.27
79.47 0.08
63.38 0.33
80.58 0.06
79.65 0.08
64.32 0.31
66.14 0.27
61.75 0.36
75.84 0.16
74.93 0.28
53.58 0.49
55.14 0.48
52.45 0.51
58.42 0.41
57.38 0.42
65.08 0.30
66.91 0.26
62.11 0.34
78.85 0.09
75.61 0.13
71.34 0.17
–
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
– showed no scavenging
activity. Values were the means
of three replicates SD
Ascorbic acid
Blank
Conclusions
The Michael acceptor 1,4-bis(arylsulfonylvinyl)benzene (5) was exploited to
prepare a new series of (1,4-phenylene)bis(arylsufonylpyrroles) (6) and (1,4-
phenylene)bis(arylsufonyl pyrazoles) (8) adopting simple and versatile 1,3-dipolar
cycloaddition methodology. All the compounds were tested for antioxidant activity.
Amongst the tested compounds, 5d was identified as the potential antioxidant agent.
It was also noticed that electron-donating groups enhanced the antioxidant activity.
Acknowledgments The authors, G. Lavanya, T. Bhanu Prakash, and G. Sravya are thankful to
University Grants Commission (UGC), New Delhi, for the sanction of UGC-BSR fellowship. One of the
authors, Dr. A. Padmaja, is grateful to Council of Scientific and Industrial Research (CSIR), New Delhi,
for financial assistance under major research project. The authors are also thankful to Prof. C. H. Appa
Rao, Department of Bio-Chemistry, S.V. University and Tirupati for providing necessary facilities to
carry out the antioxidant activity.
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