Synthesis of Some Sulfonamide Chalcones of Biological Interest

International Journal of Chemical and Physical Sciences, ISSN:2319-6602
IJCPS Vol. 4 Special Issue – NCSC Jan-2015

www.ijcps.org
Synthesis of Some Sulfonamide Chalcones of Biological Interest

S. P. BAHEKAR, P. B. SARODE, N. R. AGRAWAL AND H. S. CHANDAK
Department of Chemistry, G. S. Science, Arts and Commerce College, Khamgaon 444303, India
Corresponding author: [email protected]
Abstract
Sulfonamide compounds, identified as chemotherapeutic agents, possess broad spectrum

of biological properties. Benzenesulfonamides substituted on N of sulfonamido group
such as, sulfathiazole, sulfapyridine, sulfadiazine etc are known to possess broad
spectrum of biological properties. This work reported the synthesis of series of N-[4-
cinnamoylphenyl]-4-methylsulfonamide by Claisen-Schmidt condensation of N-(4-
acetylphenyl)-4-methylbenzenesulfonamide with aromatic aldehydes in presence of 40%
NaOH in ethanol at room temperature with higher yields
.
Keywords: Tolyl sulfonamides, chalcones, Claisen-Schmidt condensation
Introduction
Chalcones, 1,3-diphenylpropenones are precursor of flavonoids and isoflavonoids, abundantly present in
edible plants like vegeTables, fruits, tea and soy, and are essential secondary metabolites in many plants
and in bacteria. Since, easy availability of this potent tool naturally as well as synthetically, biological
studies has been done by many research groups to display potent array of pharmacological activities such
as anti-protozoal, anti-inflammatory, immuno-modulatory, nitric oxide inhibitory, anticancer, anticancer
effects and anti-HIV activities.
Sulfonamide compounds, identified as chemotherapeutic agents, possess broad spectrum of biological
properties. Benzenesulfonamides substituted on N of sulfonamido group such as, sulphathiazole,
sulphapyridine, sulphadiazine etc is known to possess broad spectrum of biological properties
Sulphonamides with various heterocyclic rings like pyrazole, isoxazole, furanone ring constitute the
present day anti-inflammatory drug such as Rofecoxib, Celecoxib and Valdecoxib. Recently,
Introduction of sulfonamide group into chalcone scaffold also proves potent tool for the designing of
even more potent biological value such as α-glucosidase inhibitors, selective TcTS inhibitors.
Chalcones are usually synthesized from acetophenones and benzaldehydes via the Claisen-Schmidt
condensation, using base in a polar solvent. The use of several other catalysts such as KOH, basic
alumina, zinc chloride, Lewis acid such as BF3, AlCl3, Mg-Al-OBu hydrotalcite, has also been reported.
Other reagents and conditions have also been used, including the use of strong alkali catalysts under
phase transfer conditions, barium hydroxide in ethanol, calcine NaNO3/natural phosphate, potassium
phosphate, the use of M.W. conditions, and ultrasonic conditions. Withers et al reported synthesis of
Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -99 -

N. R. AGRAWAL, H. S. CHANDAK
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hydroxyl derivatives of sulfonamide Chalcones utizing H2SO4 in Methanol under reflux conditions.
However harsh reaction conditions with conventional heating needs further improvement in the synthetic
strategies.
So, here we report the simple, effective protocol for the synthesis of sulfonamide Chalcones using 40%
NaOH in Ethanol at room temperature, depriving the use of harsh reaction conditions altogether with
conventional heating procedures.
Results and Discussions
To include the sulfonamide moiety in the destined motif, we prepared starting ketone by condensation of
4-aminoacetophenone and toulenesulfonic chloride in the presence of pyridine.
Later on by utilizing different aromatic aldehydes with this starting ketone, we accessed a series of
substituted chalcone (3a-3n) with better yields (Scheme 1).
Scheme 1: Synthetic strategy of Substituted Chalcones

By utilizing optimized reaction conditions, we further improves the scope of this protocol by synthesizing
the series of tolyl sulfonamide chalcone derivcatives (Table 1).
Synthesized compounds were characterized by combined application of IR, 1H NMR, 13C NMR and Mass
spectroscopy. The IR spectra of the compounds showed sharp band around 1650 cm-l respectively due to
C - O stretch whereas two peaks observed around 1330 & 1160 cm-1 observed for symmetric &
asymmetric stretching of SO2 group 1H NMR spectra of the compounds revealed the presence of singlet
at δ 2.32 of tolyl methyl protons. Another singlet for NH proton much downfield around δ 10 is also
observed, while CH=CH protons deshielded with aromatic protons in the range of δ 7-8. Mass spectra of
the compounds showed molecular ion peak at their respective values.
Experimental
All solvents and chemicals were obtained commercially and were used as received. Melting points were
determined in an open capillary and are uncorrected. IR spectra were recorded using a Spectrum-60
spectrometer instrument. NMR spectra were taken with a Bruker Avance II at 400 MHz / Bruker DMX
spectrometer at 500 MHz (1H) and 125 MHz (13C) using CDCl3 or DMSO-d6 as the solvent with TMS as
internal standard.

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Table 1: Derivatization and Physical Data of Tolyl Sulfonamide Chalcone

Entry R Yielda (%) m.p (°C)
3a Ph 92 150-152
3b 4-OMe 89 155-157
3c 4-Cl 90 181-182
3d 2-Cl 87 184-185
3e 4-F 85 185-187
3f 3-Br 80 228-230
3g 4-Br 85 190-191
3h 4-NMe2 74 165-166
3i 4-NO2 85 240-242
3j 4-CH(CH3)3 94 105-106
3k 4-Me 89 209-210
3k 3-Cl 87 187-188
3l 2-Br 80 208-210
3m 2-furyl 75 138-140
3n 3,4,5-OMe 81 195-196
Isolated pure yield
General procedure for the synthesis of N-(4-acetylphenyl)-4-methylbenzenesulfonamide (1)

To a solution of 4-aminoacetophenone (0.025 mol) and Toulene Sulfonic chloride (0.025 mol) in ethanol,
pyridine (0.025 mol) was added dropwise with constant stirring. The solid cake was obtained after 1 hr of
constant stirring at room temperature. Completion of reaction is checked over precoated TLC (30%
EtOAc:Hexane). Then it is quenched with excess of acidified water. The solid obtained was filtered,
washed with 2% NaHCO3 dried. Crude solid obtained is recrystallised in EtOH:H2O (1:1) to get pure
solid.
General procedure for the synthesis of substituted Chalcones
To a solution of 1(0.025 mol) and aromatic aldehyde (0.025 mol) in ethanol, aqueous NaOH (40%) was
added dropwise with constant stirring till solid cake was obtained. Constant stirring continued for 20-
30min at room temperature and then the reaction mass kept as it is for overnight. Completion of reaction
is checked over precoated TLC (30% EtOAc:Hexane). Then it is quenched with excess of acidified water.
The solid obtained was filtered, washed with 2% NaHCO3 dried & recrystallized from ethanol.
Analytical data of some new compounds are given below.

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N-(4-acetylphenyl)-4-methylbenzenesulfonamide (1)
Yellow solid; yield 90%, Rf 0.5 (30% EtOAc:Hexane), mp 190-192°C
IR: 3219 (NH), 1649(C=O) cm-1
1
H NMR (500 MHz, CDCl3) δppm: 2.32 (s, 3H, -CH3Ph), 2.50 (s, 3H, -COCH3), 7.18-7.83 (m, 8H, Ar-
H), 10.81 (s, 1H, -NH).
13
C NMR (100MHz, CDCl3): 21.5, 27.0, 116.8, 128.9, 129.2, 129.7, 130.4, 137.0, 137.5, 143.1, 196.9
ESMS (m/z) [M+Na]+ : 512.0925 (Calcd. 289.0773)
N-(4-cinnamoylphenyl)-4-methylbenzenesulfonamide (3a)
Pale Yellow solid; yield 92%, Rf 0.6 (30% EtOAc:Hexane), mp 150-152°C
IR: 3219 (NH), 1649(C=O), 1336 & 1163 (SO2 asymm. & unsymm.) cm-1
1
H NMR (500 MHz, CDCl3) δppm: 2.43(s, 3H, -CH3Ph), 7.27-8.77 (m, 14H, Ar-H, CH=CH), 10.80 (s,
1H, NH)
13
C NMR (100 MHz, CDCl3): 25.8, 115.1, 116.0, 123.3, 126.5, 128.8, 129.6, 131.0, 131.8, 132.1, 138.0,
138.9, 143.4, 149.2, 168.1, 189.7.
ESMS (m/z) [M+H]+ : 378.1226 (Calcd. 377.1086).
N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)-4-methylbenzenesulfonamide (3b)
Yellow solid; yield 89%, Rf 0.56 (30% EtOAc:Hexane), mp 155-157°C
IR: 3180 (NH), 1666 (C=O), 1359 & 1170 (SO2 asymm. & unsymm.) cm-1
1
1H, NH)
13
C NMR (100 MHz, CDCl3): 23.0, 115.9, 117.0, 123.5, 126.4, 129.0, 129.9, 131.3, 131.8, 132.1, 138.0,
139.0, 143.4, 148.2, 169.1, 189.0.
ESMS (m/z) [M+H]+ : 408.1300 (Calcd. 407.1191).
N-(4-(3-(4-chlorophenyl)acryloyl)phenyl)-4-methylbenzenesulfonamide (3d)
1
1H, NH)
13
C NMR (100 MHz, CDCl3) : 21.9, 115.3, 118.3, 122.1, 127.2, 128.1, 129.8, 131.2, 131.6, 132.8, 138.0,
138.7, 143.5, 147.2, 164.0, 190.0.
ESMS (m/z) [M+H]+ : 413.390 (Calcd. 411.0696)
N-(4-(3-(4-fluorophenyl)acryloyl)phenyl)-4-methylbenzenesulfonamide (3e)

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1
H NMR (500 MHz, CDCl3) δppm: 2.45(s, 3H, -CH3Ph), 7.2-8.8 (m, 14H, Ar-H, CH=CH), 10.9 (s, 1H,
NH)
13
C NMR (100 MHz, CDCl3): 22.2, 115.5, 117.1, 122.5, 127.0, 128.1, 129.0, 131.0, 131.3, 132.4, 137.9,
138.7, 143.8, 146.2, 164.5, 190.1.
ESMS (m/z) [M+H]+ : 396.111 (Calcd. 395.091).
N-(4-(3-(4-bromophenyl)acryloyl)phenyl)-4-methylbenzenesulfonamide (3g)
1
H NMR (500 MHz, CDCl3) δppm: 2.5(s, 3H, -CH3Ph), 7.17-8.7 (m, 14H, Ar-H, CH=CH), 10.82 (s, 1H,
NH)
13
C NMR (100 MHz, CDCl3): 23.2, 115.1, 116.9, 122.3, 126.5, 128.8, 129.6, 131.3, 131.8, 132.1, 138.0,
138.9, 143.4, 147.2, 166.1, 189.6.
ESMS (m/z) [M+H]+ : 457.518 (Calcd. 455.0191)
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International Journal of Chemical and Physical Sciences, ISSN:2319-6602

IJCPS Vol. 4 Special Issue – NCSC Jan-2015

Synthesis of Some Sulfonamide Chalcones of Biological Interest

Sulfonamide compounds, identified as chemotherapeutic agents, possess broad spectrum

Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -99 -

Scheme 1: Synthetic strategy of Substituted Chalcones

Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -100 -

Table 1: Derivatization and Physical Data of Tolyl Sulfonamide Chalcone

General procedure for the synthesis of N-(4-acetylphenyl)-4-methylbenzenesulfonamide (1)

Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -101 -

Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -102 -

Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -103 -

Synthesis of Some Sulfonamide Chalcones of Biological Interest S. P. BAHEKAR, P. B. SARODE, -104 -

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