A convenient and benign synthesis of sulphonamides in PEG-400

Article abstract of DOI:10.14233/ajchem.2015.16853

A simple and convenient method is reported for the synthesis of a series of sulphonamides in PEG-400 using potassium carbonate as the base. The reaction is carried out in a heterogeneous medium and consequently product recovery is simple. The desired products with a variety of aromatic amines could be synthesized in a short reaction time in good yield. The PEG could be recovered for reuse.

Full text of DOI:10.14233/ajchem.2015.16853

Asian Journal of Chemistry; Vol. 27, No. 1 (2015), 189-191
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2015.16853
A Convenient and Benign Synthesis of Sulphonamides in PEG-400
*
PRANAB JYOTI DAS and BHASKAR SARMAH
Department of Chemistry, Gauhati University, Guwahati-781 014, India
*Corresponding author: E-mail: pjd23@rediffmail.com
Received: 11 December 2013; Accepted: 17 April 2014;
Published online: 26 December 2014;
AJC-16535
A simple and convenient method is reported for the synthesis of a series of sulphonamides in PEG-400 using potassium carbonate as the
base. The reaction is carried out in a heterogeneous medium and consequently product recovery is simple. The desired products with a
variety of aromatic amines could be synthesized in a short reaction time in good yield. The PEG could be recovered for reuse.
Keywords: Sulphonamide, Aromatic amines, Heterogeneous catalysis.
INTRODUCTION
EXPERIMENTAL
Utilizing green solvents in synthesis is very important for
sustainable development. Several reports on the use of PEG-
400 as an alternative to the volatile organic carbons are available.
The low cost, reduced inflammability, reduced toxicity, reduced
environmental risks coupled with good solvating characteristics
of PEG-400 and its high molecular weight variants offers
enormous possibilities. Its use as a versatile green solvent is
spurred by the appearance of several reports in literature notable
among them are catalytic hydrogenation with PtO21, Suzuki
Miyaura cross coupling using Pd(OAc)2 /TBAB/PEG-4002,
conversion of alkyl halides to nitroalkanes3, reduction of
alkynes to cis olefins4, synthesis of 4-hydroxy chalcones5,
Michael addition reaction of αβ-unsaturated carbonyl com-
pounds6, synthesis of 2-amino-4H-chromenes7, metal free
synthesis of amides by direct oxidative amidation of aldehydes
with amines8, synthesis of 1,4 dihydropyridine9 besides others.
Herein, we reported, a simple synthesis of sulphonamides
in PEG-400 using K2CO3 in a heterogeneous reaction. Sulpho-
namides are compounds with important medicinal properties.
They exhibit a broad spectrum of bacteriostatic activity, affec-
ting Gram-positive, Gram-negative and many protozoan
organisms and are commonly used for the treatment of infec-
tions of the central nervous system, respiratory tract, gastro-
intestinal tract and the urinary tract. A variety of sulphona-
mide derivatives have also been synthesized which are potent
diuretics and hypoglycemics10-13. The use of sulphonamides
as veterinary medicine is widespread particularly as mass
medicant for control of diseases in food producing species.
They are also reported to be potent and selective Adenosine
A2B receptor antagonists14.
All aromatic amines, p-toluenesulphonyl chloride and
benzenesulphonyl chloride were purchased from Spectrochem
(India). The amines were purified by standard methods24,
the sulphonylchlorides and the liquid amines were used as
received. Melting points were recorded in open capilliaries
and are not corrected, IR spectra were recorded in Perkin Elmer
1
FT-IR 1600, H NMR spectra recorded in Bruker 300 MHz
FT-NMR using TMS as the internal standard. The suphon-
amides were identified by comparing the m.p., IR, 1H NMR,
13C NMR and the values are in agreement with those reported
in literature.
General procedure sulphonylation of amines in PEG-
400: A mixture of appropriate sulphonylchloride ( 0.01 mol)
and K2CO3 (0.01 M) is taken in 15 mL of PEG- 400 and stirred
for 0.5 h thereafter the temperature increased to 60 °C and
stirred for additional 2 h. To this mixture was added 0.01 mol
of the aromatic amine and the temperature slowly increased
to 120 °C and stirring continued. The progress of the reaction
was monitored by TLC in prepared silica gel plates using pet
ether (60-80) and 5 % EtOAc as the eluent. After completion
of the reaction as indicated by the disappearance of the amine,
the mixture was extracted with ether (50 mL × 3). The
combined ether extract was successively washed with dil HCl
to remove unreacted aniline and with water to remove unreacted
sulphonylchloride, dried over anhydrous Na2SO4 and the
solvent evaporated to obtain the desired products which were
recrystalized from ethanol (95 % v/v). For the investigation of
the probable effect of K2CO3 on the yield of the product,
various weight of the base starting from 0.0005 to 0.002 mol
was screened. Maximum yield was obtained with 1:1 equivalent

190 Das et al.
Asian J. Chem.
of the substrates and the base. Decrease in the quantity of the
base gave low yield and increase in the amount of the base
above 1 equivalent had no effect on the yield. All the known
compounds were characterized by comparing their melting
points with those reported in literature and by recording their
IR, 1H NMR and 13C NMR spectra.
N-Benzyl-p-toluenesulphonamide (entry 11): m.p.
110 °C,Yield 88 % IR in (KBr, νmax, cm-1): 3267 (N-H), 2333
(C-H) , 1323 and 1157 (sulphonamide), 875 (C-N) δH (300
MHz, CDCl3) 2.43 (3H, s, -CH3), 4.09-4.1 (2H, d, -CH2-), 7.18-
7.23 (6Harom, m, N-H merged), 7.74-7.76 (2Harom d), δC (75
MHz) 21.5, 47.16, 127.11, 127.81, 128.6, m 129.69, 136.21,
136.68, 143.47.
Spectral data of selected sulphonamides
N-Phenylbenzenesulphonamide (entry 14): m.p. 100-
102 °C,Yield 78 %, IR in (KBr, νmax, cm-1): 3214 (N-H), 2333
(C-H), 1330 and 1157 (sulphonamide), 910 (C-N) δH (300
MHz, CDCl3) 6.82 (1H, NH), 7.06-7.8 (10H, m,) δC (75 MHz)
121.53, 125.31, 127.19, 129, 129.26, 132.99, 136.38, 138.85.
N-(4-Methoxyphenyl)benzenesulphonamide (entry
15): m.p. 88-90 °C. Yield 88 % IR in (KBr, νmax, cm-1): 3256
(N-H), 2333 (C-H), 1334 and 1157 (sulphonamide), 924
(C-N) δH (300 MHz, CDCl3) 3.75 (3H, s) 6.77 (1H, s, NH),
7.26-7.72 (9H, m,) δC (75 MHz) 55.28, 114.3, 125.17, 127.18,
128.82, 132, 75, 138.72, 157.75.
N-Phenyl-p-toluenesulphonamide (entry 1): m.p. 100
°C,Yield 74 %, IR in (KBr, νmax, cm-1): 3248 (N-H), 1334 and
1153 (sulphonamides), 914 (C-N); δH (300 MHz, CDCl3) 7.05-
7.13 (5Harom, m, C6H5-), 7.21-7.23 (2Harom, m, CH3-C6H4-), 64-
7.67 (2Harom, m, CH3-C6H4), 6.83 (1H, NH), 2.18-2.47 (3H, s,
-CH3), δC (75 MHz) 21.56, 121.33, 125.14, 127.3, 129.29,
129.69, 135.9, 136.65, 143.91.
N-(4-Methylphenyl)-p-toluenesulphonamide (entry 2):
m.p. 116-118 °C, yield 80 %, IR in (KBr, νmax, cm-1): 3278
(N-H), 1319 and 1157 (sulphonamides), 914 (C-N); δH (300
MHz, CDCl3) 7.63-7.61 (4Harom, d,), 7.02-7.23 (2Harom, d,),
6.93-6.95 (2Harom, d), 6.55 (s,N-H), 2.38 (s, 3H, -CH3), 2.17
(s, 3H, -CH3), δC (75 MHz) 20.93, 21.63, 122.49, 127.35,
129.66, 129.93, 133.75, 135.55, 136.18, 143.8.
N-(4-Nitrophenyl)benzenesulphonamide (entry 18):
m.p. 128-130 °C. Yield 82 % IR in (KBr, νmax, cm-1): 3329
(N-H)., 1342 and 1157 (sulphonamide), 1519 and 1342 (-NO2)
δH (300 MHz, CDCl3) 7.25-7.29 (2Harom, d), 7.53-7.62 (2Harom,
q), 7.84-7.86 (2Harom, d), 8.07-8.1 (2Harom, d) δC (75 MHz)
118.3, 125.62, 127.04, 129.9, 133.94, 139.08, 142.9, 144.34.
N-(3-Bromophenyl)-p-toluenesulphonamide (entry 3):
m.p.119-21 °C, yield 72 %, IR in (KBr, νmax, cm-1): 3244
(N-H), 1338 and 1153 (sulphonamides), 916 (C-N), 667
(C-Br); δH (300 MHz, CDCl3) 2.40 (3H, s, CH3), 6.59 (1H, s,
N-H), 7.03-7.13 (4Harom, m,), 7.24 (2Harom, s) 7.68 (2Harom, d)
δC (75 MHz) 21.54, 119.32, 122.75, 123.71, 127.21, 128.07,
129.81, 130.55, 135.6, 137.93, 144.28.
RESULTS AND DISCUSSION
In view of their diverse applications, the synthesis of
sulphonamides have assumed importance. There are a variety
of methods available for the synthesis notable among them
are conversion of alcohols to tosylamides15, use of MnO2 under
solvent free condition16, Pd-catalyzed cross-coupling of
methanesulfonamide with aryl bromides17. The arylation of
NH and OH containing compounds at room temperature with
phenylboronic acids18. Selective conversion of benzylic
hydrocarbons to sulfonamides by Cu(CH3CN)4]PF6 catalyzed
reaction with anhydrous TolSO2NNaCl19 and A Zn/CuI-
mediated coupling of alkyl halides with vinylsulfones20, Horner
reaction of aldehydes and diphenylphosphorylmethane-
sulfonamide21 and N-heterocyclization reactions of primary
amines22.
N-(4-Methylphenyl)-p-toluenesulphonamide (entry 5):
m.p. 106 °C. Yield 84 %. IR (KBr, νmax, cm-1): 3275 (N-H),
1330 and 1157 (sulphonamide), 902 (C-N), δH (300 MHz,
CDCl3) 1.96-2.03 (3H, d, -CH3), 2.39-2.43 (3H, d, -CH3), 6.35
(1H, s, N-H), 7.59-7.62 (2Harom, d,), 7.30-7.33 (2Harom, d), 7.17-
7.23 (1Harom, m), 7.14-7.15 (1Harom, d), 7.14-7.11 (1H, d) 7.07-
7.08 (1Harom, d), δC (75 MHz) 17.52, 21.41, 124.31, 126.01,
126.66, 126.98, 129.46, 130.64, 131.57, 134.37, 136.53,
143.62.
N-(2-Chlorophenyl)-p-toluenesulphonamide (entry 6):
m.p. 104 °C. Yield 85 % IR in (KBr, νmax, cm-1): 3259 (N-H),
2357 (Aromatic C-H), 1392 and 1161 (sulphonamide), 898
(C-N), 817 (C-Cl), δH ( 300 MHz, CDCl3) 6.99 (N-H), 2.37-
2.47 (3H, d, -CH3), 7.0-7.06 ( 2Harom, m,) 7.2-7.26 (4Harom, m.)
7.63-7.67 (2Harom, m) δC (75 MHz) 21.49, 122.3, 125.01, 125,
79, 127.15, 127.77, 129.28, 129.58, 133.33, 135.7, 144.15.
N-(4-Methoxyphenyl)-p-toluenesulphonamide (entry
7): m.p. 112 °C, Yield 80 % IR in (KBr, νmax, cm-1): 3267 (N-
H), 1249 and 1026 (Ar-OCH3), 1396 and 1157 (sulphonamide),
906 ( C-N) δH (300 MHz, CDCl3) 2.36 (3H,s, -CH3), 3.73 (3H,
s, -OCH3), 6.97 (1H, s, N-H), 6.72-6.75 (2Harom, m) 6.98-7.01
(2Harom, m), 7.18-7.21 (2Harom, m), 7.59-7.62 (2Harom, m) δC
(75 MHz) 21.48 (CH3), 55.33 (OCH3), 114.29, 125.17, 127.25,
128.91, 129.49, 135.78, 143.61, 157.71.
However, almost all the methods use costly reagents,
organic solvents and some require heavy metals and complex
salts as catalyst and are often not environment friendly. In
search for effective green methodologies in organic synthesis,
it is observed that sulphonamides can be synthesized by a
reaction of an amine and suitable sulphonylchloride in a green
solvent namely PEG-400 under heterogeneous condition using
K2CO3 as the base. The procedure precludes the use of VOCs
and being heterogeneous, products recovery is simple. The
best operative experimental condition involves mixing p-
toluenesulphonylchloride or benzenesulphonyl- chloride (0.02
mole) and 0.01 mol of K2CO3 in 15 mL of PEG-400. The
mixture is preheated in an oil bath to 60 °C. To this mixture
was added 0.01 mol of the aromatic amine and the temperature
was slowly increased to 120 °C with stirring.After completion
of the reaction, the mixture was extracted with diethyl ether.
The ether layer was washed with dil. HCl to remove any trace
of amine followed by washing with demineralized water to
N-(4-Carboxyphenyl)-p-toluenesulphonamide (entry
9), m.p. 231 °C, Yield 80 % IR in (KBr, νmax, cm-1): δH (300
MHz, CDCl3) 2.48 (3H, s, -CH3), 7.14-7.17 (2Harom, d), 7.32-
7.35 (2H d), 7.66-7.69 (2Harom, d,), 7.75-7.77 (2H, d, merged
N-H) 10.8 1H, s, -COOH) δC (75 MHz) 21.14, 118.16, 125.62,
126.93, 130.05, 130.93, 136.45, 142.21, 143.93, 166.97

Vol. 27, No. 1 (2015)
A Convenient and Benign Synthesis of Sulphonamides in PEG-400 191
TABLE-1
PHYSICAL CHARACTERISTICS OF SULPHONAMIDES OBTAINED FROM VARIOUS AMINES
m.p. (oC)
Entry
Amine
Sulphonamide
Observed
102
Literature23
1
2
Aniline
N-Phenyl-p-toluenesulphonamide
103
p-Toluidine
N-(4-Methylphenyl)-p-toluenesulphonamide
N-(3-Bromophenyl)-p-toluenesulphonamide
N-(2-Carboxyphenyl)-p-toluenesulphonamide
N-( 2-Methylphenyl)-p-toluenesulphonamide
N-(2-Chlorophenyl)-p-toluenesulphonamide
N-(4-Methoxyphenyl)-p-toluenesulphonamide
N-(2-Naphthyl)-p-toluenesulphonamide
N-(4-Carboxyphenyl)-p-toluenesulphonamide
1,2-bis-(p-Toluenesulphonamido)benzene
N-Benzyl-p-toluenesulphonamide
115-116
118-20
225-228
106
116-117
122-125
227-29
109
3
3-Bromoaniline
Anthranilic acid
o-Toluidine
4
5
6
2-Chloroaniline
p-Anisidine
104
105
7
112
114
8
2-Aminonaphthalene
4-Aminobenzoic acid
o-Phenylenediamine
Benzylamine
132
133
9
231-232
201
235
10
11
12
13
14
15
16
17
18
201
108-10
158
116
Ethylenediamine
Benzidine
1,2-bis-(p-Toluenesulphonamido)ethylene
4.4-(bis-p-Toluenesulphonamido)benzidine
N-Phenylbenzenesulphonamide
160
242
243
Aniline
101
100-102
88-89
127
p-Anisidine
N-(4-Methoxyphenyl)benzenesulphonamide
N-(2-Bromophenyl)benzenesulphonamide
N-(2-Chlorophenyl)benzenesulphonamide
N-(4-Nitrophenyl)benzenesulphonamide
86-89
126-128
128-130
128-130
2-Bromoaniline
2-Chloroaniline
4-Nitroaniline
131
130
*p-Toluenesulphonylchloride used for entry 1-13 benzenesulphonylchloride used entry 14-18
remove unreacted sulphonylchloride. Ether layer was sepa-
rated, dried with anhydrous Na2SO4, filtered and solvent evapo-
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NH2
K2CO3/ PEG-400
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R
X= H, Cl, Br, OCH3, CH3, -COOH,, -SO3H , NO2
R= H, CH3
Scheme-I
Conclusion
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ACKNOWLEDGEMENTS
One of the authors (Bhaskar Sarmah), is grateful to University
Grants Commission, New Delhi, for financial assistance in
the form of Research fellowship under Major Research project.