Ionic liquid enabled sulfamoylation of arenes: An ambient, expeditious and regioselective protocol for aryl sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2003.12.132

The ionic liquid, 1-butyl-3-methylimidazolium chloroaluminate, [bmim]Cl·AlCl₃, N=0.67 mediated syntheses of aromatic sulfonamides via electrophilic substitution of arenes is reported. The protocol serves as a distinctly expeditious and ambient route towards the syntheses of these pharmaceutically useful compounds, yielding quantitative conversions at room temperature within 5-30min in most of the cases. The Lewis acidity and molar stoichiometry of the ionic liquid influences the extent of conversion. The method has been used for the syntheses of a diverse range of sulfonamides by variation of arenes and sulfamoyl chlorides. With monosubstituted benzenes, the protocol offers an added advantage of exclusive selectivity towards the formation of para substituted sulfonamides over the ortho products.

Full text of DOI:10.1016/j.tetlet.2003.12.132

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1933–1936
Ionic liquid enabled sulfamoylation of arenes: an ambient,
expeditious and regioselective protocol for aryl sulfonamides
Prashant U. Naik, Jitendra R. Harjani, Susheel J. Nara and Manikrao M. Salunkhe*
Department of Chemistry, The Institute of Science, 15-Madam Cama Road, Mumbai 400-032, India
Received 10 October 2003; revised 17 December 2003; accepted 23 December 2003
Abstract—The ionic liquid, 1-butyl-3-methylimidazolium chloroaluminate, [bmim]ClꢀAlCl3, N ¼ 0:67 mediated syntheses of aro-
matic sulfonamides via electrophilic substitution of arenes is reported. The protocol serves as a distinctly expeditious and ambient
route towards the syntheses of these pharmaceutically useful compounds, yielding quantitative conversions at room temperature
within 5–30 min in most of the cases. The Lewis acidity and molar stoichiometry of the ionic liquid influences the extent of con-
version. The method has been used for the syntheses of a diverse range of sulfonamides by variation of arenes and sulfamoyl
chlorides. With monosubstituted benzenes, the protocol offers an added advantage of exclusive selectivity towards the formation of
para substituted sulfonamides over the ortho products.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The utility of ionic liquids in catalysis and as neoteric
solvents for various synthetic processes is now well
recognised by chemists all over the world. The remark-
able attributes possessed by them such as non-volatility,
recyclability, thermal stability, diverse solvating ability
and tunability have made them popular as environ-
mentally benign counterparts to conventional reaction
media.1 The fact that the other ionic liquid-specific
properties2 such as Lewis acidity, viscosity, density,
hydrophobicity, hydrophilicity, etc. can be tailored, has
provided an enormous scope for innovation in the area
of solvent engineering.
used as environmentally benign alternatives. This fea-
ture of chloroaluminates demands that they must be
handled with exclusion of moisture-laden atmospheres,
usually in a glove box. Despite these disadvantages, the
chloroaluminates are often a preferred choice, firstly
owing to their diverse solvating ability and variable
Lewis acidity, which in an ensemble provides a tunable
Lewis acidic medium for execution of reactions in a
homogenous phase. Secondly, in certain reactions this
conglomerate of properties has demonstrated a pro-
found positive effect on the yield4 or rate5 or selectivity6
of the reaction, when compared with the prototypical
procedures.
The realm of these unconventional reaction media began
with molten salt chemistry, which subsequently evolved
into the ambient temperature ionic liquids very fre-
quently referred to as organoaluminates or chloroalu-
minate ionic liquids. This interesting class of liquids not
only served the purpose of reaction media, but also
acted as the catalyst3 in Lewis acid mediated reactions.
The major setback in their development and widespread
acceptance is their water sensitive nature. Furthermore,
a product of their reaction with water is corrosive HCl,
which destroys the very purpose of these liquids being
Over the past three years, we have been engaged in
exploring newer reactions in chloroaluminate ionic liq-
uids7 with emphasis on those reactions where their
employment is aptly warranted.5;8 To this end, we herein
report the sulfamoylation of arenes with N,N-dialk-
ylsulfamoyl chloride (Scheme 1) in Lewis acidic 1-
butyl-3-methylimidazolium chloroaluminate, [bmim]Clꢀ
AlCl3, 0:50 < N 6 0:67 ionic liquid (N is the apparent
O
S
O
S
R
R
[bmim]Cl.AlCl3
0.67
Ar
N
Cl
N
Ar-H
+
N
R'
0.50
O
Keywords: Arene; Sulfamoyl chloride; Ionic liquid; Sufamoylation;
N,N-Dialkylsulfonamide.
R'
O
Scheme 1. Sulfamoylation of arenes in [bmim]ClꢀAlCl3, N ¼ 0:50–
* Corresponding author. Tel./fax: +91-22-22816750; e-mail: mmsalun-
khe@hotmail.com
0.67.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.132

1934
P. U. Naik et al. / Tetrahedron Letters 45 (2004) 1933–1936
Table 1. The effect of molar stoichiometry of [bmim]ClꢀAlCl3,
N ¼ 0:67 on the extent of conversion in the sulfamoylation of benzene
with piperidylsulfamoyl chloridea
mole fraction of AlCl3 in the liquid). Aromatic sulfon-
amides are of considerable importance owing to their
bioactive nature. Compounds possessing this function-
ality have great potential as pharmaceuticals and over
30 drugs containing this moiety are presently in clinical
use as antibacterials, diuretics, anticonvulsants,
hypoglycemics and HIV protease inhibitors.9 The con-
ventional methods for synthesising N,N-dialkyl-
sulfonamides includes chlorosulfonylation of arenes
followed by the condensation of arylsulfonyl chloride
with N,N-dialkylamine.10 Besides these, other methods
include, alkylation of sulfonamides with an alkyl halide,11
oxidation of sulfonamides,12 substitution of N,N-di-
chlorosulfonamide,13 reaction of sulfinyl halides with
hydroxylamine derivatives14 and reaction of trialkylar-
ylstannanes with sulfonyl isocyanates.15 The electro-
philic substitution of arenes with N,N-dialkylsulfamoyl
chloride has not been investigated in great detail except
Molar equivalents of
Percentage conversionb
[bmim]ClꢀAlCl3, N ¼ 0:67
0.24
0.48
0.72
1.00
22
48
75
96
a Reactions performed at rt for 30 min.
b Conversions monitored by HPLC.19
Table 2. The effect of the Lewis acidity of [bmim]ClꢀAlCl3, N ¼ 0:50–
0.67 on the extent of conversion in the sulfamoylation of benzene with
piperidylsulfamoyl chloridea
Mole fraction of AlCl3 in the
ionic liquid (N)
Percentage conversionb
for AlCl3 and metal triflate17 mediated sulfamoylation.
16
0.56
0.59
0.63
0.67
20
53
72
96
Yet another strategy for N,N-dialkylsulfonamide syn-
thesis utilises the thia-Fries rearrangement of O-sulfa-
mates to hydroxyl sulfonamides.18 These reported
protocols suffer from the disadvantage of both longer
reaction times and high temperatures. For instance, in
the AlCl3 catalysed reactions, temperatures in the range
of 70–80 ꢁC were required for 4 h to obtain the optimal
yields and in the case of the best metal triflate amongst
those tried, that is In(OTf)3, a temperature of 100 ꢁC was
required for 24 h for optimal product formation.17 In
contrast to these catalysts, [bmim]ClꢀAlCl3, N ¼ 0:67
ionic liquid proved to be so effective that in an unopti-
mised experiment, with one mole equivalent of the ionic
liquid, the reaction of piperidylsulfamoyl chloride with
benzene was completed within 30 min at room temper-
ature (as indicated by TLC). To the best of our
knowledge, this is the first report on Lewis acid medi-
ated sulfamoylation achieved at room temperature.
Encouraged by these preliminary observations, we
planned a systematic study wherein we monitored the
influence of parameters such as molar stoichiometry,
Lewis acidity of the ionic liquid and the time of reaction
on the extent of conversion. The reaction of piper-
idylsulfamoyl chloride with benzene was selected as a
model for all the further investigations.
a Reactions performed at rt with 1 mol equiv of ionic liquid.
b Conversions monitored by HPLC.19
increased progressively as was evident from the results
obtained (Table 2).
Under the optimised conditions of molar stoichiometry,
Lewis acidity of the ionic liquid and reaction tempera-
ture, we adjudged the catalytic efficacy of this liquid by
monitoring the conversion as a function of time.19;20 For
the conversions to reach maximum, the optimal reaction
time was 30 min (Table 3).
To extend the scope of the reaction and to generalise the
procedure, we investigated the reaction of several arenes
with a variety of N,N-dialkylsulfamoyl chlorides as
sulfamoylating agents (Table 4). The reaction worked
well with benzene, toluene, p-xylene, mesitylene, durene,
alkoxy benzenes and naphthalene.20 With alkoxy benz-
enes, (entries 11–13) the reaction was expeditious
enough to afford good yields of the corresponding sul-
fonamides within 5 min at room temperature. An
interesting feature that we observed with such arenes
under the reported reaction conditions was no detect-
able dealkylation as was observed with the conventional
AlCl3 catalysed reactions, which resulted in a consider-
able reduction in yields of the corresponding sulfon-
To optimise the molar stoichiometry of [bmim]ClꢀAlCl3,
N ¼ 0:67 ionic liquid required for the reaction, we car-
ried out several experiments and found that the con-
versions improved as the amount of ionic liquid was
increased from 0 to 1 mol equiv and 1 mol equiv of
[bmim]ClꢀAlCl3, N ¼ 0:67 sufficed to afford almost
quantitative conversions at room temperature after
30 min (Table 1).19;20 The variation of the apparent mole
fraction of AlCl3 in chloroaluminate ionic liquids facil-
itates the variation of Lewis acidity of the medium. This
feature of chloroaluminates prompted us to investigate
the influence of variable Lewis acidity on the extent of
conversion.19;20 The reaction did not occur in basic
(N < 0:50) and neutral (N ¼ 0:50) ionic liquids even
after a prolonged reaction time of 24 h. We observed
that as the Lewis acidity of the ionic liquid was increased
from N ¼ 0:50 to 0.67, the percentage conversion
Table 3. The effect of reaction time on the extent of conversion in the
[bmim]ClꢀAlCl3, N ¼ 0:67 mediated sulfamoylation of benzene with
piperidylsulfamoyl chloridea
Reaction time (min)
Percentage conversionb
5
40
58
77
85
90
96
10
15
20
25
30
a Reactions performed at rt with 1 mol equiv of ionic liquid.
b Conversions monitored by HPLC.19

P. U. Naik et al. / Tetrahedron Letters 45 (2004) 1933–1936
1935
Table 4. The scope of [bmim]ClꢀAlCl3, N ¼ 0:67 mediated sulfamoylations of arenesa
Entry
Arene
Sulfamoyl chloride
Time, temperature
Sulfonamide
Percentage yieldb
90
O
O
1
30 min, rt
Cl
S
N
S
N
O
O
O
S
O
S
2
3
30 min, rt
30 min, rt
92
94
Cl
N
N
O
O
O
S
O
S
Cl
Cl
N
N
N
O
O
O
S
O
S
4
5
30 min, rt
30 min, rt
89
92
N
N
O
O
O
S
O
S
.
Cl
Cl
N
O
O
O
S
O
.
6
7
30 min, rt
30 min, rt
88
91
N
S
N
O
O
O
S
O
S
.
N
Cl
Cl
N
O
O
O
S
.
N
O
S
8
9
30 min, rt
30 min, rt
87
93
N
N
O
O
O
S
O
S
.
Cl
N
O
O
O
S
O
S
10
11
12
13
30 min, rt
5 min, rt
5 min, rt
5 min, rt
89
91
88
84
Cl
Cl
Cl
Cl
N
N
O
O
O
S
O
S
.
N
MeO
MeO
EtO
N
O
O
O
S
O
S
EtO
N
N
N
O
O
O
S
O
MeO
MeO
S
N
O
O
O
S
O
.
88 (a:b ¼ 94:6)c
Cl
N
14
30 min, rt
S
N
O
O
a One mole equivalent of the ionic liquid was used.
b Indicates the yield of product isolated by column chromatography.
c Obtained by GC–MS.21
amides. On the other hand, In(OTf)3 mediated sulfa-
moylations of alkoxy benzenes gave good yields of the
corresponding sulfonamides, but the protocol affords
poor regioselectivities in addition to the drastic reaction
conditions.17 The present protocol leads to exclusive
selectivity for the para substituted sulfonamides with
alkoxy benzenes. With alkoxy benzenes, longer reaction
times (longer than 5 min) in the ionic liquid were detri-
mental for the formation of the desired sulfonamides
because of the dealkylation. In the case of naphthalene,
the protocol offers the best selectivity for the a-substi-
tuted product. The reaction of dibutylsulfamoyl chloride

1936
P. U. Naik et al. / Tetrahedron Letters 45 (2004) 1933–1936
9. (a) Hansch, C.; Sammes, P. G.; Taylor, J. B. In Compre-
hensive Medicinal Chemistry; Pergamon: Oxford, 1990;
Vol. 2, Chapter 7.1; (b) Connor, E. E. Sulfonamide
Antibiotics Prim. Care Update Ob./Gyn. 1998, 5, 32; (c)
Hanson, P. R.; Probst, D. A.; Robinson, R. E.; Yau, M.
Tetrahedron Lett. 1999, 40, 4761, and references cited
therein.
with naphthalene (entry 14) resulted in an 88% yield of
product in an a:b ratio of 94:6, (by GC–MS21), which
confirmed the fact that the reaction conditions are
promising for the formation of the kinetically favoured
products over the thermodynamically favoured ones.
Similarly, the reaction of naphthalene with diethyl-
sulfamoyl chloride gave the corresponding sulfonamide
in 87% yield (with a:b ¼ 82:1821). It is noteworthy that,
in terms of the isomer distribution observed for the
naphthyl sulfonamides, the present protocol is distinctly
complementary to the earlier one.17 In the case of
deactivated arenes such as chlorobenzene, no reaction
was observed at room temperature. At higher tempera-
tures however, we obtained a 65% yield of product
within 30 min at 100 ꢁC, which was exclusively para. To
the best of our knowledge, the sulfonamides in entries 4,
6, 8 and 9 of Table 4 are unknown in the literature.
10. Huntress, E. H.; Carten, F. H. J. Am. Chem. Soc. 1940, 62,
511.
11. (a) Valkanas, G.; Hopff, H. J. Chem. Soc. 1963, 1923; (b)
Sandler, M.; Burmeister, D. Chem. Ber. 1962, 95, 964; (c)
Carothers, W. H.; Bickford, C. F.; Hurwitz, G. J. J. Am.
Chem. Soc. 1927, 49, 2908; (d) Hendrickson, J. B.;
Bergeron, R.; Sternbach, D. D. Tetrahedron 1975, 31,
2517.
12. Becker, H. J. Rec. Trav. Chim. 1915, 70, 254.
13. (a) Kremler, M. M.; Naumenst, D. Khim. Tekhnol. 1970,
163; (b) Terauchi, H.; Yamasaki, A.; Takemura, S. Chem.
Pharm. Bull. 1975, 23, 3162; (c) Sharpless, K. B.; Chong,
A. O.; Oshima, K. J. Org. Chem. 1976, 41, 177.
14. Bouma, W. J.; Engberts, J. B. F. N. J. Org. Chem. 1976,
41, 143.
15. Arnswald, M.; Neumann, W. P. Chem. Ber. 1991, 124,
1997.
16. Gupta, S. K. Synthesis 1977, 39.
17. Frost, C. G.; Hartley, J. P.; Griffin, D. Synlett 2002, 1928.
18. Benson, G. A.; Maughan, P. J.; Shelly, D. P.; Spillane,
W. J. Tetrahedron Lett. 2001, 42, 8729.
To conclude, the present protocol serves as an expedi-
tious route to earlier methods, providing almost quan-
titative yields of aromatic sulfonamides under ambient
conditions in most of the cases. In the case of mono-
substituted benzenes, an added advantage is the regio-
selectivity offered by the procedure. The ionic liquid
served a dual purpose of solvent as well as catalyst. The
present method for effecting the sulfamoylation of are-
nes will therefore be a useful addition in the scientific
literature.
19. The conversion in all the cases was monitored on a
reversed-phase HPLC using anisole as an external stan-
dard. The extent of conversion was monitored with respect
to the formation of the product (kmax 224 nm). The HPLC
analysis was performed on a Merck Lachrome, equipped
with the Inertsil ODS3 column (250 mm · 4.6 mm, 5l) and
a UV detector, which was tuned to measure the absor-
bance at 220 nm. The elution was performed with CH3CN/
aqueous buffer, pH 2.5 (0.05 M KH2PO4/H3PO4) taken in
a 65/35 ratio by volume, maintaining a flow rate of
References and notes
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R. Chem. Commun. 2001, 2399.
1 mL minꢁ1
.
20. Typical experimental procedure: to the arene (5.5 mmol)
and sulfamoyl chloride (5 mmol) was added [bmim]Clꢀ
AlCl3, 0:50 < N 6 0:67 (5 mmol or as specified in the text)
and the reaction mixture stirred for a specified time at
room temperature. All the additions were performed
under N2 atmosphere in a glove box. The reaction mixture
was quenched by adding 6 M aq HCl solution under cold
conditions. The product was extracted using (3 · 15 mL) of
ethyl acetate. The combined organic extracts were dried
over Na2SO4 and concentrated under reduced pressure.
The crude reaction mixture was chromatographed using
toluene on a silica gel column to yield the purified product,
which was characterised by melting point IR and 1H
NMR. Spectral data of 1-[(2,3,5,6-tetramethylphenyl)sul-
fonyl]-piperidine (Table 4, entry 4): mp 82–84 ꢁC. IR
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1
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NMR (300 MHz, CDCl3): d 1.57 (br s, 6H, 3 ꢂ –CH2–
cyclic), 2.27 (s, 6H, 2 ꢂ –CH3), 2.54 (s, 6H, 2 ꢂ –CH3), 3.15
(br s, 4H, 2 ꢂ –CH2– cyclic) and 7.16 (s, 1H, 1 ꢂ CH
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QP-2010 instrument equipped with a dp-5 column. The
detector temperature was set at 280 ꢁC. The column was
programmed initially at 60 ꢁC for 15 min and then with a
gradient of 10 ꢁC/min to 270 ꢁC.