Synthesis, in vitro antibacterial and carbonic anhydrase II inhibitory activities of N-acylsulfonamides using silica sulfuric acid as an efficient catalyst under both solvent-free and heterogeneous conditions

Article abstract of DOI:10.1016/j.bmc.2008.04.011

Silica sulfuric acid catalyzes efficiently the reaction of sulfonamides with both carboxylic acid anhydrides and chlorides under solvent-free and heterogeneous conditions. All the reactions were done at room temperature and the N-acylsulfonamides were obtained with high yields and purity via an easy work-up procedure. This method is attractive and is in a close agreement with green chemistry. These compounds were also investigated for antibacterial activity, including Gram-positive cocci and Gram-negative bacilli, and carbonic anhydrase II inhibitory activity.

Full text of DOI:10.1016/j.bmc.2008.04.011

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 5465–5472
Synthesis, in vitro antibacterial and carbonic anhydrase
II inhibitory activities of N-acylsulfonamides using silica
sulfuric acid as an efficient catalyst under both solvent-free
and heterogeneous conditions
b,
c
d
Ahmad Reza Massah,a,* Hadi Adibi, Reza Khodarahmi, Ramin Abiri,
Mohammad Bagher Majnooni,b Sherita Shahidi,a Beheshteh Asadi,a
Masomeh Mehrabib and Mohammad Ali Zolfigole
*
aDepartment of Chemistry, Islamic Azad University, Shahreza Branch, Shahreza 86145-311, Islamic Republic of Iran
bDepartment of Medicinal Chemistry, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah 67145-1673,
Islamic Republic of Iran
cDepartment of Pharmacognosy and Biotechnology, Faculty of Pharmacy, and Medical Biology Research Center,
Kermanshah University of Medical Sciences, Kermanshah 67145-1673, Islamic Republic of Iran
dDepartment of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Islamic Republic of Iran
eFaculty of Chemistry, Bu-Ali Sina University, Hamadan 65174, Islamic Republic of Iran
Received 12 February 2008; revised 5 April 2008; accepted 8 April 2008
Available online 11 April 2008
Abstract—Silica sulfuric acid catalyzes efficiently the reaction of sulfonamides with both carboxylic acid anhydrides and chlorides
under solvent-free and heterogeneous conditions. All the reactions were done at room temperature and the N-acylsulfonamides were
obtained with high yields and purity via an easy work-up procedure. This method is attractive and is in a close agreement with green
chemistry. These compounds were also investigated for antibacterial activity, including Gram-positive cocci and Gram-negative
bacilli, and carbonic anhydrase II inhibitory activity.
ꢀ 2008 Elsevier Ltd. All rights reserved.
1. Introduction
most important disadvantage of the described methods.
Direct coupling of sulfonamides with carboxylic acids
has used condensing agents such as carbodiimides
(EDC and DCC) and 1,10-carbonyl diimidazole.2,10 Re-
cently, Katrizky et al. were reported N-acylation of sul-
fonamides using N-acyl benzotriazole as an acylating
agent.11 However, some of the above-mentioned meth-
ods suffer from one or more of the following disadvan-
tages: long reaction times, vigorous reaction
conditions, use of expensive or unavailable reagents,
low yield of product, and tedious work-up.
N-Acylsulfonamides have received considerable atten-
tion due to their diverse biological activities as precur-
sors of therapeutic agents for Alzheimer’s disease,1
antibacterial inhibitors of tRNA synthetases,2 antago-
nists for Angiotensin II,3 and Leukotriene D4-
receptors.4
Most N-acylation of sulfonamides has utilized carbox-
ylic acid chlorides or anhydrides in the presence of trial-
kylamines, pyridine,5,6 or alkali hydroxides7–9 in
appropriate solvent. The occurrence of the side reaction
especially formation of bis-acylated by product, is the
There are few limited procedures that have described the
formation of N-acylsulfonamides under protic acid con-
ditions.12,13 From the standpoint of environmental de-
mand for chemical processes, much attention has been
paid to the development of solid acidic reagents for or-
ganic functional groups transformations.14 On the other
hand, any reduction in the amount of protic acid needed
Keywords: N-Acylsulfonamides; Silica sulfuric acid; Solvent-free; An-
tibacterial activity; Carbonic anhydrase II inhibitor.
*
Corresponding authors. Tel.: +98 831 4276482; fax: +98 831
4276493; e-mail addresses: massah@iaush.ac.ir; hadibi@kums.ac.ir
0968-0896/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.04.011

5466
A. R. Massah et al. / Bioorg. Med. Chem. 16 (2008) 5465–5472
and/or any simplification in handling procedures is re-
quired for risk reduction, economic advantage and envi-
ronmental protection. Thus, there is still a demand to
develop new and mild methods for the N-acylation of
sulfonamides in the presence of inexpensive and bench-
top reagents.
component of the reaction. Then a similar reaction was
studied in the presence of various amounts of SSA. We
have observed that the reaction between benzensulfona-
mide (1 mmol), acetic anhydride or acetyl chloride
(2 mmol), and silica sulfuric acid (0.008 g) was com-
pleted after 8–25 min in a solvent-free condition at room
temperature. For comparing the solvent-free results with
solvent added ones, the reaction of benzensulfonamide
with acetic anhydride and also acetyl chloride was car-
ried out under various solvents. Chloroform led to the
smallest amount of side products with high yields and
it was selected as the solvent for further study.
At least 14 different cytosolic (CA I, II, O, and VII) and
membrane-bound (CA IV, IX, XII, and XIV) carbonic
anhydrase (E.C. 4.2.1.1) isoforms were isolated in higher
vertebrates. These enzymes catalyze a very simple phys-
iological reaction, the interconversion between carbon
dioxide and bicarbonate ion, and are thus involved in
crucial physiologic processes connected with respiration
and transport of CO2/bicarbonate between metabolizing
tissues and lungs, pH, and CO2 homeostasis, electrolyte
secretion in a variety of tissues/organs, biosynthetic
reactions, bone resorption, calcification, tumorigenicity,
and many other physiologic or pathologic processes.
Several important physiologic and physio-pathologic
functions played by many carbonic anhydrase isoe-
zymes, are strongly inhibited by aromatic and heterocy-
clic sulfonamides as well as by inorganic, metal
complexing anions.15
2.2. Generality of silica sulfuric acid catalyzed N-acyla-
tion of sulfonamides
To explore the scope and limitation of the described reac-
tions, we studied the reaction of benzensulfonamide, 4-
methylbenzensulfonamide, and methansulfonamide with
several aliphatic and aromatic carboxylic acid anhydrides
or chlorides in the presence of SSA. The reaction pro-
ceeded very efficiently in all the cases. As it is shown in Ta-
ble 1, several structurally varied sulfonamides and
acylating agents underwent clean and remarkably fast
N-acylation reaction. The aliphatic anhydride with a long
chain, like pentanoic anhydride (Table 1, entries 1e, 1k,
and 1q) could be used as effectively as one with a short
chain. Also, it seemed that there was no steric bulk effect
from the substituents at the anhydride moiety since isob-
utanoic anhydride could be applied as an efficient candi-
date for N-acylation of different sulfonamides to offer
the expected N-acylsulfonamides in excellent yields in
both heterogeneous and solvent-free conditions (Table
1, entries 1d, 1j, and 1p). Carboxylic acid anhydrides were
found to be more reactive than carboxylic acid chlorides.
These results show that the acylinium ion was formed and
then reacted with sulfonamide. This fact was further sup-
ported by N-acylation of sulfonamides with trifluoroace-
tic anhydride. For example, the reaction of
benzensulfonamide with trifluoroacetic anhydride did
not proceed considerably and only 10% of the product
was obtained after 8 h. Comparison between the results
obtained in solution and those under solvent-free condi-
tions shows that the reaction proceeded faster in sol-
vent-free conditions. Therefore, omitting of solvent (i.e.,
solvent-free conditions) makes an easy work-up proce-
dure and increases the rate of reaction.
Since the catalytic and inhibition mechanisms of the CA
isoenzymes have been understood in detail, the design of
potent specific isoenzymes and organ-selective inhibitors
can be important due to their various clinical applica-
tions. Several sulfonamide compounds that interact with
CA have recently been synthesized and applied as anti-
glucoma, antiepileptic, and for the treatment of other
neurological disorders, anti cancer and also as diagnos-
tic tools in PET and MRI. The CA II is present in some
cells of virtually all tissue types and plays a vital role in
respiration and acid–base balance.16
Recently, silica sulfuric acid (SSA) has been introduced
as a novel solid inorganic acidic proton source catalyst17
by the reaction of silica gel and chlorosulfonic acid for
the various functional group transformations.18–29 In
continuation of our studies in this regard,29 we report
our efforts toward a new solvent-free and heterogeneous
procedure for the synthesis of N-acylsulfonamides with
carboxylic acid anhydrides and chlorides in the presence
of a catalytic amount of silica sulfuric acid and evalua-
tion of their in vitro antibacterial activity. Furthermore,
the inhibitory effects of N-acylsulfonamides were tested
on the cytosolic human carbonic anhydrase II in the mi-
cro-to-nanomolar range.
2.3. Chemoselectivity and large-scale use
In order to show the chemoselectivity of the method for
the reaction of sulfonamides with different carbonyl
groups, we designed a number of competitive reactions.
As shown in Scheme 1 selectivity of the method is very
promising and discriminates between different CO func-
tionalities. In fact, sulfonamide reacted with carbonyl
group that formed more stable acylinium ion. We have
also conducted a similar reaction on a large-scale oper-
ation. For this purpose benzensulfonamide (1.56 g,
10 mmol) was reacted with acetic anhydride (2.04 g,
20 mmol) in the presence of a catalytic amount of SSA
(0.08 g). The reaction proceeded very fast in less than
8 min to produce N-acetyl sulfonamide in 88% yield.
2. Chemistry
2.1. Optimization of reaction conditions
A variety of reaction conditions were performed to opti-
mize the reaction. To illustrate the need of catalyst for
these reactions, an experiment was conducted in which
the reaction of benzensulfonamide and acetic anhydride
or acetyl chloride was studied in the absence of SSA.
The reaction did not occur, even after 24 h in the ab-
sence of the catalyst. Obviously, the SSA is an essential

Table 1. N-Acylation of sulfonamides in chloroform or solvent-free conditions
O
O
O
O
O
S
O
S
Silica sulfuric acid
R
N
H
R' (R")
R
NH2
+
or
R'
R"
Cl
R'
O
CHCl3, Reflux
or Solvent-free, r.t
O
O
R=CH3, C6H5, p-CH3C6H5
R'=CH3, C2H5, n-C3H7, iso-C3H7, n-C4H9, C6H5
R"=CH3, C2H5, C6H5
Solvent-freea
CHCl3
b
Entry
Sulfonamide
Acylating agent
Product
Time (min)
Yield (%)c
Time (min)
Yield (%)c
80
1a
1b
1c
1d
1e
1f
H3COOCOCH3
8
85
45
SO2NH2
SO2NHCOCH3
SO2NHCOC2H5
SO2NHCOC3H7-n
SO2NHCOC3H7-iso
SO2NHCOC4H9-n
SO2NHCOC6H5
SO2NHCOC6H5
SO2NHCOCH3
SO2NHCOC2H5
SO2NHCOCH3
SO2NHCOC2H5
H5C2COOCOC2H5
n-H7C3COOCOC3H7-n
iso-H7C3COOCOC3H7-iso
n-H9C4COOCOC4H9-n
H5C6COOCOC6H5
H5C6COCl
8
5
88
90
95
90
88
84
82
84
84
85
90
40
80
82
94
80
80
85
70
82
73
75
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
8
45
10
90
35
25
20
10
10
70
180
180
90
1f
1a
1b
1g
1h
H3CCOCl
H5C2COCl
50
H3COOCOCH3
50
SO2NH2
H3C
H3C
H3C
H3C
H5C2COOCOC2H5
50
SO2NH2
(continued on next page)

Table 1 (continued)
Entry
Sulfonamide
Acylating agent
Product
Solvent-freea
Time (min)
Yield (%)c
CHCl3
Time (min)
b
Yield (%)c
85
1i
n-H7C3COOCOC3H7-n
iso-H7C3COOCOC3H7-iso
n-H9C4COOCOC4H9-n
H5C6COOCOC6H5
H5C6COCl
10
15
89
93
88
88
95
90
88
45
50
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
SO2NH2
H3C
H3C
H3C
H3C
H3C
H3C
H3C
SO2NHCOC3H7-n
SO2NHCOC3H7-iso
SO2NHCOC4H9-n
SO2NHCOC6H5
SO2NHCOC6H5
SO2NHCOCH3
H3C
H3C
H3C
H3C
H3C
H3C
H3C
1j
88
89
83
83
78
82
1k
1l
15
65
120
35
240
135
75
1l
1g
1h
H3CCOCl
25
H5C2COCl
30
55
SO2NHCOC2H5
1m
1n
1o
1p
1q
1r
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3C–SO2NH2
H3COOCOCH3
H3C–SO2NHCOCH3
H3C–SO2NHCOC2H5
H3C–SO2NHCOC3H7-n
H3C–SO2NHCOC3H7-iso
H3C–SO2NHCOC4H9-n
H3C–SO2NHCOC6H5
H3C–SO2NHCOC6H5
H3C–SO2NHCOCH3
H3C–SO2NHCOC2H5
5
5
80
78
78
85
75
98
94
81
80
30
20
70
75
80
85
73
80
78
70
74
H5C2COOCOC2H5
n-H7C3COOCOC3H7-n
iso-H7C3COOCOC3H7-iso
n-H9C4COOCOC4H9-n
H5C6COOCOC6H5
H5C6COCl
3
10
10
5
5
10
90
60
20
20
15
1r
120
55
1m
1n
H3CCOCl
H5C2COCl
40
a At room temperature.
b Reflux conditions.
c Isolated yields.

A. R. Massah et al. / Bioorg. Med. Chem. 16 (2008) 5465–5472
5469
SSA
O
O
N C
O
O
Solvent-free
SO2NH2
NO2
NO2
N C
NO2
NO2
SO
SO
C O C
+
+
+
2 H
2 H
or CHCl3, Reflux
100%
O
0%
SSA
Solvent-free
O
O
O
H3C SO2NH2
N C
H3C SO
C O C
N C
H3C SO
+
2 H
2 H
or CHCl3, Reflux
80%
20%
O
O
C O C
SSA
O
O
N C
Solvent-free
SO2NH2
N C
NO2
SO
+
SO
+
O
2 H
O
2 H
or CHCl3, Reflux
NO2
O2N
C O C
100%
0%
Scheme 1. Chemoselectivity of the reaction.
3. Results and discussion
ventional agar-dilution method.30 The MICs (minimum
inhibitory concentrations) values were determined by
comparison to sulfamethoxazole as the reference drug
and are presented in Table 2.
3.1. In vitro antibacterial activity
The test compounds were evaluated for their antibacte-
rial activity against three Gram-positive cocci (Staphylo-
coccus aureus ATCC 25922, clinical strains of S. aureus
and Enterococcus sp.) and three Gram-negative bacilli
(Pseudomonas aeruginosa ATCC 27853, clinical strains
of Klebsiella pneumonia and Escherichia coli) using con-
Turbidity of all the bacterial cultures was adjusted to 0.5
McFarland Standard by preparing bacterial suspension
of 3–5 well-isolated colonies of the same morphological
type selected from an agar plate culture. The cultures
were further diluted 1000-fold to get an inoculum size
Table 2. In vitro antibacterial activity of N-acylsulfonamides against Gram-positive and Gram-negative bacteria (MICs in lg/mL)
Compound
E. coli
E. faecium
K. pneumoniae
S. aureus
S. aureus
P. aeruginosa
(clinical isolated) (clinical isolated) (clinical isolated) (clinical isolated) ATCC 25922 ATCC 27853
H3C–SO2NHCOC6H51r
256
256
256
256
500
256
256
500
500
256
500
256
SO2NHCOC6H5
1f
H3C
H3C
SO2NHCOC6H5
64
128
256
256
256
256
1l
SO2NHCOC2H5
128
64
500
128
64
500
1h
SO2NHCOC2H5
256
64
256
256
128
500
1b
Sulfamethoxazole
2
4
8
4
2
8
SO2NHCOCH3
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
1a
SO2NHCOC4H9-n
1e
H3C
SO2NHCOC4H9-n
1k

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A. R. Massah et al. / Bioorg. Med. Chem. 16 (2008) 5465–5472
of 1.5 · 105 CFU/mL. The test compounds (50 mg) were
dissolved in DMSO (0.5 mL) and the solution was di-
luted with water (4.5 mL) to get a stock solution of
10,000 mg/mL of each compound. Further progressive
double dilution with Muller–Hinton broth was per-
formed to obtain the required concentrations of 1000,
512, 256, 128, 64, 32, 16, 8, 4, and 2 lg/mL.31 To ensure
that the solvent had no effect on the bacterial growth, a
control test was performed with a test medium supple-
mented with DMSO at the same dilutions as used in
the experiment. Our results indicated that all the test
compounds tested in this study demonstrated lower
activity against both Gram-positive and Gram-negative
microorganisms than the reference drug.
published literature, the reference drug dorzolamide
(with known IC50) showed very good in vitro inhibitory
properties against the isoenzyme II. Also as indicated in
Figure 1, the strongest CA II inhibitor was compound
1h (with potency comparable to that of dorzolamide).
Contrary to compound 1h, 1e, and 1k showed relatively
weaker inhibitory effects in the CA assay. The potencies
for CA II inhibition for the test compounds (compared
to dorzolamide result) are in the following order: Dorzo-
lamide > 1h > 1b > 1f > 1e > 1k. Other compounds (1a
and 1r) lacked significant CA II inhibitory activity in
our assay (data not shown).
4. Conclusions
The standard antibiotic (sulfamethoxazole) was also di-
luted in the same manner. Each microwell in a series of
12 microwells was inoculated with 75 lL of the serial
dilutions, and then 75 lL of the bacterial suspension
was added. After overnight incubation at 37 ꢁC, growth
was surveyed. Data of MICs of the test compounds and
the control drug are shown in Table 2.
In conclusion, we have been able to introduce an effi-
cient and environmentally friendly approach for the syn-
thesis of N-acylsulfonamides via N-acylation of
sulfonamides with carboxylic acid chlorides or anhy-
drides, using SSA as a solid acid catalyst in solvent-free
and heterogeneous conditions. The reactions are charac-
terized by non-corrosiveness, safety, low cost and waste,
ease of separation, high yields, and chemoselectivity.
Replacement of the liquid acids with a solid acid catalyst
is a desirable feature of the reactions that may be impor-
tant in their industrial manufacture. The solvent-free N-
acylation has special advantages over the existing sol-
vent added synthesis and is a green chemistry approach
to the preparation of these compounds. Furthermore,
microbiological activity of the test compounds was eval-
uated against a panel of resistant and susceptible Gram-
positive and Gram-negative microorganisms in vitro
comparable to that of sulfamethoxazole and also to
some degree of CA II inhibitory activity. On the other
3.2. Carbonic anhydrase II inhibitory activity
The enzyme identity and purity was tested through SDS-
electrophoretic analysis and by comparing with com-
mercial CA enzyme (Sigma), as a standard. The SDS–
PAGE analysis is shown in Figure 1 (Inset), it clearly
indicates the reasonable purity of the isolated enzyme.
The potency of test compounds (1a, 1b, 1e, 1f, 1h, 1k,
and 1r) for the inhibition of CA II has been studied
in vitro. Figure 1 summarizes the relative inhibitory
potencies of the test compounds. Consistent with the
95%
100
85%
90
80
70
60
50
40
30
20
10
0
38%
28%
22%
2%
Figure 1. Inhibition of CA II activity by dorzolamide and synthesized test compounds. The reported results of CA II enzyme inhibition are averages
of two separate experiments whenever the coefficients of variation were less than 5%. The final concentration of enzyme and CA/inhibitor molar ratio
were 0.05 mg/mL and 1/15, respectively. Inset: the SDS–PAGE pattern of purified (lanes 1–3) and commercial (lane 4) carbonic anhydrase.
Electrophoresis performed according to Laemmli on 10% slab gel.35

A. R. Massah et al. / Bioorg. Med. Chem. 16 (2008) 5465–5472
5471
hand, we need to determine the mode (reversibility and/
or irreversibility) of CA inhibition of the test com-
pounds and also evaluate them quantitatively (determin-
ing of Ki and IC50 parameters), by comparing with
reference inhibitors. Also, in our laboratory, further
work is in process to design more potent and isoen-
zyme-specific CA inhibitors containing unsubstituted
sulfonamide moiety.
(2 mmol) was refluxed in chloroform (5 mL) in the pres-
ence of silica sulfuric acid (0.008 g) for an appropriate
time (Table 1). The progress of the reaction was moni-
tored by TLC. After the completion of the reaction,
chloroform (20 mL) was added and the solid catalyst
was removed by filtration. The filtrate was washed with
water and dried over MgSO4. After evaporation of the
solvent, the crude product was purified just like the
above-mentioned procedure for the solvent-free condi-
tion. The structural assignments of the products are
1
5. Experimental
based on their IR, H NMR, 13C NMR or by compar-
ison of their melting point with those of the known
compounds.
5.1. General methods
All chemicals were purchased from Merck and Fluka
chemical companies. Infrared spectra were recorded on
Nicollet (impact 400D model) FTIR spectrophotometer.
1H NMR and 13C NMR spectra were recorded on Bru-
ker DRX 300 Avance spectrophotometer in DMSO-d6
as the solvent and TMS as the internal standard. Col-
umn chromatography was performed using silica gel
60 (230–400 mesh). All yields refer to isolated products.
Human CA II isoenzyme was purified according to Ny-
man’s method with some minor modifications.32 Protein
concentration for carbonic anhydrase II was determined
5.4.1. N-Pentanoyl benzensulfonamide (1e). Mp 79–
1
81 ꢁC; IR t (cmꢀ1) 3214, 1688, 1608, 1350, 1164; H
NMR (300 MHz, DMSO-d6)
d
(ppm) 0.77 (t,
J = 7.2 Hz, 3H), 1.13 (sextet, J = 7.4 Hz, 2H), 1.37
(quintet, J = 7.4 Hz, 2H), 2.19 (t, J = 7.3 Hz, 2H),
7.59–7.91 (m, 5H), 12.03 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) d (ppm) 13.47, 21.31, 26, 34.97, 127.36,
129.04, 133.55, 139.38, 171.57.
5.4.2. N-Isobutanoyl-4-methyl benzensulfonamide (1j).
Mp 111–113 ꢁC; IR t (cmꢀ1) 3259, 1731, 1329, 1171;
1H NMR (300 MHz, DMSO-d6) d (ppm) 0.92 (d,
J = 6.8 Hz, 6H), 2.38 (s, 3H), 2.41–2.46 (m, 1H), 7.4
(d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H), 11.99 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d (ppm) 16.92,
19.57, 32.75, 125.97, 128.03, 135.03, 142.61, 173.72.
by absorbance at 280 nm with an extinction coefficient
(e280) of 5.7 · 104 molꢀ1 cmꢀ1
33
.
5.2. Enzyme assay
The enzymatic activity of CA solution in the presence or
absence of the enzyme inhibitor (reference drug and or
test compounds) was determined based on p-nitrophenyl
acetate esterase activity of the enzyme according to Poc-
ker and co-workers.34 The stock solution of the tested
compounds and dorzolamide (1 mM) were dissolved in
acetonitrile and distilled water, respectively. The CA
inhibition potency of test compounds was determined
by comparing the resulting initial rate with the initial
rate of p-nitrophenyl acetate hydrolysis by the enzyme
alone under all identical conditions.
5.4.3. N-Pentanoyl methansulfonamide (1q). Mp 69–
1
71 ꢁC; IR t (cmꢀ1) 3269, 1720, 1330, 1158; H NMR
(300 MHz, DMSO-d6) d (ppm) 0.86 (t, J = 7.3 Hz,
3H), 1.26 (sextet, J = 7.4 Hz, 2H), 1.48 (quintet,
J = 7.4 Hz, 2H), 2.25 (t, J = 7.3 Hz, 2H), 3.2 (s, 3H),
11.62 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d (ppm)
14.06, 21.96, 26.62, 35.52, 43.55, 173.09.
Acknowledgments
5.3. Solvent-free synthesis of N-acylsulfonamides
We gratefully acknowledge the Kermanshah University
of Medical Sciences Research Council for financial sup-
port. We also thank Dr. Taki for his kind help and also
partial financial support of Islamic Azad University of
Shahreza Research Council.
To a vigorously stirred mixture of sulfonamide (1 mmol)
and silica sulfuric acid (0.008 g) carboxylic acid chloride
(2 mmol) or carboxylic acid anhydride (2 mmol) was
added at room temperature. The progress of the reac-
tion was monitored by TLC. After completion of the
reaction, ethyl acetate (20 mL) was added and the solid
catalyst was removed by filtration. The filtrate was
washed with water (15 mL) and dried over MgSO4.
After evaporation of the solvent, the crude product
was purified by column chromatography on silica gel
(60–120 mesh) using EtOAc–petroleum ether as eluent
or recrystallized (toluene or ethyl acetate–n-hexane
mixed solvent) to afford the corresponding N-acylsulf-
onamide in good to high yield.
References and notes
1. Hasegawa, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2000,
73, 423.
2. Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Forrest, A.
K.; Karoli, T.; March, D. R.; Mensah, L.; Nairn, M. R.;
O’Hanlon, P. J.; Oldham, M. D.; Yue, W. Bioorg. Med.
Chem. Lett. 2000, 10, 2263.
3. Chang, L. L.; Ashton, W. T.; Flanagan, K. L.; Chen, T.
B.; O’Malley, S. S.; Zingaro, G. J.; Siegl, P. K. S.;
Kivlighn, S. D.; Lotti, V. J.; Chang, R. S. L.; Greenless,
W. J. J. Med. Chem. 1994, 37, 4464.
5.4. Synthesis of N-acylsulfonamides in chloroform
4. Musser, J. H.; Kreft, A. F.; Bender, R. H. W.; Kubrak, D.
M.; Grimes, D.; Carlson, R. P.; Hand, J. M.; Chang, J. J.
Med. Chem. 1990, 33, 240.
A mixture of sulfonamide (1 mmol), carboxylic acid
chloride (2 mmol), or carboxylic acid anhydride

5472
A. R. Massah et al. / Bioorg. Med. Chem. 16 (2008) 5465–5472
5. Kondo, K.; Sekimoto, E.; Nakao, J.; Murakami, Y.
Tetrahedron 2000, 56, 5843.
6. Kondo, K.; Sekimoto, E.; Miki, K.; Murakami, Y. J.
Chem. Soc. Perkin Trans. 1998, 1, 2973.
20. Shimizu, K.; Hayashi, E.; Hatamachi, T.; Kodama, T.;
Kitayama, Y. Tetrahedron Lett. 2004, 45, 51351.
21. Shabani, A.; Rahmati, A. J. Mol. Catal. A: Chem. 2006,
249, 246.
7. Ishizuka, N.; Matsumura, K. I.; Hayashi, K.; Sakai, K.;
Yamamori, T. Synthesis 2000, 784.
22. Zolfigol, M. A.; Mohammadpoor-Baltork, I.; Mirjalili, B.
F.; Bamoniri, A. Synlett 2003, 1877.
8. Ishizuka, N.; Matsumura, K. I. Japanese Patent JP-
10045705, 1998.
9. Inoe, T.; Myahara, O.; Takahashi, A.; Nakamura, Y.
Japanese Patent JP-08198840, 1996.
10. Wang, Y.; Soper, D. L.; Dirr, M. J.; Delong, M. A.; De,
B.; Wos, J. A. Chem. Pharm. Bull. 2000, 48, 1332.
11. Katritzky, A. R.; Hoffmann, S.; Suzuki, K. Arkivoc 2004,
12, 14.
12. Morisawa, Y.; Kataoka, M.; Negahori, H.; Sakamoto, T.;
Kitano, N.; Kusano, K. J. Med. Chem. 1980, 23, 1376.
13. Martin, M. T.; Roschangar, F.; Eaddy, J. F. Tetrahedron
Lett. 2003, 44, 5461.
23. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Badaghifard,
M. A. Phosphorus, Sulfur, Silicon Relat. Elem. 2004,
179, 1113.
24. Zolfigol, M. A.; Bamoniri, A. Synlett 2002, 1621.
25. Zolfigol, M. A.; Mirjalili, B. F.; Bamoniri, A.; Karimi, M.
A.; Zarei, A.; Khazdooz, L.; Noei, J. Bull. Korean Chem.
Soc. 2004, 25, 1.
26. Desai, U. V.; Thopate, T. S.; Pore, D. M.; Wadgaonkar,
P. P. Cat. Commun. 2006, 7, 508.
27. Mukhopadhyay, B. Tetrahedron Lett. 2006, 47, 4337.
28. Wu, H.; Shen, Y.; Fan, L.-Y.; Wan, Y.; Shi, D.-Q.
Tetrahedron 2006, 62, 7995.
14. Singh, D. U.; Singh, P. R.; Samant, S. D. Tetrahedron
Lett. 2004, 45, 4805.
15. Supuran, C. T.; Scozzafava, A. Exp. Opin. Ther. Patents
2000, 10, 575.
16. Knudsen, J. F.; Carlsson, U.; Hammarstrom, P.; Sokol,
G. H.; Cantilena, L. R. Inflammation 2004, 28, 285.
17. Zolfigol, M. A. Tetrahedron 2001, 57, 9509.
18. See an excellent review about SSA Salehi, P.; Zolfigol, M.
A.; Shirini, F.; Baghbanzadeh, M. Curr. Org. Chem. 2006,
10, 2171.
29. Massah, A. R.; Kazemi, F.; Azadi, D.; Farzaneh, S.;
Aliyan, H.; Javaherian Nagash, H.; Momeni, A. R. Lett.
Org. Chem. 2006, 3, 235.
30. Baron, E. J.; Finegold, S. M. In Bailey and Scott’s
Diagnostic Microbiology, 8th ed.; C.V. Mosby: St. Louis,
1990; pp 184–188.
31. Andrews, J. M. J. Antimicrob. Chemother. 2001, 48, 5.
32. Nyman, P. O. Biochim. Biophys. Acta 1961, 52, 1.
33. Yazdanparast, R.; Khodarahmi, R.; Soori, E. Arch.
Biochem. Biophys. 2005, 437, 178.
19. Mirjalili, B. F.; Zolfigol, M. A.; Bamoniri, A.; Hazar, A.
Bull. Korean Chem. Soc. 2004, 25, 865.
34. Pocker, Y.; Stone, G. Biochemistry 1967, 6, 668.
35. Laemmli, U. K. Nature 1970, 227, 680.