Facile synthesis of N-acylsulfonamide in the presence of silica chloride (SiO2-Cl) both under heterogeneous and solvent-free conditions

Article abstract of DOI:10.1080/00397910701750185

Sulfonamides were converted to the corresponding N-acyl sulfonamides with carboxylic acid chlorides and anhydrides in the presence of silica chloride. All reactions were performed in both heterogeneous and solvent-free conditions. This method provides the N-acyl sulfonamides products in good to high yield and purity. Copyright Taylor & Francis Group, LLC.

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Facile Synthesis of N‐Acylsulfonamide in
the Presence of Silica Chloride (SiO2‐Cl)
both under Heterogeneous and Solvent‐Free
Conditions
Ahmad Reza Massah a , Ahmad Reza Momeni a , Mina Dabagh a , Hamid
Aliyan a & Hamid Javaherian Naghash a
a Department of Chemistry , Islamic Azad University , Shahreza Branch,
Shahreza, Isfahan, Iran
Published online: 18 Jan 2008.
To cite this article: Ahmad Reza Massah , Ahmad Reza Momeni , Mina Dabagh , Hamid Aliyan & Hamid
Javaherian Naghash (2008) Facile Synthesis of N‐Acylsulfonamide in the Presence of Silica Chloride (SiO2‐Cl)
both under Heterogeneous and Solvent‐Free Conditions, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:2, 265-273, DOI: 10.1080/00397910701750185
To link to this article: http://dx.doi.org/10.1080/00397910701750185
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Synthetic Communicationsw, 38: 265–273, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701750185
Facile Synthesis of N-Acylsulfonamide in the
Presence of Silica Chloride (SiO2-Cl) both
under Heterogeneous and Solvent-Free
Conditions
Ahmad Reza Massah, Ahmad Reza Momeni, Mina Dabagh,
Hamid Aliyan, and Hamid Javaherian Naghash
Department of Chemistry, Islamic Azad University, Shahreza Branch,
Shahreza, Isfahan, Iran
Abstract: Sulfonamides were converted to the corresponding N-acyl sulfonamides
with carboxylic acid chlorides and anhydrides in the presence of silica chloride. All
reactions were performed in both heterogeneous and solvent-free conditions. This
method provides the N-acyl sulfonamides products in good to high yield and purity.
Keywords: N-acylation, N-acylsulfonamide, heterogeneous, silica chloride, solvent-
free
Solid supports have wide applications in organic reactions from different
views.[1] They mostly facilitate the workup of the reaction mixtures, and
usually high selectivity accompanied by high yields of the products is
observed. Silica gel is one of the extensively used supports for different
purposes in organic chemistry.[2] Modified silica supports for functional
group transformation is also of interest. Silica chloride (SiO2-Cl), which
Received in the U.K. December 12, 2006
Address correspondence to Ahmad Reza Massah, Department of Chemistry,
Islamic Azad University, Shahreza Branch, P.O. Box: 86145-311, Shahreza, Isfahan,
Iran. E-mail: E-mail: Massah@iaush.ac.ir
265

266
A. R. Massah et al.
was easily prepared from silica gel and thionyl chloride, is a good solid acid
because of convenience, low cost, easy production, and insolubility in organic
solvents. Because of its insolubility in organic solvents, excellent in-situ
proton generation, and acceptance of different nucleophiles, it can be used
for different purposes in organic chemistry,[3] such as transthioacetalization
reactions;[4] deprotection of oximes, hydrazones, and semicarbazones;[5] acet-
alization of alcohols;[6] oxidation of urazoles;[7] nitrosation of amines;[8] con-
version of alcohols to chlorides and iodides;[9] condensation of pyrrole with
aromatic aldehydes;[10] and dehydration of tertiary alcohols.[11]
The N-acylsulfonamides constitute an important class of drugs with
several types of pharmacological agents.[12] The most practical methods
for the N-acylation of sulfonamides are the reaction of parent sulfonamide
with acyl chlorides or anhydrides in basic condition.[13] The less common
reports mentioning this transformation under acidic conditions do not sys-
tematically examine the scope and limitations of the reactions. Acylation
of sulfonamides with concentrated H2SO4 in the carboxylic acid
anhydride as solvent[14] or in acetonitrile[15] and use of Fe-exchanged mon-
tmorillonite K10[16] are some of these methods. However, most of the
reported methods suffer from one or more of the following disadvantages:
long reaction time, vigorous reaction conditions, and the occurrence of
side reactions (specially formation of bis-acylated by-product), use of
expensive or unavailable reagents, low yield of product, and tedious
workup. A literature survey shows that less attention has been paid to
solid acids as potential heterogeneous catalysts in N-acylation of sulfona-
mides. 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. In continuation of our studies on the application of SiO2-
Cl[17] and solvent-free reactions,[18] we were interested in using this
reagent for the synthesis of N-acylsulfonamides.
In this communication, we report a simple method for the effective N-
acylation of sulfonamides using carboxylic acid anhydride or chloride in the
presence of SiO2-Cl in heterogeneous or solvent-free conditions
(Scheme 1). In a simple procedure, a mixture of reactants was vigorously
stirred at 808C in solvent-free conditions or refluxed in n-hexane for the appro-
priate time. The progress of the reactions was monitored by thin-layer
Scheme 1. N-Acylation of sulfonamides with carboxylic acid anhydride or chloride.

Synthesis of N-Acylsulfonamide
267
chromatography (TLC), and the products were isolated in good to high yield in
an easy workup.
A variety of reaction conditions were performed to optimize the
reaction with respect to solvent, amount of catalyst, temperature, and
reaction time. To find the best solvent, the reaction of benzensulfonamide
with acetic anhydride was carried out in chloroform, n-hexane, ethyl
acetate, acetonitrile, dichloromethane, and toluene. n-Hexane led to the
smallest amount of side products and to high yield, and it was selected as
the solvent for further study. Also, the N-acylation of benzensulfonamide
was tried with varying amounts of SiO2-Cl in n-hexane and solvent-free con-
ditions. Furthermore, we experimented with different ratios of sulfonamide,
carboxylic acid anhydride, and chloride. When the molar ratio of sulfona-
mide–acylating agent was 1:2 in the presence of 0.3 g of SiO2-Cl, the
reaction gave the best results in both n-hexane and solvent-free conditions.
In addition, at low temperature and long reaction times, only small amounts
of the desired products were obtained.
Under the optimized conditions, various sulfonamides, such as benzen-
sulfonamide, 4-methylbenzensulfonamide, and methansulfonamide, reacted
with acylating agents including aliphatic and aromatic carboxylic acid
anhydride or chloride in the presence of SiO2-Cl to produce the correspond-
ing N-acylsulfonamides. The results in Tables 1 and 2 show that this method
is efficient, with almost quantitative conversion in most cases. Generally, the
steric bulk or electronic nature of the sulfonamide had little effect on the
efficiency of process. Also, a bulky substituent on the acylating agents
does not interfere in the reaction as evidentced by isobutanoic anhydride
undergoing acylation. The reaction of sulfonamides with trifloroacetic
anhydride was found to be unsuccessful, and only 10% of product was
obtained after 12 h. This may be due to an unfavorable acylinum ion
intermediate in this case. Comparison between the results obtained in
solution and those under solvent-free conditions shows that reaction
proceeded faster in solvent-free conditions. Therefore, omitting solvent
(i.e., solvent-free conditions) makes for an easy workup procedure and
increases the rate of reaction. On the other hand, comparison of the
results in Table 1 with Table 2 indicates that there are only small differences
between the results obtained when carboxylic acid chlorides were used as
acylating agent and those obtained in the presence of carboxylic acid
anhydride.
In summary, in this study, we have presented a new application of
silica chloride as an efficient catalyst that works under heterogeneous
and solvent-free condition for N-acylation of sulfonamides. The yields
of the reactions, facile workup, easy availability of silica chloride, and
low cost are the strong practical points of the presented method.
Solvent-free N-acylation has special advantages over existing solvent-
added synthesis and is a green approach to the preparation of these
compounds.

Table 1. N-Acylation of sulfonamides with carboxylic acid anhydrides in n-hexane or solvent-free condition
Solvent freea
n-hexaneb
Carboxylic acid
anhydride
Entry
1
Sulfonamide
Product
Time (h)
2.5
Yield (%)c
85
Time (h)
Yield (%)c
80
1.5
0.5
0.6
0.4
2
3
4
0.3
0.4
0.3
90
92
98
85
90
95
5
6
6
90
82
6
80
74
1.1
1.2
7
8
9
0.4
0.5
0.4
87
90
98
0.6
0.6
0.5
85
93
95

10
11
12
13
14
6
70
87
90
90
98
7
60
88
85
80
95
H3C-SO2NH2
H3C-SO2NH2
H3C-SO2NH2
H3C-SO2NH2
0.9
0.15
0.2
0.15
1.2
0.3
0.4
0.25
15
H3C-SO2NH2
3.5
87
5
85
a808C.
bReflux.
cIsolated yield.

Table 2. N-Acylation of sulfonamides with carboxylic acid chlorides in n-hexane or solvent-free condition
Solvent freea
n-hexaneb
Carboxylic
acid anhydride
Entry
1
Sulfonamide
Product
Time (h)
5
Yield (%)c
95
Time (h)
Yield (%)c
90
2.5
1.5
1.8
7
2
3
4
5
6
7
8
9
1.8
2.5
6
92
85
80
85
87
90
92
85
85
80
75
78
75
85
90
80
1
1.5
1.5
2.3
1.2
1
1.2
2
H3C-SO2NH2
H3C-SO2NH2
H3C-SO2NH2
1
0.3
a808C.
bReflux.
cIsolated yield.

Synthesis of N-Acylsulfonamide
271
EXPERIMENTAL
All chemicals were purchased from Merck and Fluka chemical companies.
The products were characterized by comparing the physical data and
spectral data with those of known samples. Infrared spectra were recorded
1
on Nicollet (impact 400D model) FTIR spectrophotometer. H NMR and
13C NMR spectra were recorded on Bruker DRX 300 Avance spectropho-
tometer in DMSO-d6 as the solvent and TMS as internal standard. Column
chromatography was performed using silica gel 60 (230–400 mesh). All
yields refer to isolated yields.
Preparation of Silica Chloride
Thionyl chloride (40 mL) was added to oven-dried (1208C, vacuum) silica gel
(10 g) in a round-bottomed flask (250 mL) equipped with a condenser and
drying tube and refluxed for 48 h. The unreacted thionyl chloride was
distilled off. The resulting white-grayish powder was flame dried and stored
in a tightly capped bottle. This silica chloride can be stored for months in
the absence of moisture without decreasing its activity.
General Procedure for N-Acylation of Sulfonamides under Solvent-
Free Condition
To a vigorously stirred mixture of sulfonamide (1 mmol) and silica chloride
(0.3 g), carboxylic acid chloride (2 mmol) or carboxylic acid anhydride
(2 mmol) was added at 808C in two portions. The progress of the reaction
was monitored by TLC. After completion of the reaction, ethyl acetate
(20 ml) was added, and the solid catalyst was removed by filtration. The
solvent was washed with water and dried over MgSO4. After evaporation of
the solvent, the crude product was purified by column chromatography on
silica gel (60–120 mesh, EtOAc–petroleum ether) or by recrystallization
(toluene or ethyl acetate–n-hexane) to afford the corresponding N-acyl sulfo-
namide in good to high yield.
General Procedure for N-Acylation of Sulfonamides in n-Hexane
A mixture of sulfonamide (1 mmol), carboxylic acid chloride (2 mmol), or
carboxylic acid anhydride (2 mmol) was refluxed in n-hexane (5 mmol) in
the presence of silica chloride (0.3 g) for the appropriate time. The progress
of the reaction was monitored by TLC. After completion of the reaction, the
catalyst was filtered off, and water (10 mL) was added and extracted with
ethyl acetate (2 Â 10 mL). The solvent was evaporated, and the crude

272
A. R. Massah et al.
product was purified by column chromatography on silica gel (60–120 mesh,
EtOAc–petroleum ether) or recrystallization (toluene or ethyl acetate–n-
hexane) to afford the pure product.
Spectral Data of Some Isolated N-Acylsulfonamides
N-Isobutanoyl-4-methyl Benzensulfonamide (Table 1, Entry 9)
mp 111–1138C, IR y (cm21) 3259, 1731, 1329, 1171; 1H NMR (DMSO-d6): d
0.92 (d, J ¼ 6.8 Hz, 6H), 2.38 (s, 3H), 2.41–2.46 (m, 1H), 7.4 (d, J ¼ 7.8 Hz,
2H), 7.78 (d, J ¼ 7.8 Hz, 2H), 11.99 (s, 1H); 13C NMR (DMSO-d6): d 16.92,
19.57, 32.75, 125.97, 128.03, 135.03, 142.6, 173.7.
N-Propanoyl Methansulfonamide (Table 1, Entry 12)
mp 70–728C, IR y (cm21) 3143, 1687, 1343, 1158; 1H NMR (DMSO-d6): d
0.99 (t, J ¼ 7.5 Hz, 3H), 2.27 (q, J ¼ 7.5 Hz, 2H), 3.22 (s, 3H), 11.63 (s, 1H);
13C NMR (DMSO-d6): d 8.84, 29.16, 43.58, 173.72.
N-Butanoyl Methansulfonamide (Table 1, Entry 13)
mp 68–708C, IR y (cm21) 3203, 1700, 1330, 1151; 1H NMR (DMSO-d6): d
0.86 (t, J ¼ 7.3 Hz, 3H), 1.53 (sext, J ¼ 7.3 Hz, 2H), 2.23 (t, J ¼ 7.3 Hz, 3H),
3.22 (s, 3H), 11.64 (s, 1H); 13C NMR (DMSO-d6): d 13.22, 17.50, 37.14,
40.88, 172.46.
N-Isobutanoyl Methansulfonamide (Table 1, Entry 14)
mp 97–998C, IR y (cm21) 3213, 1717, 1329, 1158; 1H NMR (DMSO-d6): d
1.03 (d, J ¼ 6.8 Hz, 6H), 2.49 (sept, J ¼ 6.8 Hz, 1H), 3.22 (s, 3H), 11.64
(s, 1H); 13C NMR (DMSO-d6): d 19.05, 34.73, 41.32, 176.85.
ACKNOWLEDGMENT
We thank Dr. Taki for his kind help and also Islamic Azad University of
Shahreza Research Council for partial support.
REFERENCES
1. (a) McKillop, A.; Young, D. W. Synthesis 1979, 401; (b) Cornelis, A.; Laszlo, P.
Synthesis 1985, 909.

Synthesis of N-Acylsulfonamide
273
2. (a) Keinan, E.; Mazur, Y. J. Org. Chem. 1978, 43, 1020; (b) Tal, D. M.; Keinan, E.;
Mazur, Y. Tetrahedron 1981, 37, 4327; (c) Onoferio, F. D.; Scettri, A. Synthesis
1985, 1159; (d) Chavez, F.; Suarez, S.; Diaz, M. A. Synth. Commun. 1994, 24,
2325; (e) Nishiguchi, T.; Kamio, C. J. Chem. Soc. Perkin Trans.I 1989, 707.
3. Salehi, P.; Zolfigol, M. A.; Shirini, F.; Baghbanzadeh, M. Curr. Org. Chem. 2006,
10, 2171.
4. (a) Firouzabadi, H.; Iranpoor, N.; Karimi, B.; Hazarkhani, H. Synlett. 2000, 263;
(b) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. Phosphorus, Sulfur Relat.
Elem. Silicon 2002, 177, 2847.
5. Shirini, F.; Zolfigol, M. A.; Khaleghi, M.; Mohammadpour-Baltork, I. Synth.
Commun. 2003, 33, 1839.
6. Shirini, F.; Zolfigol, M. A.; Khaleghi, M. Phosphorus, Sulfur Relat. Elem. Silicon
2003, 178, 1999.
7. Zolfigol, M. A.; Torabi, M.; Mallakpour, S. E. Tetrahedron 2001, 57, 8381.
8. Zolfigol, M. A.; Shirini, F.; Ghorbani, A. Synth. Commun. 2002, 32, 1809.
9. Firouzabadi, H.; Iranpoor, N.; Karimi, B.; Hazarkhani, H. Synth. Commun. 2003,
33, 3671.
10. Sharghi, H.; Hassani Nejad, A. R. J. Chem. Res. 2003, 87.
11. Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H.; Karimi, B. Synth. Commun. 2003,
33, 3653.
12. (a) Hasegawa, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 423;
(b) 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; (c) 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.; Greenlee, W. J.
J. Med. Chem. 1994, 37, 4464; (d) 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.
13. (a) Kondo, K.; Sekimoto, E.; Nakao, J.; Murakami, Y. Tetrahedron. 2000, 56,
5843; (b) Kondo, K.; Sekimoto, E.; Miki, K.; Murakami, Y. J. Chem. Soc.,
Perkin Trans.1 1998, 2973; (c) Ishizuka, N.; Matsumura, K. I.; Hayashi, K.;
Sakai, K.; Yamamori, T. Synthesis. 2000, 6, 784; (d) Ishizuka, N.;
Matsumura, K. I Japanese Patent JP-10045705; (e) Inoe, T.; Myahara, O.;
Takahashi, A.; Nakamura, Y. Japanese Patent JP-08198840.
14. Morisawa, Y.; Kataoka, M.; Nagahori, H.; Sakamoto, T.; Kitano, N.; Kusano, K.;
Sato, K. J. Med. Chem. 1980, 23, 1376.
15. Martin, M. T.; Roschangar, F.; Eaddy, J. F. Tetrahedron. Lett. 2003, 44, 5461.
16. Singh, D. U.; Singh, P. R.; Samant, S. D. Tetrahedron Lett. 2004, 45, 4805.
17. (a) Mohanazadeh, F.; Momeni, A. R.; Ranjbar, Y. Tetrahedron Lett. 1994, 35,
6127; (b) Mohanazadeh, F.; Momeni, A. R. J. Sci. I. R. Iran 1996, 7, 261.
18. Massah, A. R.; Kazemi, F.; Azadi, D.; Farzaneh, S.; Aliyan, H.; Javaherian, H.;
Momeni, A. R. Lett. Org. Chem. 2006, 3, 235.