Cs2CO3 catalyzed rapid and efficient conversion of amines into sulfonamides; Alcohols and phenols into sulfonic esters

Article abstract of DOI:10.1080/10426507.2010.544271

A simple and efficient method has been developed for the sulfonylation of several amines, alcohols, and phenols by p-toluenesulphonylchloride (p-TsCl) in the presence of catalytic amount of Cs₂CO₃ at 25C to obtain sulfonamides and sulfonic esters in very good yields. Cs2CO3 has been found to be highly efficient catalyst. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.544271

This article was downloaded by: [University of Tennessee, Knoxville]
On: 18 April 2013, At: 09:28
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Cs2CO3 Catalyzed Rapid and Efficient
Conversion of Amines into Sulfonamides;
Alcohols and Phenols into Sulfonic Esters
M. B. Madhusudana Reddy a & M. A. Pasha a
a Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bengaluru, India
Version of record first published: 24 Aug 2011.
To cite this article: M. B. Madhusudana Reddy & M. A. Pasha (2011): Cs2CO3 Catalyzed Rapid
and Efficient Conversion of Amines into Sulfonamides; Alcohols and Phenols into Sulfonic Esters,
Phosphorus, Sulfur, and Silicon and the Related Elements, 186:9, 1867-1875
To link to this article: http://dx.doi.org/10.1080/10426507.2010.544271
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 186:1867–1875, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.544271
Cs2CO3 CATALYZED RAPID AND EFFICIENT CONVERSION
OF AMINES INTO SULFONAMIDES; ALCOHOLS AND
PHENOLS INTO SULFONIC ESTERS
M. B. Madhusudana Reddy and M. A. Pasha
Department of Studies in Chemistry, Central College Campus, Bangalore
University, Bengaluru, India
GRAPHICAL ABSTRACT
R
HN
O
S
R
R'
N
R'
O
85-95%
R = H, Alkyl, aryl
R' = Aryl, alkyl
O
S
Cs2CO3, MeCN
10-30 min
Cl
25 oC
O
O
HO R''
S
O
R''
O
90-98%
Abstract A simple and efficient method has been developed for the sulfonylation of several
amines, alcohols, and phenols by p-toluenesulphonylchloride (p-TsCl) in the presence of cat-
alytic amount of Cs2CO3 at 25◦C to obtain sulfonamides and sulfonic esters in very good
yields. Cs2CO3 has been found to be highly efficient catalyst.
Keywords Sulfonylation; amines; alcohols; phenols; ce´sium carbonate
INTRODUCTION
Sulfonylation of amines, alcohols, and phenols is an important reaction in synthetic
organic chemistry. Sulfonamides are known to have extensive applications as pharma-
ceuticals because of their wide range of biological activities, such as anti-inflammatory,
antiviral, and anticancer activities.1 In addition, the sulfonyl group is one of the versatile
Received 11 October 2010; accepted 26 November 2010.
Address correspondence to M. A. Pasha, Department of Studies in Chemistry, Central College Campus,
Bangalore University, Bengaluru–560 001, India. E-mail: m af pasha@ymail.com
1867

1868
M. B. MADHUSUDANA REDDY AND M. A. PASHA
amino and hydroxyl-protecting groups in organic synthesis.2 The sulfonyl derivatives are
useful as drugs for Alzheimer’s disease,3 inhibitors of t-RNA synthetases, as an antibacterial
agents,4 etc. Prostaglandin F1α sulfonamides are potential drugs in the treatment of osteo-
porosis,5 find application as antagonists for angiotensin II,6 and leukotriene D4-receptors
incorporate this functional group.7
Arylsulfones on the other hand have received much attention as powerful anti-HIV-1
agents.8 In particular, sulfonylation is an important reaction in the synthesis of certain
naturally occurring bioactive molecules;9 and sulfonamides are found in a number of
biologically active molecules.10
Sulfonylation of amines and alcohols is reported in the literature.11–23 For example
p-TSA(p-toluenesulfonic acid) reacts with amines in the presence of cyanuric chloride-
DMF,12 p-TsCl with In-MeCN13 Zn-THF,14 Na2CO3 or K2CO3,15 pyridine,16 NaOH,17 and
triethylamine.18 Wang et al. have reported the use of ionic scavenger,19 Jafarpour et al.
have reported the use of silica gel,20 Dabkowaski et al. have reported the use of triazole
for the synthesis of sulfonamides from acid chlorides;21 while Xia et al. used microwave
radiation to promote this reaction,22 Jonathan et al. have described the applicability of
pentafluorophenol sulfonates instead of sulfonyl chlorides.23
The available methods for the sulfonylation suffer from disadvantages such as the
use of expensive reagents, formation of side products,11b high temperature or microwave
oven or sonicator,22 or certain reagents, such as indium salts.13 which are difficult to
procure. Therefore, a mild, convenient and high yielding procedure for sulfonylation using
an inexpensive catalyst would be valuable.
In continuation of our work on the development of new methods using simple and
readily available catalysts for the synthesis of biologically active molecules,24 we report
herein, a rapid, convenient, and novel procedure for the sulfonylation of amines, phenols,
and alcohols using p-toluenesulfonyl chloride (p-TsCl) with Cs2CO3 as catalyst under
mild conditions (Scheme 1). All the compounds synthesized are known and they were
characterized by IR and GC-mass spectral analysis; physical property such as mp also
agrees with the reported values.
R
HN
O
S
R
R'
N
R'
O
85-95%
R = H, Alkyl, aryl
R' = Aryl, alkyl
O
S
Cs2CO3, MeCN
10-30 min
Cl
25 oC
O
O
HO R''
S
O
R''
O
90-98%

Cs2CO3 CATALYSED SYNTHESIS OF SULFONAMIDES AND SULFONIC ESTERS
1869
RESULTS AND DISCUSSION
As shown in Scheme 1, the reaction between p-TsCl and the substrates proceed
smoothly in the presence of Cs2CO3. Initially, to optimize the reaction conditions, effect of
the solvent and catalyst was studied for the reaction between 4-methoxyaniline and p-TsCl.
It was observed that the yields obtained were highest in acetonitrile among the solvents
used that includes DMF, diethyl ether, toluene, and tetrahydrofuran (Table 1). It appears
that the accetonitrile enhances the rate of the reaction giving high yield of the sulfonamide
(Table 1). With regard to the amount of catalyst required for completion of the reaction, it
was found that the decreasing in the quantity of catalyst from 1 to 0.5 mol% reduces the
yield substantially from 93 to 75% (Table 1, entries e and f). However, the increase in the
quantity of catalyst from 1 to 1.5 mol% has little effect on the yield of the product (Table
1, entries e and g).
However, when the same reaction was carried out in the absence of Cs2CO3 only 10%
product was realized even after 25 min (Table 1, entry h), demonstrating that, the catalyst is
necessary for initiating the reaction (Table 1, entries a–h), and 1 mol% of Cs2CO3 appears
to be optimum for the efficient by catalyzing the reaction.
We next examined the sulfonylation reaction of a variety of amines with p-TsCl under
the optimized conditions and the results are presented in Table 2. Amines with electron
donating (Table 2, entries b and r) as well as electron withdrawing groups (Table 2, entries
c–h) react readily with p-TsCl to give substituted sulfonamides in good yields. Diphenyl
amine (2j) and dicylcohexylamine (2n) also react to give the corresponding products in high
yields (85 and 80%, Table 2, entries 3j and 3n). The method was found to be applicable
to N-hetrocycles as well for example piperidine (2p) and imidazole (2q) also produce the
desired sulfonamides 3p and 3q in 86 and 88% respectively. When primary amines such as
benzyl amine (2o) and cyclohexylamine (2m) were treated with p-TsCl (1), the respective
sulfonamides 3m and 3o were obtained in 83 and 84% yields.
Notably, the same procedure could be utilized to the synthesis of sulfonic esters. The
reaction of phenols with p-TsCl readily gives the respective sulfonic esters in excellent yield,
for example, phenol derivatives could be employed to obtain sulfonic esters. The results
of this study are presented in Table 3. Even deactivated phenols such as 4-fluorophenol
(4c), 4-chlorophenol (4d), and 4-bromophenol (4e) produce the respective sulfonic esters
in excellent yield (Table 3, entries c, d, and e). Similarly, the reaction of naphthalen-1-ol
Table 1 Optimization of reaction conditions for the sulfonylation of 4-methoxyaniline with p-TsCla
Entry
Catalyst (mol%)
Solvent (5 ml)
Yield (%)
a
b
c
d
e
f
1
1
1
1
1
0.5
1.5
—
DMF
55
47
45
60
93
75
91
10
Diethyl ether
Toluene
THF
MeCN
MeCN
MeCN
MeCN
g
h
aAll the reactions were carried out in a 25 ml rb flask; 5 mmol of 4-methoxyaniline, 5.5 mmol of p-TsCl and
Cs2CO3; rapidly stirred for 25 min at 25 ◦C.

1870
M. B. MADHUSUDANA REDDY AND M. A. PASHA
Table 2 Cs2CO3 catalyzed synthesis of sulfonamides
Entry
a
Amine (2)
Product (3)a
Time (min)
Yield (%)b [Ref]
96 [11(d)]
15
18
21
23
25
b
c
d
e
95 [11(d)]
93 [18(a)]
92 [11(d)]
93 [11(d)]
f
25
30
30
93 [11(d)]
83 [11(d)]
80 [11(d)]
g
h
i
j
30
28
81 [(16)]
85[15(a)]
k
l
29
30
87 [15(a)]
81 [15(a)]

Cs2CO3 CATALYSED SYNTHESIS OF SULFONAMIDES AND SULFONIC ESTERS
1871
Table 2 Cs2CO3 catalyzed synthesis of sulfonamides (Continued)
Entry
m
Amine (2)
Product (3)a
Time (min)
27
Yield (%)b [Ref]
83 [12]
n
30
80 [18]
o
28
84[20]
p
q
r
25
30
20
86[11d]
88 [21]
93[11d]
aAll the reactions were performed using an amine (5 mmol), p-TsCl (5.5 mmol) and 1 mol% of Cs2CO3.
bIsolated yield, and all the compounds are known and physical properties agree with the reported values;
characterized by IR and GC-mass spectral analysis.
(4i) and naphthalen-2-ol (4j) with p-TsCl resulted in expected sulfonic esters 5i and 5j in
high yield (Table 3, entries 5i and 5j). In particular, cyclohexyl-methanol (4l) reacts readily
with p-TsCl to give 5l in good yield (Table 3, entry 5l). Further, 4-acetylphenol (4o) was
also found to react readily with p-TsCl to give the sulfonic ester in excellent yield (Table
3, entry 5o).
A comparative study of efficiency of different catalysts used for the synthesis of
p-toluene sulfonamides with the catalyst presently employed is presented in Table 4. It is
evident that the present catalyst Cs2CO3 is best suited.
According to the literature reports, the Cs2CO3 acts as base25 and helps in the
deprotonation of substrate molecules, which in turn facilitates the removal of chloride
ion from p-TsCl and hence leading to the formation of the desired product.

1872
M. B. MADHUSUDANA REDDY AND M. A. PASHA
Table 3 Cs2CO3 catalyzed synthesis sulfonic esters
Entry
a
Phenol/alcohol (4)
Product (5)a
Time (min)
Yield (%)b [Ref]
98 [11(d)]
10
12
15
b
c
95 [22]
96 [22]
d
e
15
22
95 [17]
92 [11(d)]
f
20
25
28
97 [11(d)]
89 [11(d)]
80 [11(d)]
g
h
i
30
91 [22]
j
25
27
96 [18]
k
90 [15(b)]
l
30
83 [11(d)]

Cs2CO3 CATALYSED SYNTHESIS OF SULFONAMIDES AND SULFONIC ESTERS
1873
Table 3 Cs2CO3 catalyzed synthesis sulfonic esters
Entry
m
Phenol/alcohol (4)
Product (5)
Time (min)
23
Yield (%)b [Ref]
81 [17]
n
o
30
28
82 [17]
95 [18]
aAll the reactions were performed using a phenol (or alcohol) (5 mmol), p-TsCl (5.5 mmol), and 1 mol% of
Cs2CO3.
bIsolated yield, and all the compounds are known and physical properties agree with the reported values; were
characterized by IR and GC-Mass spectral analysis.
Conclusions
In conclusion, a novel, efficient, and high yielding method for the sulfonylation of
amines, phenols, and alcohols using p-TsCl as a sulfonylation agent and Cs2CO3 as a
◦
catalyst at 25 C has been developed. This is a simple and economically viable method
for the synthesis of sulfonamides from amines, and sulfonic esters from phenols and
alcohols.
Table 4 Catalytic activity of Cs2CO3 with other reported catalysts for the synthesis of p-sulfonamides present
at 25 ◦C system with the reported methods
Entry
Reagents
Time (min)
Yielda [Ref]
a
b
c
d
p-TsCl/CuO/MeCN
2,4,6-trichloro-1,3,5-triazine/DMF
Na2CO3 or K2CO3
60
50
60
25
92 [11(d)]
64 [12]
78 [15(a)]
93b,c
p-TsCl/Cs2CO3/MeCN
aIsolated yield.
bPresent method.
cReaction conditions: 4-methoxyaniline (5mmol), p-TsCl (5.5mmol), Cs2CO3 (1 mol%), and acetonitrile (5mL)
at stirred at 25 ◦C.

1874
M. B. MADHUSUDANA REDDY AND M. A. PASHA
EXPERIMENTAL
Materials and Methods
The chemicals used were commercial samples, and all the reactions were carried at
25 ◦C. GC-mass spectra were obtained using a Shimadzu GC-MS QP 5050A spectrometer
equipped with a 30 m length and 0.32 mm dia BP-5 column with the column temperature
◦
maintained at 80–15–250 C. Infrared spectra were recorded using a Shimadzu FT-IR-
8400s spectrophotometer as KBr pellets for solids and as thin films between NaCl plates
in the case of liquids. Melting points (mp) were determined using a Raaga, Chennai, India.
Typical Procedure for Sulfonylation of 4-Methoxyaniline with p-TsCl
To a solution of 4-methoxyaniline (5 mmol) in MeCN (5 mL), p-TsCl (5.5 mmol),
and Cs2CO3 (1 mol%), were added. The reaction mixture was stirred rapidly at 25 ◦C for
25 min. The progress of the reaction was monitored by thin-layer chromatography (TLC).
After completion of the reaction, the mixture was diluted with water (20 mL) and product
was extracted with ethyl acetate (20 mL). The organic extract was dried over anhydrous
MgSO4 and it was concentrated under reduced pressure to get a cream colored N-(4-
methoxyphenyl)-4-methyl-benzenesulfonamide solid (93%; mp 103 ◦C). The purity of the
compounds were a checked by GC/MS analysis. In all the cases the sulfonylation product
was found to be of high purity.
REFERENCES
1. (a) C. T. Supuran, A. Casini, and A. Scozzafava, Med. Res. Rev., 5, 535–558 (2003); (b) A.
Scozzafava, T. Owa, A. Mastrolorenzo, and C. T. Supuran, Curr. Med. Chem., 10, 925–953
(2003); (c) W. G. Harter, H. Albrect, K. Brady, B. Caprathe, J. Dunbar, J. Gilmore, S. Hays, C.
R. Kostlan, B. Lunney, and N. Walker, Bioorg. Med. Chem. Lett., 14, 809–812 (2004); (d) N.
S. Reddy, M. R. Mallireddigari, K. G. Cosenza, S. C. Bell, E. P. Reddy, and M. V. R. Reddy,
Bioorg. Med. Chem. Lett., 14, 4093–4097 (2004); (e) B. R. Stranix, J. F. Lavallee, G. Sevigny, J.
Yelle, V. Perron, N. Leberre, D. Herbart, and J. J. Wu, Bioorg. Med. Hem. Lett., 16, 3459–3462
(2006).
2. (a) A. Nishida, T. Hamada, and O. Yonemitsu, J. Org. Chem., 53, 3386–3387 (1988); (b) W.
Yuan, K. Fearson, and M. H. Gelb, J. Org. Chem., 54, 906–910 (1989); (c) J. F. O’Connell and
H. Rapoport, J. Org. Chem., 57, 4775–4777 (1992); (d) S. Chandrasekhar and S. Mohapatra,
Tetrahedron Lett., 39, 695–698 (1998).
3. T. Hasegawa and H. Yamamoto, Bull. Chem. Soc. Jpn., 73, 423–428 (2000).
4. M. G. Banwell, C. F. Crasto, C. J. Easton, A. K. Forrest, T. Karoli, D. R. March, L. Mensah, M.
R. Nairn, P. J. O’Hanlon, M. D. Oldham, and W. Yue, Bioorg. Med. Chem. Lett., 10, 2263–2266
(2000).
5. Y. Wang, D. L. Soper, M. J. Dirr, M. A. Delong, B. De, and J. A. Wos, Chem. Pharm. Bull., 48,
1332–1337 (2000).
6. L. L. Chang, W. T. Ashton, K. L. Flanagan, T. B. Chen, S. S. O’Malley, G. J. Zingaro, P. K.
S. Siegl, S. D. Kivlighn, V. J. Lotti, R. S. L. Chang, and W. J. Greenlee, J. Med. Chem., 37,
4464–4478 (1994).
7. J. H. Musser, A. F. Kreft, R. H. W. Bender, D. M. Kubrak, D. Grimes, R. P. Carlson, J. M. Hand,
and J. Chang, J. Med. Chem., 33, 240–245 (1990).

Cs2CO3 CATALYSED SYNTHESIS OF SULFONAMIDES AND SULFONIC ESTERS
1875
8. J. B. Mc Mohan, R. J. Gulakowsky, O. S. Weislow, R. J. Schultz, V. L. Narayanan, D. J. Clanton,
R. Pedemonte, F. W. Wassmundt, R. W. Buckheit Jr, W. D. Decker, E. L. White, J. P. Bader, and
M. R. Boyd, Antimicrob. Agents. Chemother., 37, 754–760 (1993).
9. (a) Y. Yoshida, Y. Sakakura, N. Aso, S. Okada, and Y. Tanabe, Tetrahedron, 55, 2183–2192
(1999); (b) Y. Tanabe, H. Yamamoto, Y. Yoshida, T. Miyawaki, and N. Utsumi, Bull. Chem. Soc.
Jpn., 68, 297–300 (1995); (c) Y. Yoshida, K. Shimonishi, Y. Sakakura, Y. S. Okada, N. Aso, and
Y. Tanabe, Synthesis, 143, 1633–1636 (1999).
10. (a) J. Schroder, A. Henke, H. Wenzel, H. Brandstetter, H. G. Stammler, A. Stammler, W. D.
Pfeiffer, and H. Tschesche, J. Med. Chem., 44, 3231–3243 (2001); (b) Y. Tamaru, F. Watanabe, T.
Nakatani, K. Yasui, M. Fuji, T. Komurasaki, H. Tsuzuki, R. Maekawa, T. Yoshioka, K. Kawada,
K. Sugita, and M. Ohtani, J. Med. Chem., 41, 640–649 (1998).
11. (a) K. K. Anderson, In Comprehensive Organic Chemistry, D. N. Jones, Ed. (Pergamon Press,
Oxford, 149, 1979), Vol 3, 331–340, 345–350; (b) A. Yasuhara, M. Kameda, and T. Sakamoto,
Chem. Pharm. Bull., 47, 809–812 (1999); (c) M. Mokhtar, T. S. Saleh, N. S. Ahmed, S. A.
Al-Thabaiti, and R. A. Al-Shareef, Ultrason. Sonochem., 18(1), 172–176 (2011); (d) G. A.
Meshram and V. D. Patil, Tetrahedron Lett., 50, 1117–1121 (2009); (e) S. Velusamy, K. J. S.
Kumar, and T. Punniyamurthy, Tetrahedron Lett., 45, 203–205 (2004).
12. S. S. Pandit, V. U. Pandit, and B. P. Bandgar, J. Sulfur Chem., 29(6), 619–622 (2008).
13. J.-G. Kim and D. O. Jang, Synlett, 16, 2501–2504 (2007).
14. M. S. R. Murty, R. N. Reddy, and J. S. Yadav, J. Sulfur Chem., 27(6), 589–593 (2006).
15. (a) A. R. Massah, F. Kazemi, D. Azadi, S. Farzaneh, H. Aliyan, H. J. Naghash, and A. R. Momeni,
Lett. Org. Chem., 3, 235–241 (2006); (b) F. Kazemi, A. R. Massah, M. Javaherian, and I. Zanjan,
Tetrahedron, 63(23), 5083–5087 (2007).
16. S. K. Nayak, Synthesis, 11, 1575–1578 (2000).
17. N. Zhao, Y. Li, Y. wang, and J. wang, J. Sulfur Chem., 27(5), 427–432 (2006).
18. (a) K. K. Park, J. J. Lee, and J. Ryu, Tetrahedron, 59(39), 7651–7659 (2003); (b) D. Zim, V. R.
Lando, J. Dupont, and A. L. Monteiro, Org. Lett., 3(19), 3049–3051 (2001); (c) T. Ankner and
G. R. Hilmersson, Org. Lett., 11(3), 503–506 (2009); (d) N. A. Suttle and A. Williams, J. Chem.
Soc. Perkin Trans. II, 10, 1563–1567 (1983).
19. M. Lei, X.-L. Tao, and Y. G. Wang, Helvet. Chim. Acta, 89, 532–536 (2006).
20. M. Jafarpour, A. Rezaeifard, and M. Aliabadi, Appl. Catal., A: General, 358(1), 49–53 (2009).
21. W. Dabkowski, J. Michalski, and Z. Skrzypczynski, Phosphorus, Sulfur Silicon Relat. Elem.,
26(3), 321–326 (1986).
22. L. W. Xu and C. G. Xia, Synth. Commun., 34(7), 1199–1205 (2004).
23. J. D. Wilden, L. Geldeard, C. C. Lee, D. B. Judd, and S. Caddick, Chem. Commun., 1074–1076
(2007).
24. (a) M. A. Pasha, M. B. M. Reddy, Synth. Commun., 39, 2928–2934 (2009); (b) M. A. Pasha
and V. P. Jayashankara, Bioorg. Med. Chem. Lett., 17, 621–623 (2007); (c) M. A. Pasha, V. P.
Jayashankara, and N. R. Swamy, Synth. Commun., 37, 1551–1556 (2007).
25. Y. Nishiyama, Y. Koguma, T. Tanaka, and R. Umeda, Molecules, 14, 3367–3375 (2009).