Base-free monosulfonylation of amines using tosyl or mesyl chloride in water

Article abstract of DOI:10.1016/j.tetlet.2007.11.044

A mild and efficient procedure has been developed for the monosulfonylation of various amines using mesyl or tosyl chlorides in water at room temperature to afford the corresponding sulfonamides in high yields.

Full text of DOI:10.1016/j.tetlet.2007.11.044

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 348–353
Base-free monosulfonylation of amines using tosyl
or mesyl chloride in water
Ahmed Kamal,* J. Surendranadha Reddy, E. Vijaya Bharathi and D. Dastagiri
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 August 2007; revised 30 October 2007; accepted 7 November 2007
Available online 13 November 2007
Abstract—A mild and efficient procedure has been developed for the monosulfonylation of various amines using mesyl or tosyl
chlorides in water at room temperature to afford the corresponding sulfonamides in high yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Sulfonamides are a diverse group of pharmaceutically
important compounds1,2 widely used as antibacterial,
anticancer, anticonvulsant, antiinflammatory and anti-
viral agents and HIV protease inhibitors. Examples of
recently approved drugs possessing a sulfonamide
include the antihypertensive agent bosentan,3 the antivi-
ral HIV protease inhibitor amprenavir4 and the phos-
phodiesterase-5 inhibitor sildenafil.5 In addition,
numerous sulfonamide derivatives have been in preclin-
ical development. Sulfonylation is a significant reaction
in the synthesis of naturally occurring bioactive mole-
cules and is an important method for the protection
of amines.6,7 Although many efforts have been made
towards the development of novel sulfonamides,8 the
conventional synthesis involves the reaction of amino
compounds with sulfonyl chlorides.9 However, these
procedures involve the use of organic solvents, base
and elevated temperatures, especially for less reac-
tive aniline substrates. For sterically hindered primary
amines with electron withdrawing substituents, bis-
sulfonylation is a common side reaction, which necessi-
tates a further mono desulfonylation step.10 Recently,
Deng and Mani reported11 the synthesis of sulfonamides
in water. However, pH control with Na2CO3 was neces-
sary and the isolation of the product involved acidifi-
cation up to pH 2 with HCl.
In recent years, organic reactions in water have received
considerable attention. The use of water as a solvent has
several advantages, including preventing the generation
of waste, avoiding the use of hazardous substances
(e.g., halogenated and high-boiling solvents)12 and min-
imization of energy requirements.13 Thus, the use of
water instead of organic solvents has gained much
importance in the development of sustainable chemis-
try.14 There are only limited examples of organic reac-
tions that have been carried out in water, particularly
in the absence of a catalyst.15 In continuation of our
efforts to develop environmentally friendly synthetic
methodologies,16,17 we have investigated the base-free
monosulfonylation of amines in water. In these mono-
sulfonylation reactions, comparable yields were
obtained using tap as well as distilled water; here, the
reactions were carried out in tap water.
In a typical procedure, a suspension of amine in water
was treated with an addition of p-toluenesulfonyl chlo-
ride or methanesulfonyl chloride at room temperature
to afford the corresponding sulfonamide in high yields
ranging from 85% to 95% (Scheme 1). The reactions
were rapid with most of the amines studied (20–
60 min) and were compatible with a variety of primary
R2
H
TsCl/MsCl
N
N
R1
R
R1
rt, water
R
Keywords: Sulfonamides; Amines; p-Toluenesulfonyl chloride;
Methanesulfonyl chloride; Water.
R = aryl, benzyl, furfuryl, cycloalkyl; R1 = H ; R2 = Ts, Ms
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@
iictnet.org
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.044

A. Kamal et al. / Tetrahedron Letters 49 (2008) 348–353
349
Table 1. Sulfonamide synthesis in water
Entry
Substrate
NH2
Product
Time (min)
25
Yield (%)
H
1
95
91
90
N
Ts
H
NH2
N
2
3
35
30
Ms
H
NH2
N
Ts
F
F
F
H
NH2
N
Ms
4
35
85
F
Ts
N
NH2
NH2
5
6
25
35
89
87
H
Ms
N
H
Ts
N
NH
NH
7
8
30
40
90
87
Ms
N
Ts
N
NH
9
30
92
O
O
O
Ms
N
NH
10
11
35
25
87
95
O
H
NH2
N
Ts
Br
Br
Br
H
NH2
N
Ms
12
13
35
30
91
Br
H
NH2
Cl
N
Ts
90
Cl
(continued on next page)

350
A. Kamal et al. / Tetrahedron Letters 49 (2008) 348–353
Table 1 (continued)
Entry
Substrate
NH2
Product
Time (min)
35
Yield (%)
85
H
N
14
15
Ms
Cl
Cl
CH3
CH3
H
NH2
NH2
N
25
35
89
87
Ts
I
I
I
CH3
CH3
H
N
16
Ms
I
H
NH2
N
Ts
17
18
19
20
30
40
30
35
90
87
92
87
OCH3
OCH3
H
NH2
N
Ms
OCH3
OCH3
H
NH2
N
Ts
COOH
COOH
H
N
NH2
Ms
COOH
COOH
Ts
N
NH
NH
21
22
25
35
95
91
N
N
N
Boc
Boc
Boc
Ms
N
N
Boc
Ts
N
NH
23
30
90
N
N
Ph
Ph
Ms
N
NH
NH
24
25
35
25
85
89
N
N
N
Ph
Bn
Ph
Ts
N
N
Bn

A. Kamal et al. / Tetrahedron Letters 49 (2008) 348–353
351
Table 1 (continued)
Entry
Substrate
Product
Time (min)
35
Yield (%)
Ms
N
NH
26
27
87
N
N
Bn
Bn
Ms
N
NH
NH
NH
NH
N
N
30
40
30
90
OMe
OMe
Ts
N
N
N
28
29
87
92
OMe
OMe
Ms
N
N
F
N
F
Ts
N
N
F
N
F
30
31
32
33
34
35
25
35
25
35
87
95
91
89
87
N
N
N
NH
Ms
N
N
N
NH
Ts
H
NH2
N
Ms
O
O
O
H
NH2
N
Ts
O
H
MeO
MeO
NH2
NH2
MeO
MeO
N
Ms
Ts
35
36
30
40
90
87
OMe
OMe
OMe
OMe
H
N
MeO
MeO
MeO
MeO
and secondary amines (Table 1). Bis-sulfonylated prod-
ucts were not observed using this procedure. All the
products were characterized by 1H NMR as well as mass
spectral data, and by a comparison with known com-
pounds. Further, the reaction rates with amines possess-
ing different electronic and steric characteristics have

352
A. Kamal et al. / Tetrahedron Letters 49 (2008) 348–353
14. (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998; (b) Li, C. J.;
Chang, T. H. Organic Reactions in Aqueous Media; Wiley:
New York, 1997; (c) Azizi, N.; Saidi, M. R. Org. Lett.
2005, 7, 3649.
15. (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int.
Ed. Engl. 1971, 10, 496; (b) Larpent, C.; Patin, H.
Tetrahedron 1988, 44, 6107; (c) Larpent, C.; Meignan,
G.; Patin, H. Tetrahedron 1990, 46, 6381; (d) Jenner, G.
Tetrahedron 1996, 52, 13557; (e) Azizi, N.; Saidi, M. R.
Org. Lett. 2005, 7, 3649; (f) Zhang, X.; Houk, K.
Tetrahedron Lett. 2000, 41, 3107.
16. (a) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2004, 45,
8801; (b) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2005,
46, 1489; (c) Kamal, A.; Chouhan, G. Tetrahedron:
Asymmetry 2005, 16, 2784; (d) Kamal, A.; Reddy, D. R.;
Rajendar J. Mol. Catal. A: Chem. 2007, 227, 26.
17. (a) Kamal, A.; Reddy, D. R.; Rajendar Tetrahedron Lett.
2006, 47, 2261; (b) Kamal, A.; Shankaraiah, N.; Reddy,
K. L.; Devaiah, V. Tetrahedron Lett. 2006, 47, 4253; (c)
Kamal, A.; Shankaraiah, N.; Reddy, K. L.; Devaiah, V.
Tetrahedron Lett. 2006, 47, 6553.
18. General experimental procedure: To a stirred solution of
amine (1 mmol) in water (10 mL) was added TsCl or MsCl
(1.2 mmol) at room temperature and stirring was contin-
ued until the reaction was complete (monitored by TLC).
The reaction mixture was extracted with ethyl acetate,
dried over anhydrous sodium sulfate, concentrated under
reduced pressure and the residue was purified by column
chromatography (EtOAc–hexane) on silica gel (60–120
mesh) to yield the pure product.
been studied. The formation of sulfonamide product
was more rapid with the aliphatic amines when com-
pared to aromatic amines due to nucleophilicity. The
involvement of hydrogen bonds in determining the rate
of the reaction was clearly observed with furfurylamine.
Intramolecular hydrogen bond formation between the
N–H hydrogen atom and the oxygen of the furan ring
increases the nucleophilicity at the nitrogen atom and
should enhance the rate of the reaction. However, the
opposite was observed, probably because intramolecular
hydrogen bond formation in 2-furfuryl amine prevented
the hydrogen bond formation between the N–H hydro-
gen and the oxygen of water, which in turn decreased the
rate of the reaction.
In conclusion, we have developed a simple methodology
for the monosulfonylation of various amines in water
without the use of a base.18,19 The products were
obtained in high yields. This could find several applica-
tions in the syntheses of biologically important organic
compounds.
Acknowledgement
The authors (J.S.N.R., E.V.B. and D.D.) thank the
CSIR New Delhi, for the award of research fellowships.
19. Spectral data for novel sulfonamides (Table 1): 1-(2-
Methoxyphenyl)-4-(methylsulfonyl)piperazine (entry 27):
1H NMR (300 MHz, CDCl3): d 2.75 (s, 3H), 3.14 (s, 4H),
3.40 (s, 4H), 3.80 (s, 3H), 6.85–7.12 (m, 4H) ppm; 13C
NMR (75 MHz, CDCl3): d 33.9, 45.2, 49.8, 55.1, 113.5,
115.7, 118.2, 121.3, 143.1, 150.8 ppm; IR (KBr): 3262,
References and notes
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Antibiotics Primary Care Update Obstetricians/Gynecolo-
gists 1998, 5, 32.
2. Yoshino, H.; Ueda, N.; Nijima, J.; Sugumi, H.; Kotake,
Y.; Koyanagi, N.; Yoshimatsu, N. K.; Asada, M.;
Watanabe, T.; Nagasu, T.; Tsukahara, K.; Iijima, A.;
Kitoh, K. J. Med. Chem. 1992, 35, 2496.
3. Wu, C.; Decker, E. R.; Holland, G. W.; Brown, F. D.;
Stavros, F. D.; Brock, T. A.; Dixon, R. A. C. Drugs Today
2001, 37, 441.
4. De Clercq, E. Curr. Med. Chem. 2001, 8, 1543.
5. Rotella, D. P. Nat. Rev. Drug Discovery 2002, 1, 674.
6. Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63,
9455.
7. Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 31, 2209.
8. (a) Wright, S. W.; Hallstrom, K. N. J. Org. Chem. 2006,
71, 1080; (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.;
Vakulenko, A. V.; Tao, H. J. Org. Chem. 2005, 70, 9191;
(c) Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem.
Soc. 2004, 126, 1024; (d) Pandya, R.; Murashima, T.;
Tedeschi, L.; Barrett, A. G. M. J. Org. Chem. 2003, 68,
8274; (e) Lee, J. W.; Louie, Y. Q.; Walsh, D. P.; Chang, Y.
T. J. Comb. Chem. 2003, 5, 330; (f) Frost, C. G.; Hartley,
J. P.; Griffin, D. Synlett 2002, 1928.
9. Andersen, K. K.. In Comprehensive Organic Chemistry;
Jones, D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3.
10. Yasuhara, A.; Kameda, M.; Sakamoto, T. Chem. Pharm.
Bull. 1999, 47, 809.
11. Deng, X.; Mani, N. S. Green Chem. 2006, 8, 835.
12. Clark, J. H. Green Chem. 1999, 1.
3000, 2948, 2834, 1597, 1326, 1129, 897, 751 cmÀ1
;
MS(ESI): m/z 271 (M+1)+; HRMS m/z: (M+1)+ calcd
for C12H19N2O3S, 271.1116; found, 271.1118; 1-(2-
Methoxyphenyl)-4-tosylpiperazine (entry 28): 1H NMR
(300 MHz, CDCl3): d 2.47 (s, 3H), 3.18 (s, 4H), 3.26 (s,
4H), 3.78 (s, 3H), 6.77–6.99 (m, 4H), 7.37 (d, J = 8.0 Hz,
2H), 7.64 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d 21.3, 46.1, 50.0, 55.3, 111.1, 118.3, 120.7, 123.7,
125.5, 127.8, 129.6, 132.0, 143.6, 151.8 ppm; IR (KBr):
3449, 2953, 2914, 2830, 1593, 1344, 1136, 949, 759 cmÀ1
;
MS(ESI): m/z 347 (M+1)+; HRMS m/z: (M+1)+ calcd for
C18H23N2O3S, 347.1429; found, 347.1433; 1-(2-Fluoro-
phenyl)-4-(methylsulfonyl)piperazine (entry 29): 1H NMR
(300 MHz, CDCl3): d 2.75 (s, 3H), 3.15 (s, 4H), 3.40 (s,
4H), 6.88–7.13 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3):
d 34.1, 45.9, 50.1, 116.2, 119.3, 123.4, 124.5, 154.0,
157.3 ppm; IR (KBr): 3287, 2930, 1631, 1316, 984,
;
751 cmÀ1 MS(ESI): m/z 259 (M+1)+; HRMS m/z:
(M+1)+ calcd for C11H16FN2O2S, 259.0916; found,
259.0916; 1-(2-Fluorophenyl)-4-tosylpiperazine (entry
30): 1H NMR (300 MHz, CDCl3): d 2.45 (s, 3H), 3.15
(s, 4H), 3.42 (s, 4H), 6.72–6.96 (m, 4H), 7.30 (d,
J = 8.2 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H) ppm; 13C
NMR (75 MHz, CDCl3): d 21.4, 46.1, 52.1, 115.8, 118.6,
122.7, 123.5, 126.8, 130.1, 132.8, 143.5, 153.2, 156.1 ppm;
IR (KBr): 3426, 3043, 2983, 2830, 1595, 1345, 1124, 956,
727 cmÀ1
;
MS(ESI): m/z 335 (M+1)+; HRMS m/z:
(M+1)+ calcd for C17H20FN2O2S, 335.1229; found,
335.1234; 1-(Methylsulfonyl)-4-[(E)-3-phenyl-2-propenyl
]piperazine (entry 31): 1H NMR (300 MHz, DMSO): d
2.72 (s, 3H), 3.14 (s, 4H), 3.36 (s, 4H), 3.88 (d, J = 7.2 Hz,
2H), 6.23–6.42 (m, 1H), 6.78(d, J = 15.8 Hz, 1H), 7.12 (d,
13. Tundo, P.; Anastas, P.; Black, D. S.; Breen, J.; Collins, T.;
Memoli, S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure
Appl. Chem. 2000, 72, 1207.

A. Kamal et al. / Tetrahedron Letters 49 (2008) 348–353
353
J = 7.9 Hz, 2H), 7.32–7.49 (m, 3H) ppm; 13C NMR
(75 MHz, DMSO): d 34.2, 42.6, 49.8, 56.9, 116.3, 125.1,
126.0, 126.8, 129.4, 138.2 ppm; IR (KBr): 3442, 3017,
2923, 1620, 1332, 976, 746 cmÀ1; MS(ESI): m/z 282
(M+1)+; HRMS m/z: (M+1)+ calcd for C14H21N2O2S,
281.1323; found, 281.1347; 1-[(4-Methylphenyl)sulfonyl]-
4-[(E)-3-phenyl-2-propenyl]piperazine (entry 32): 1H
NMR (300 MHz, DMSO): d 2.4 (s, 3H), 3.04 (s, 4H),
3.24 (s, 4H), 3.88 (d, 2H, J = 7.2 Hz), 6.23–6.42 (m, 1H),
6.78 (d, J = 15.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.24–
7.43 (m, 3H), 7.51 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 7.9 Hz,
2H) ppm; 13C NMR (75 MHz, DMSO): d 20.8, 42.8, 49.5,
57.1, 116.9, 125.2, 126.5, 127.3, 128.4, 129.6, 131.4, 134.9,
139.0, 143.8 ppm; IR (KBr): 3455, 3026, 2921, 2859, 1648,
1349, 978, 816, 728 cmÀ1; MS(ESI): m/z 357 (M+1)+;
HRMS m/z: (M+1)+ calcd for C20H25N2O2S, 357.1636;
found, 357.1653; N-(furan-2-ylmethyl)methanesulfonamide
amide (entry 34): 1H NMR (300 MHz, CDCl3): d 2.45
(s, 3H), 4.15 (d, J = 6.04 Hz, 2H), 6.06 (s, 1H), 6.17 (s,
1H), 7.19 (s, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.71 (d,
J = 8.3 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d 21.3,
40.0, 108.1, 110.2, 126.9, 129.5, 136.7, 142.3, 143.3,
149.5 ppm; IR (KBr): 3443, 3017, 2923, 1620, 1332, 976,
746 cmÀ1
;
MS(ESI): m/z 252 (M+1)+; HRMS m/z:
(M+1)+ calcd for C12H14NO3S, 252.0694; found,
252.0690; N-(3,4,5-trimethoxyphenyl)methanesulfonamide
1
(entry 35): H NMR (300 MHz, CDCl3): d 2.98 (s, 3H),
3.78 (s, 3H), 3.84 (s, 6H), 6.47 (s, 2H) ppm; 13C NMR
(75 MHz, CDCl3): d 34.7, 55.1, 60.3, 97.8, 132.7,133.9,
151.4 ppm; IR (KBr): 3208, 2969, 2846, 1603, 1320, 1125,
885, 756 cmÀ1; MS(ESI): m/z 262 (M+1)+; HRMS m/z:
(M+1)+ calcd for C10H16NO5S, 262.3026; found,
262.3033; 4-Methyl-N-(3,4,5-trimethoxyphenyl)benzene-
sulfonamide (entry 36): 1H NMR (300 MHz, CDCl3): d
2.46 (s, 3H), 3.62 (s, 3H), 3.82 (s, 6H), 6.43 (s, 2H), 7.31 (d,
J = 7.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H) ppm; 13C NMR
(75 MHz, CDCl3): d 20.8, 55.2, 60.2, 98.0, 126.4, 128.8,
133.1, 133.9, 136.2, 142.5, 152.5 ppm; IR (KBr): 3262,
2948, 2834, 1597, 1326, 1129, 897, 751 cmÀ1; MS(ESI):
m/z 262 (M+1)+; HRMS m/z: (M+1)+ calcd for
C16H20NO5S, 338.1062; found, 338.1072.
1
(entry 33): H NMR (300 MHz, CDCl3): d 2.77 (s, 3H),
4.26 (d, J = 5.2 Hz, 2H), 6.31 (s, 2H), 7.36 (s, 1H) ppm;
13C NMR (75 MHz, CDCl3): d 34.5, 42.6, 107.5, 109.8,
141.8, 149.2 ppm; IR (KBr): 3287, 2930, 1631, 1316, 984,
751 cmÀ1
;
MS(ESI): m/z 176 (M+1)+; HRMS m/z:
(M+1)+ calcd for C6H10NO3S, 176.0381; found,
176.0384; N-(furan-2-ylmethyl)-4-methylbenzenesulfon-