A novel approach for the synthesis of alkyl and aryl sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2007.01.091

A novel approach for the synthesis of alkyl and aryl sulfonamides by the reaction of sulfonic acids, isocyanides and water in dichloromethane is reported at ambient temperature in excellent yields within 20 min. To the best of our knowledge this is the first report on the synthesis of this biologically important family using easily available sulfonic acids and isocyanides.

Full text of DOI:10.1016/j.tetlet.2007.01.091

Tetrahedron Letters 48 (2007) 2185–2188
A novel approach for the synthesis of alkyl and aryl sulfonamides
Ahmad Shaabani,* Ebrahim Soleimani and Ali Hossein Rezayan
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
Received 29 November 2006; revised 7 January 2007; accepted 17 January 2007
Available online 23 January 2007
Abstract—A novel approach for the synthesis of alkyl and aryl sulfonamides by the reaction of sulfonic acids, isocyanides and water
in dichloromethane is reported at ambient temperature in excellent yields within 20 min. To the best of our knowledge this is the first
report on the synthesis of this biologically important family using easily available sulfonic acids and isocyanides.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In continuation of our interest in isocyanide-based mul-
ti-component reactions,8 herein we report on a hitherto
unknown reaction, which starting from simple and read-
ily available precursors, affords alkyl and aryl sulfon-
amide derivatives (Scheme 1).
Sulfonamides, an important class of pharmaceutical
compounds exhibit a wide spectrum of biological activ-
ities.1 Over 30 drugs containing this functionality are in
clinical use, including, antibacterials, diuretics, anticon-
vulsants, hypoglycemics and HIV protease inhibitors.2
More recently, sulfonamides have been found to be
potent cysteine protease inhibitors, which could possibly
extend their therapeutic applications to include condi-
tions such as Alzheimer’s disease, arthritis and cancer.3
As indicated in Table 1, alkyl or aryl sulfonic acid 1 and
isocyanide 2, in the presence of water, undergo a smooth
1:1:1 addition reaction in dichloromethane at room tem-
perature to produce sulfonamide derivatives 4.
The structures of the products were deduced from their
IR, 1H and 13C NMR spectra. The mass spectra of these
compounds displayed molecular ion peaks at the appro-
priate m/z values.
The vast majority of sulfonamides are prepared from the
reaction of a sulfonyl chloride with ammonia or primary
or secondary amines or via related transformations.4,5
In turn, arenesulfonyl chlorides are prepared from are-
nes by electrophilic aromatic substitution using an ex-
cess of chlorosulfonic acid or from arenesulfonic acids
by reaction with phosphorus pentachloride.6 Given the
harshness of these reaction conditions, sulfonyl chlo-
rides are rarely introduced into an advanced intermedi-
ate via C–S bond formation. As a consequence, the
diversity of sulfonamide functionality is actually limited
and cannot be readily varied at both nitrogen and sulfur
in the final step of the generation of a large ensemble of
compounds. Furthermore, as previously reported, sulfo-
nyl chlorides have disadvantages and can be difficult to
handle and are not amenable to long-term storage.7
Only a very small number of these compounds are com-
mercially available due to their instability.
To illustrate the need for H2O, the reaction of camphor-
sulfonic acid and cyclohexyl isocyanide was studied in
the absence of H2O in dry dichloromethane. Under
these conditions no product was obtained even after
24 h at room temperature.
Although the mechanism of the reaction between the
isocyanide and alkyl or aryl sulfonic acid has not yet
been recognized experimentally, a possible explanation
is proposed in Scheme 2. On the basis of the well estab-
lished reaction chemistry of isocyanides with acids,9 it is
O
O
H
CH2Cl2
R1
S
N R2
R1
S
OH
+
R2
N
+
C
H2O
r.t., 20 min
O
O
Keywords: Isocyanide; Sulfonamides; Sulfonic acid.
4
3
1
2
*
Corresponding author. Fax: +98 21 22431666; e-mail: a-shaabani@
cc.sbu.ac.ir
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.091

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A. Shaabani et al. / Tetrahedron Letters 48 (2007) 2185–2188
Table 1. Synthesis of sulfonamides
Entry
R1
R2
Product
Yield (%)
90
O
S
H
N
Me
1
Cyclohexyl
Me
O
4a
Me
Me
Me
Me
O
S
H
N
2
Cyclohexyl
93
O
O
O
4b
(-)
O
S
H
N
Me
Me
3
tert-Butyl
89
Me
Me
O
4c
Me
Me
O
S
H
N
4
tert-Butyl
92
O
O
O
4d
(-)
O
S
H
N
5
Benzyl
91
Me
Me
O
4e
O
H
N
6
Benzyl
86
S
O
4f
reasonable to assume that protonation of the isocyanide
by the alkyl or aryl sulfonic acid produces intermediate
5, which followed by quenching with water generates
intermediate 6. Elimination of formic acid from interme-
diate 6 produces product 4.
2. Typical procedure for the preparation of N-tosyl-
cyclohexanamine (4a)
To a magnetically stirred mixture of p-toluenesulfonic
acid (0.19 g, 1.0 mmol) and H2O (1 mL) in CH2Cl2
(10 mL) was added cyclohexyl isocyanide (0.11 g,
1 mmol) and the resulting mixture was stirred for
20 min at room temperature. After completion of the
reaction, the solvent was removed under vacuum and
the residue was crystallized from ethyl acetate and the
product 4a was obtained in the form of colourless crys-
In conclusion, we have developed a new and general
method for the preparation of alkyl and aryl sulfon-
amides from the readily available alkyl and aryl
sulfonic acids and isocyanides under neutral condi-
tions without using any catalyst. The reaction has
been shown to display good functional group toler-
ance and is high yielding and product isolation is very
straightforward. We hope that this approach may be
of value to others seeking novel synthetic fragments
with unique properties for medicinal chemistry
programs.
tals (0.23 g, yield 90%); mp 181–182 °C. IR (KBr) (mmax
/
cmÀ1): 3045, 2940, 2861, 1600, 1535, 1452. MS, m/z (%):
253 (M+, 1), 238 (M+ÀMe, 5), 172 (55), 155 (M+À
C6H12N, 25), 107 (55), 100 (50), 91 (M+ÀC6H12NO2S,
100), 65 (95), 57 (95), 39 (95). 1H NMR (300 MHz,
CDCl3): dH (ppm) 0.97–1.89 (10H, m, 5CH2 of cyclo-

A. Shaabani et al. / Tetrahedron Letters 48 (2007) 2185–2188
2187
O
S
R2
N
H
O
O
S
R1
R2
N
CH
R1
OH
+
R2
N
C
O
R1
+
O
S
5
O
O
O
+
1
2
H2O
O
R2
N
O
S
H
-CH2O2
R1
R1
N
R2
S
HO
O
O
OH
6
4
Scheme 2.
hexyl), 2.38 (3H, s, CH3), 2.82 (1H, m, CH–N of cyclo-
1514. MS, m/z (%): 287 (M+, 2), 233 (90), 215,
(M+ÀC4H10N, 25), 151 (M+ÀC4H10NO2S, 75), 113
(90), 109 (100), 81 (95), 58 (100), 39 (45). 1H NMR
(300 MHz, CDCl3): dH (ppm) 0.84, 1.10 (6H, 2s,
2CH3), 1.43 (9H, s, C(CH3)3), 1.65–2.69 (6H, m, 3CH2
3
hexyl), 7.23 (2H, d, JHH = 7.9 Hz, H–Ar), 7.65 (1H, br
3
s, NH), 7.78 (2H, d, JHH = 7.9 Hz, H–Ar). 13C NMR
(75 MHz, CDCl3): dC (ppm) 21.32 (CH3), 24.56, 24.57,
30.61 (5CH2 of cyclohexyl), 50.69 (CH–N of cyclo-
hexyl), 125.97, 129.02, 140.72, 141.36 (C–Ar).
3
of camphor), 2.80 (1H, d, JHH = 14.7 Hz CH2–SO2),
2.86 (1H, m, CH of camphor), 3.32 (1H, d,
3JHH = 14.7 Hz, CH2–SO2), 7.53 (1H, br s, NH). 13C
NMR (75 MHz, CDCl3): dC (ppm) 19.78, 20.04
(2CH3), 24.53, 26.96 (C-camphor), 27.61 (C(CH3)3),
42.60, 42.82, 47.54, 47.89, 58.45 (C-camphor), 52.33
(C(CH3)3), 216.79 (C@O).
3. N-Cyclohexyl-C-(7,7-dimethyl-2-oxo-
bicyclo[2.2.1]hept-1-yl)-methanesulfonamide (4b)
Colourless crystals (0.29 g, yield 93%); mp 225–226 °C.
IR (KBr) (mmax/cmÀ1): 2931, 2858, 1742, 1635, 1548,
1492. MS, m/z (%): 313 (M+, 1), 233 (4), 215
(M+ÀC6H12N, 3), 151 (M+ÀC6H12NO2S, 25), 109
6. Phenyl-N-tosylmethanamine (4e)
1
(70), 81 (70), 56 (100), 42 (80). H NMR (300 MHz,
CDCl3): dH (ppm) 0.84, 1.08 (6H, 2s, 2CH3 of camphor),
1.20–2.65 (17H, m, 8CH2 3and CH of cyclohexyl and
camphor), 2.78 (1H, d, JHH = 14.7 Hz, CH2–SO2),
3.11 (1H, m, CH–N of cyclohexyl), 3.30 (1H, d,
3JHH = 14.7 Hz, CH2–SO2), 7.51 (1H, br s, NH). 13C
NMR (75 MHz, CDCl3): dC (ppm) 19.78, 19.97
(2CH3), 24.42, 24.53, 30.75 (5CH2 of cyclohexyl),
24.82, 26.98, 42.61, 42.85, 47.44, 47.93, 58.43 (C-cam-
phor), 50.66 (CH–N of cyclohexyl), 216.65 (C@O).
Colourless crystals (0.24 g, yield 91%); mp 166–168 °C.
IR (KBr) (mmax/cmÀ1): 2950, 1637, 1630, 1488, 1448.
MS, m/z (%): 261 (M+, 2), 172 (75), 155 (M+ÀC7H8N,
10), 106 (M+ÀC7H7O2S, 100), 91 (M+ÀC7H8NO2S,
98), 79 (95), 77 (90), 65 (75), 42 (70), 34 (75). 1H
NMR (300 MHz, CDCl3): dH (ppm) 2.28 (3H, s, CH3),
4.00 (2H, s, CH2), 7.11–7.42 (9H, m, H–Ar), 8.16 (1H,
br s, NH). 13C NMR (75 MHz, CDCl3): dC (ppm)
21.18 (CH3), 42.96 (CH2), 126.00, 128.51, 128.92,
129.04, 129.26, 134.32, 138.24, 146.04 (C–Ar).
4. 2-Methyl-N-tosylpropan-2-amine (4c)
7. Naphthalene-1-sulfonic acid benzylamide (4f)
Colourless crystals (0.20 g, yield 89%); mp 221–222 °C.
IR (KBr) (mmax/cmÀ1): 3041, 2922, 1630, 1526, 1494,
1403. MS, m/z (%): 227 (M+, 1), 185 (3), 172 (75), 155
(M+ÀC4H10N, 5), 107 (55), 91 (M+ÀC4H10NO2S, 95),
77 (35), 65 (55), 58 (100), 39 (60). 1H NMR
(300 MHz, CDCl3): dH (ppm) 1.28 (9H, s, C(CH3)3),
Colourless crystals (0.26 g, yield 86%); mp 166–168 °C.
IR (KBr) (mmax/cmÀ1): 3052, 1624, 1517, 1382, 1216.
MS, m/z (%): 297 (M+, 2), 208 (95), 191 (M+ÀC7H8N,
2), 144 (25), 127 (M+ÀC7H8NO2S, 65), 115 (100), 106
(90), 91 (M+ÀC10H8NO2S, 45), 79 (80), 53 (60), 34
3
1
2.38 (3H, s, CH3), 7.21 (2H, d, JHH3 = 7.9 Hz, H–Ar),
(75). H NMR (300 MHz, CDCl3): dH (ppm) 4.05 (2H,
7.71 (1H, br s, NH), 7.80 (2H, d, JHH = 7.9 Hz, H–
Ar). 13C NMR (75 MHz, CDCl3): dC (ppm) 21.35
(CH3), 27.46 (C(CH3)3), 52.33 (C(CH3)3), 126.03,
128.98, 140.58, 141.53 (C–Ar).
s, CH2), 7.39–8.85 (12H, m, H–Ar), 8.16 (1H, br s,
NH). 13C NMR (75 MHz, CDCl3): dC (ppm) 47.58
(CH2), 129.09, 129.41, 129.71, 130.87, 130.95, 131.66,
131.85, 132.73, 133.07, 133.74, 133.87, 134.11, 134.85,
139.82 (C–Ar).
5. N-tert-Butyl-C-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-
1-yl)-methanesulfonamide (4d)
Acknowledgement
Colourless crystals (0.26 g, yield 92%); mp 287–290 °C.
IR (KBr) (mmax/cmÀ1): 3032, 2955, 1743, 1634, 1538,
We gratefully acknowledge financial support from the
Research Council of Shahid Beheshti University.

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A. Shaabani et al. / Tetrahedron Letters 48 (2007) 2185–2188
Hamza, D.; Wadman, S. J.; Wilden, J. D. Org. Lett. 2002,
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