Direct conversion of thiols and disulfides into sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2010.07.056

The H₂O₂-ZrCl₄ reagent system is used as a new and efficient reagent for the conversion of thiols and disulfides into sulfonamides. The protocol offers several advantages such as excellent yields of products and extremely fast reactions at room temperature. The reagent system is very easy to handle and is environmentally safe and economical.

Full text of DOI:10.1016/j.tetlet.2010.07.056

Tetrahedron Letters 51 (2010) 4843–4846
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Tetrahedron Letters
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Direct conversion of thiols and disulfides into sulfonamides
a,b,
a
Kiumars Bahrami a,b, , Mohammad M. Khodaei
, Mehdi Soheilizad
*
*
a Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran
b Nanoscience and Nanotechnology Research Center (NNRC), Razi University, Kermanshah 67149-67346, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The H2O2–ZrCl4 reagent system is used as a new and efficient reagent for the conversion of thiols and
disulfides into sulfonamides. The protocol offers several advantages such as excellent yields of products
and extremely fast reactions at room temperature. The reagent system is very easy to handle and is envi-
ronmentally safe and economical.
Received 6 May 2010
Revised 21 June 2010
Accepted 9 July 2010
Available online 14 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
H2O2-ZrCl4
H
R
SH
+
R
S
N R'
R' NH2
Sulfonamides have long been the subject of pharmaceutical
interest as a result of their potent biological activities.1 A large num-
ber of pharmaceutically active compounds contain arylsulfonamide
motifs,2 which are employed in the prevention and treatment of bac-
terial infections, diabetes mellitus, oedema, hypertension, and gout.
Some have proved to be useful as herbicides3 and plaguicides.4 Sul-
fonamide derivatives of azo dyes have been reported to improve
light-stability and fibre fixation.5
CH3CN, pyridine, rt
O
R, R' = Alkyl, aryl
Scheme 1. Synthesis of sulfonamides from thiols.
nitrile and 1,4-dioxane were suitable, giving rise to relatively fast
reaction rates at room temperature.
There are various synthetic methods available for the prepara-
tion of sulfonamides.6 The most common involve nucleophilic at-
tack by ammonia or primary or secondary amines on sulfonyl
chlorides in the presence of a base. Although this method is effi-
cient, it requires the availability of sulfonyl chlorides.
Recently, we found that the H2O2–ZrCl4 system can be used for
the conversion of thiols into sulfonyl chlorides,7 which are impor-
tant synthetic precursors.8 As an extension to this work and in con-
tinuation of our interest in developing new routes for the
formation of sulfonamides,9 we report a new, mild and efficient
synthesis of such compounds via the reaction of amines with thiols
in the presence of H2O2–ZrCl4 in acetonitrile at room temperature
(Scheme 1). To the best of our knowledge such a sulfonamide prep-
aration has not been described in the literature.
To optimize the reaction conditions, thiophenol and 4-methy-
laniline were used as model substrates. The best result was
achieved by carrying out using a 3:1:1:1 mole ratio of H2O2, ZrCl4,
thiophenol and 4-methylaniline in the presence of pyridine
(0.5 mL) at 25 °C for 2 min with acetonitrile as solvent (Table 1).
This method was then applied to a variety of commercially
available thiols and amines. As can be seen from the results in
Table 2, aryl thiols possessing either electron-donating or elec-
tron-withdrawing substituents reacted very well to give the
corresponding sulfonamides. Furthermore 2-naphthyl thiol and
Table 1
Optimization of the reaction conditionsa
Zirconium tetrachloride (ZrCl4) is a promising, mild and selec-
tive reagent. Due to its low toxicity, low cost, ease of handling
and high activity, the application of ZrCl4 in organic synthesis is
of interest.10,11 However, there are no examples of the use of ZrCl4
as a promoter for the synthesis of sulfonamides.
Hydrogen peroxide (H2O2) is an attractive and inexpensive oxi-
dant widely used in laboratory and industrial synthesis.12 The
choice of the organic solvent was of particular importance. Aceto-
O
H
SH
+
H2N
Me
S
N
Me
O
Entry
ZrCl4 (mmol)
30% H2O2 (mmol)
Yield%b
1
2
3
4
5
6
0.5
0.7
0.8
1
4
4
4
2
3
4
40
57
80
70
98
98
1
1
a
Reaction conditions: thiophenol (1 mmol), 4-methylaniline (1 mmol), pyridine
* Corresponding authors. Fax: +98 831 4274559.
E-mail addresses: Kbahrami2@hotmail.com (K. Bahrami), mmkhoda@razi.ac.ir
(M.M. Khodaei).
(0.5 mL) as base, 2 min, 25 °C.
b
Isolated yield.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.056

4844
K. Bahrami et al. / Tetrahedron Letters 51 (2010) 4843–4846
Table 2
2, entries 4 and 12). The mechanism for the reaction was studied
by NMR and sulfonyl chloride was confirmed as the reaction
intermediate.
Formation of sulfonamides from various thiols and aminesa
O
S
H
Disulfides are important compounds possessing unique and di-
verse chemistry in the synthetic and biochemical areas.13 The
disulfide bond is strong, the typical bond dissociation energy being
60 kcal/mol. Being about 40% weaker than C–C and C–H bonds, the
disulfide bond is thus often the ‘weak link’ in many molecules. Fur-
thermore, reflecting the polarizability of divalent sulfur, the S–S
bond is susceptible to scission by polar reagents, both electrophiles
and especially nucleophiles.14
R
SH
+
R
N
R'
R' NH2
O
Entry
1
Sulfonamide
Time (min)
2
Yieldb (%)
98
Ref.
15
O
H
N
S
O
O
H
In a recent Letter,7 we demonstrated the intermediacy of disul-
fides in the oxidative chlorination of thiols using H2O2–ZrCl4. There-
fore, the reactions were repeated with various symmetric disulfides
(Scheme 2). The optimum conditions required 30% H2O2 (2 mmol),
ZrCl4 (1 mmol), disulfide (1 mmol), amine (2 mmol) and pyridine
(0.5 mL) in acetonitrile at room temperature.
The generality and scope of the reaction were investigated and a
series of sulfonamides having different steric and electronic prop-
erties were synthesized (Table 3). The sulfonamides were obtained
in excellent yields and with high purity.
S N
O
Me
2
3
2
2
98
97
15
15
O
H
Me
S N
O
Me
O
4
3
96
16
S
N
O
O
O
In conclusion, a simple and convenient method for the synthesis
of sulfonamides utilizing H2O2–ZrCl4 has been established. The
protocol offers several advantages such as excellent yields of prod-
ucts and extremely fast reactions at room temperature. Most
importantly, the reagent system is very easy to handle, environ-
mentally safe and economical. Further investigations into the
scope and synthetic applications of this reaction are currently un-
der investigation in our laboratory.
S
5
6
2
3
99
96
17
—
N
H
O
H
Br
S N
O
O
S
O
H
N
7
3
97
—
NO2
2. General procedure for the synthesis of sulfonamides
O
O
S
N
H
8
9
2
3
96
91
—
9
A mixture of thiol (1 mmol), H2O2 (30%, 3 mmol, 0.3 mL) and
ZrCl4 (1 mmol, 0.233 g) was stirred in CH3CN at 25 °C for the
appropriate period of time. After consumption of the thiol as indi-
cated by TLC, a solution of amine (1 mmol) in pyridine (0.5 mL)
was added. The resulting mixture was stirred at room temperature
until TLC showed complete disappearance of substrates. The mix-
ture was acidified with 2 N HCl and extracted with EtOAc
(4 Â 5 mL). The organic layer was washed with H2O (2 Â 10 mL)
and brine (10 mL) and dried over MgSO4. The filtrate was evapo-
rated and the corresponding sulfonamide was obtained as a crys-
talline solid. Recrystallization from a mixture of EtOH and H2O
gave the analytically pure product. An identical procedure was em-
ployed using disulfide (1 mmol), amine (2 mmol), 30% H2O2
(2 mmol, 0.2 mL) and ZrCl4 (1 mmol, 0.233 g) for the conversion
of disulfides into sulfonamides.
O
N
H
N
S
Br
N
H
O
O
Me
S NH2
O
NH2
10
11
12
2
3
3
99
99
97
18a
18b
18c
S
O
O
O
S
O
N
The purified products were characterized by mp and 1H and 13C NMR
a
spectroscopy.
The known compounds were characterized easily by compari-
son with authentic samples (1H NMR, 13C NMR, mp). Spectral
and analytical data for new compounds follow.
b
Yield refers to pure isolated product.
benzyl thiol afforded the corresponding sulfonamides in excellent
yields (Table 2, entries 8 and 11). Benzimidazole-2-sulfonyl chlo-
ride is unstable at room temperature and rapidly decomposes to
2-chlorobenzimidazole and 2-hydroxybenzimidazole,6a whereas
the reaction of 2-mercaptobenzimidazole with 4-bromoaniline,
contrary to our expectation, gave an excellent yield of product (Ta-
ble 2, entry 9). It is noteworthy that this rapid reaction permits for-
mation of the corresponding heterocyclic sulfonamide.
2.1. N-Cyclohexyl-4-bromobenzenesulfonamide (Table 2, entry 6)
Mp = 100 °C. 1H NMR (200 MHz, CDCl3): d 1.15 (m, 5H), 1.53–
1.74 (m, 5H), 3.10 (m, 1H), 4.96 (d, 1H, J = 7.5 Hz, NH), 7.63 (d,
2H, J = 8 Hz), 7.75 (d, 2H, J = 8 Hz). 13C NMR (50 MHz, CDCl3): d
24.6, 25.0, 33.8, 52.7, 127.3, 128.5, 132.3, 140.6. Anal. Calcd for
C12H16NSO2Br: C, 45.28; H, 5.03; N, 4.40; S, 10.06. Found: C,
Aromatic amines possessing either electron-donating or elec-
tron-withdrawing substituents reacted efficiently and gave excel-
lent yields. Also, aryl amines appeared to be insensitive to
substitution. Ammonia and primary and secondary alkyl amines
gave excellent yields of sulfonamides. Interestingly, this method
proved to be very useful even for sterically hindered amines such
as diphenylamine and diethylamine, the corresponding sulfona-
mides were obtained in 96% and 97% yields, respectively (Table
45.25; H, 5.01; N, 4.23; S, 9.77.
O
S
H2O2-ZrCl4
H
RS SR
+
R
N R'
R' NH2
CH3CN, pyridine, rt
O
R, R' = Alkyl, aryl
Scheme 2. Synthesis of sulfonamides from disulfides.

K. Bahrami et al. / Tetrahedron Letters 51 (2010) 4843–4846
4845
Table 3
Formation of sulfonamides from various disulfides and aminesa
O
S
H
RS
SR
+
R' NH2
R
N R'
O
Entry
1
Disulfide
Sulfonamide
Time (min)
2
Yieldb (%)
O
H
S
S
S
N
S
O
O
97
95
2
2
2
S N
O
2
3
4
2
1
2
O
O
S
99
97
N
H
O
H
Me
S
S
Me
S N
Me
2
2
O
O
S NH2
O
O
Me
Br
Me
Br
5
6
1
2
98
98
H
S
S N
O
2
N
O
N
H
N
S
S
Br
7
8
2
2
92
96
N
H
N
H
O
2
S
S
O
O
O
S
N
2
H
Cl
O
S
9
2
1
95
99
2
N
H
NH2
CH2S
S
10
2
O
O
a
The purified products were characterized by mp and 1H and 13C NMR spectroscopy.
Yield refers to pure isolated product.
b
2.2. N-3-(Nitrophenyl)benzenesulfonamide (Table 2, entry 7)
122.3, 128.2, 128.3, 128.5, 128.6, 129.5, 129.6, 129.7, 130.0,
132.0, 134.7, 136.6, 137.1. Anal. Calcd for C16H12NSO2Cl: C, 60.48;
H, 3.78; N, 4.41; S, 10.07. Found: C, 60.31; H, 3.87; N, 4.14; S, 9.88.
Mp = 134 °C. 1H NMR (200 MHz, CDCl3): d 7.43–7.63 (m, 6H),
7.84–7.86 (m, 1H), 7.87–7.79 (m, 1H), 7.93–7.97 (m, 2H). 13C
NMR (50 MHz, CDCl3): d 114.8, 119.4, 125.9, 126.8, 129.0, 129.9,
133.3, 137.4, 137.9, 148.3. Anal. Calcd for C12H10N2SO4: C, 51.80;
H, 3.59; N, 10.07; S, 11.51. Found: C, 51.45; H, 3.63; N, 10.06; S,
11.13.
Acknowledgement
We are thankful to the Razi University Research Council for par-
tial support of this work.
2.3. N-Cyclohexyl-2-naphthalenesulfonamide (Table 2, entry 8)
Supplementary data
Mp = 128–130 °C. 1H NMR (200 MHz, CDCl3): d 1.15–1.77 (m,
10H), 3.19 (m, 1H), 4.65 (br s, 1H, NH), 7.57–7.69 (m, 2H), 7.82–
7.98 (m, 4H), 8.46 (s, 1H). 13C NMR (50 MHz, CDCl3): d 24.8, 25.2,
33.7, 52.5, 122.7, 127.3, 128.0, 128.2, 129.0, 129.6, 129.7, 132.2,
134.4, 139.7. Anal. Calcd for C16H19NSO2: C, 66.44; H, 6.57; N,
4.84; S, 11.07. Found: C, 66.17; H, 6.39; N, 4.56; S, 10.68.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.056.
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