One-pot synthesis of sulfonamides and sulfonyl azides from thiols using chloramine-T

Article abstract of DOI:10.1002/hlca.201200648

A convenient synthesis of sulfonamides and sulfonyl azides from thiols is described. In situ preparation of sulfonyl chlorides from thiols was accomplished by oxidation with chloramine-T (=N-chlorotosylamide=N-chloro-4- methylbenzenesulfonamide), tetrabutylammonium chloride (Bu₄NCl), and H₂O. The sulfonyl chlorides were then further allowed to react with excess amine or NaN₃ in the same pot.

Full text of DOI:10.1002/hlca.201200648

Helvetica Chimica Acta – Vol. 96 (2013)
2147
One-Pot Synthesis of Sulfonamides and Sulfonyl Azides from Thiols using
Chloramine-T
by Behrooz Maleki*a), Saba Hemmatib), Reza Tayebeea), Sirous Salemia), Yasaman Farokhzadc),
Mehdi Baghayeria), Farrokhzad Mohammadi Zonoza), Elahe Akbarzadehd), Rohollah Moradic),
Azam Entezaric), Mohammad Reza Abdic), Samaneh Sedigh Ashrafia), Fereshteh Taimazia), and
Majid Hashemie)
a) Hakim Sabzevari University, Department of Chemistry, Sabzevar 96179-76487, Iran
(phone: þ 985714410104; fax: þ 9857144111161; e-mail: Malekibehrooz@gmail.com)
b) Young Researchers and Elite Club, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
c) Payame Noor University (PNU), Department of Chemistry, Tehran 19395-4697, Iran
d) Kharazmi University, Department of Chemistry, Shahid Mofatteh Ave. No. 43, Tehran, Iran
e) Center for Research and Development of Petroleum Technologies at Kermanshah, Kermanshah,
Iran
A convenient synthesis of sulfonamides and sulfonyl azides from thiols is described. In situ
preparation of sulfonyl chlorides from thiols was accomplished by oxidation with chloramine-T (¼ N-
chlorotosylamide ¼ N-chloro-4-methylbenzenesulfonamide), tetrabutylammonium chloride (Bu4NCl),
and H2O. The sulfonyl chlorides were then further allowed to react with excess amine or NaN3 in the
same pot.
Introduction. – Frequently, sulfonamides are formed from a sulfonyl chloride, and a
primary or secondary amine. In turn, sulfonyl chlorides can be prepared from the
corresponding thiols using a number of methods, commonly by bubbling Cl2 gas into
aqueous acid or a biphasic mixture containing the thiol [1]. Although this methodology
is relatively general, issues associated with the use of excess oxidant and/or aqueous
acid have prompted the development of alternative methods [2]. Recently, the direct
oxidative conversions of thiols to sulfonamides using various catalysts were reported
[3].
The most practical method for preparing sulfonyl azides involves the reaction of
sulfonyl chlorides with azides [4]. The reaction requires the availability of sulfonyl
chlorides, which are troublesome to prepare and handle. Generally, sulfonyl chlorides
are prepared by treating sulfonic acids with chlorinating agents such as SOCl2 [5],
POCl3 [6], PCl5 [7], triphosgene [8], and cyanuric chloride [9]. A convenient one-pot
synthesis of sulfonyl azides from sulfonic acids was reported by Kim and Jang [10].
Results and Discussion. – Herein, as part of our ongoing study on the application of
N-halogen reagents in organic synthesis [11], we present the direct convenient one-pot
synthesis of sulfonamides and sulfonyl azides from thiols using chloramine-T (¼ N-
chlorotosylamide ¼ N-chloro-4-methylbenzenesulfonamide) under mild conditions
(Scheme 1).
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 1
Initially, we surmised that it might be possible to generate controlled amounts of Cl2
in nonprotic organic solvents by mixing a tetraalkylammonium chloride with chlor-
amine-T. Indeed, we found that treatment of Bu4NCl (3 equiv.) and H2O (2.5 equiv.)
with chloramine-T (3 equiv.) in MeCN (20 min, room temperature) provided a light
yellow solution as a good oxidizing and chlorinating system to afford phenylmetha-
nesulfonyl chloride from phenylmethanethiol under mild conditions. Based on this
result, we studied the use of this system for the in situ preparation of sulfonyl chlorides
from thiols to synthesize sulfonamides in one pot. Subsequent addition of a primary or
secondary amine afforded the desired sulfonamide. To optimize the reaction
conditions, the reaction of phenylmethanethiol and benzylamine in MeCN at room
temperature was selected as model. Repeating the reaction of phenylmethanethiol
(1 equiv.) and Bu4NCl (4 equiv.), H2O (2.5 equiv.) with chloramine-T (3 equiv.) in
MeCN (20 min, room temperature), followed by addition of benzylamine (4 equiv.,
20 min), provided the corresponding sulfonamide in 98% yield.
Encouraged by our initial studies, we then investigated the generality and versatility
of this procedure by using a series of structurally different thiols and amines
(commercially available) under these optimized conditions. A combinatorial library
(parallel format) of sulfonamides was prepared in good-to-high yields. The results are
compiled in Table 1. Arenethiols carrying either electron-donating or electron-with-
drawing substituents reacted smoothly to give the corresponding sulfonamides with
equal efficiency. Also, areneamines appeared to be insensitive to substitution. Primary
and secondary alkenamines and also NH3 undergo this reaction with equal efficiency.
Butane-1-thiol (Table 1, Entry 9) also was oxidized efficiently.
The present system was further examined for the synthesis of sulfonyl azides
from thiols in excellent yield. The results are collected in Table 2 (Entries 1 – 8). We
developed a one-pot process for preparing sulfonyl azides from thiols with chloramine-
T, Bu4NCl, and H2O. The reaction offers convenience, efficiency, and generality for the
preparation of sulfonyl azides from various thiols. Employing less toxic reagents render
this process attractive from the standpoint of environmental protection.
A plausible mechanism for this transformation is presented in Scheme 2. Molecular
Cl2 generated from chloramine-T and Bu4NCl effects the oxidative chlorination. It is
assumed that the thiol can be chlorinated in the presence of Cl2. Therefore, the
mechanism proceeds through hydroxylation of thiol, leading to the formation of
sulfenic acid I, which gives the corresponding symmetric disulfide II. Then, the
successive oxidation of both S-atoms of the disulfide by HOCl affords the intermediate

Helvetica Chimica Acta – Vol. 96 (2013)
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Table 1. Synthesis of Various Sulfonamides (RꢀSO2ꢀNR1R2) from Thiols (RꢀSH) and Amines
(R1R2NH)
Entry
R
R1
R2
Time [min]
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PhCH2
PhCH2
PhCH2
Naphthalen-2-yl
Naphthalen-2-yl
Naphthalen-2-yl
4-MeOꢀC6H4
Pyridin-2-yl
Bu
PhCH2
H
H
H
H
H
PhCH2
H
40
0.7
1.2
2
1.5
2
2
2
1.5
1
1
1.2
1
1
1
1
98
98
98
90
92
90
94
90
90
98
96
90
98
96
90
98
cyclopentyl
4-MeꢀC6H4ꢀCH2
PhCH2
cyclopentyl
PhCH2
4-MeꢀC6H4ꢀCH2
ꢀCH2CH2OCH2CH2ꢀ
4-MeꢀC6H4ꢀCH2
H
H
H
H
H
H
H
Et
Ph
Ph
4-MeꢀC6H4
2-ClꢀC6H4
Ph
4-MeꢀC6H4
4-BrꢀC6H4
PhCH2
Cyclohexyl
H
H
Et
4-MeOꢀC6H4
Ph
Table 2. Synthesis of Various Sulfonyl Azidesa) from Thiols
Entry
Sulfonyl azide
Time [min]
Yield [%]
Ref.
1
2
3
4
5
6
7
8
PhCH2ꢀSO2ꢀN3
45
60
45
60
45
90
45
70
98
98
98
92
95
88
90
85
[10]
[10]
[10]
[10]
[10]
[3a]
[10]
[10]
PhꢀSO2ꢀN3
4-MeꢀC6H4ꢀSO2ꢀN3
4-MeOꢀC6H4ꢀSO2ꢀN3
4-ClꢀꢀC6H4ꢀSO2ꢀN3
4-NO2ꢀC6H4ꢀSO2ꢀN3
(Naphthalene-1-yl)ꢀSO2ꢀN3
EtꢀSO2ꢀN3
a) Products were characterized by their physical properties, comparison with authentic samples, and by
spectroscopic methods.
III that undergoes rapid isomerization to the thiosulfonate IV, which can easily furnish
sulfonyl chloride V. Then, V reacts with with amine or azide to form the corresponding
sulfonamides VI or sulfonyl azides VII, respectively.
In conclusion, we have developed a mild, one-pot procedure for the preparation of
alkene- and arenesulfonamides from thiols in the presence of primary and secondary
amines by using readily available chloramine-T in MeCN. Also, we have developed a
one-pot process for preparing sulfonyl azides from thiols under these conditions in the
presence of NaN3. The advantages are excellent yields, the inexpensiveness and
availability of the reagents, easy and clean workup, extremely fast reaction, high
chemoselectivity, and operation at room temperature. No side reactions/products were
observed during the course of the reaction. Therefore, we assume that this method-
ology would open new possibilities for medicinal chemistry and material sciences and
could be an important contribution to the existing procedures.

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 2
We are grateful to Hakim Sabzevari, Young Researchers Club, and Payame Noor University (PNU)
for partial support of this work.
Experimental Part
General. Chemicals were obtained from Merck and Fluka. M.p.: Stuart SMP3 apparatus;
.
uncorrected. IR Spectra: Shimadzu-435-U-04 spectrophotometer; KBr pellets; ˜n in cmꢀ1 1H- and
13C-NMR Spectra: Bruker FT NMR spectrometer, at 200 and 50 MHz in CDCl3, d in ppm rel. to Me4Si as
internal reference, J in Hz. MS: MAT 8200 Finnigan high-resolution mass spectrometer; m/z.
General Procedure for the Conversion of Thiols to Sulfonamides. To a stirred mixture of thiol
(1 mmol), Bu4NCl (4 mmol), and H2O (2.5 mmol) in MeCN (10 ml) at 08, chloramine-T (3 equiv.) was
added as a solid in portions over 1 – 2 min. After 30 min, the amine (1 mmol) was added to the mixture
over 1 – 2 min. The resulting mixture was stirred at r.t. until TLC showed complete disappearance of
starting material (Table 1). The mixture was filtered and rinsed twice with MeCN (10 ml). The filtrate
was evaporated, and the corresponding pure sulfonamide was obtained as a crystalline solid.
Recrystallization from EtOH/H2O afforded anal. pure product.
General Procedure for the Conversion of Thiols to Sulfonyl Azides. To a stirred mixture of thiol
(1 mmol), Bu4NCl (4 mmol), and H2O (2.5 mmol) in MeCN (5 ml) at 08, chloramine-T (3 equiv.) was
added as solid in portions over 1 – 2 min. After 30 min, NaN3 (2.2 mmol) was added to the mixture over
1 – 2 min. The resulting mixture was stirred at r.t. for 3 h. The mixture was diluted with CH2Cl2 (15 ml)
and washed with H2O (5 ml). The org. layer was dried (MgSO4). After filtration, the solvent was
removed, and the residue was purified by column chromatography (CC; SiO2; hexane/AcOEt 20 :1) to
give the corresponding sulfonyl azide in good-to-excellent yield.
Data for Selected Compounds. N-Benzyl-1-phenylmethanesulfonamide (Entry 1, Table 1): IR: 1138,
1310 (SO2), 3287 (NH). 1H-NMR: 4.13 (s, 2 H); 4.21 (s, 2 H); 7.25 – 7.38 (m, 10 H). 13C-NMR: 47.6; 59.3;
128.0; 128.1; 128.5; 128.8; 129.1; 130.6; 133.3; 136.8. MS: 261, 256, 239, 196, 182, 120, 106, 91, 77, 65. Anal.
calc. for C14H15NO2S: C 64.34, H 5.79, N 5.36; found: C 64.65, H 5.70, N 5.18.

Helvetica Chimica Acta – Vol. 96 (2013)
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N,N-Dibenzylnaphthalene-2-sulfonamide (Entry 6, Table 1): IR: 1157, 1329 (SO2). 1H-NMR: 4.38 (s,
4 H); 7.09 – 7.66 (m, 10 H); 7.78 – 7.98 (m, 6 H); 8.39 (s, 1 H). 13C-NMR: 50.5; 123.4; 127.6; 128.3; 128.6;
128.7; 129.0; 129.3; 131.3; 132.5; 134.8. MS: 387, 318, 296, 254, 196, 159, 127, 115, 91, 77, 65, 43. Anal. calc.
for C24H21NO2S: C 74.39, H 5.46, N 3.61; found: C 74.22, H 5.60, N 3.65.
4-Methoxy-N-(4-methoxybenzyl)benzenesulfonamide (Entry 7, Table 1): IR: 1154, 1325 (SO2), 3280
(NH). 1H-NMR: 3.79 (s, 3 H); 3.91 (s, 3 H); 4.08 (s, 2 H); 6.82 – 7.52 (m, 8 H); 7.82 (s, 1 H). 13C-NMR:
46.8; 55.3; 55.6; 114.1; 114.3; 128.4; 129.3; 129.3; 131.6; 159.4; 163.0. Anal. calc. for C15H17NO4S: C 58.61,
H 5.57, N 4.56; found: C 58.76, H 5.56, N 4.81.
N-(2-Chlorophenyl)-4-methylbenzenesulfonamide (Entry 11, Table 1): IR: 1108, 1373 (SO2), 3258
(NH). 1H-NMR: 2.36 (s, 3 H); 6.95 – 7.06 (m, 2 H); 7.15 – 7.22 (m, 4 H); 7.60 – 7.62 (m, 3 H). 13C-NMR:
22.5; 122.8; 125.5; 126.3; 127.9; 128.3; 129.8; 130.2; 133.9; 136.3; 144.8.
4-Bromo-N-cyclohexylbenzenesulfonamide (Entry 13, Table 1): IR: 1155, 1386 (SO2), 3242 (NH).
1H-NMR: 1.20 – 1.43 (m, 5 H); 1.54 – 1.79 (m, 5 H); 3.22 – 3.54 (m, 1 H); 4.98 (d, J ¼ 7, NH); 7.72 (d, J ¼
6.8, 2 H); 7.81 (d, J ¼ 6.8, 2 H). 13C-NMR: 24.8; 25.32; 33.8; 52.7; 127.3; 128.6; 132.3; 140.6.
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Received December 16, 2012