A green, catalyst-free method for the synthesis of sulfonamides and sulfonylazides

Article abstract of DOI:10.1080/10426507.2010.488257

A novel, green method for the efficient synthesis of sulfonamide and sulfonylazide derivatives by the reaction of sulfonyl chlorides with amines or sodium azide under catalyst-free conditions has been developed. The reactions proceed with high yields and excellent selectivities in short reaction times. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.488257

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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A Green, Catalyst-Free Method for
the Synthesis of Sulfonamides and
Sulfonylazides
Maasoumeh Jafarpour a , Abdolreza Rezaeifard a & Tayebeh Golshani
a
a Catalysis Research Laboratory, Department of Chemistry, Faculty of
Science, University of Birjand, Birjand, South Khorasan, Iran
Version of record first published: 13 Jan 2011.
To cite this article: Maasoumeh Jafarpour , Abdolreza Rezaeifard & Tayebeh Golshani (2010): A
Green, Catalyst-Free Method for the Synthesis of Sulfonamides and Sulfonylazides, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:1, 140-148
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Phosphorus, Sulfur, and Silicon, 186:140–148, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.488257
A GREEN, CATALYST-FREE METHOD FOR THE
SYNTHESIS OF SULFONAMIDES AND SULFONYLAZIDES
Maasoumeh Jafarpour, Abdolreza Rezaeifard,
and Tayebeh Golshani
Catalysis Research Laboratory, Department of Chemistry, Faculty of Science,
University of Birjand, Birjand, South Khorasan, Iran
GRAPHICAL ABSTRACT
O
R1
R2
R1
R2
Water or Ethanol
Water or Ethanol
NH
N
S
X
SO2Cl
O
+
O
S
X
N3
NaN3
X
O
X= H, Me, NO2, Br
R1, R2 = H, Alkyl, Aryl
Abstract A novel, green method for the efficient synthesis of sulfonamide and sulfonylazide
derivatives by the reaction of sulfonyl chlorides with amines or sodium azide under catalyst-
free conditions has been developed. The reactions proceed with high yields and excellent
selectivities in short reaction times.
Keywords Aqueous media; catalyst-free; sulfonamides; sulfonyl chloride; sulfonylazides
INTRODUCTION
Environmentally benign methods for the synthesis of pharmaceutically and industri-
ally important compounds are in extreme demand.1 The elimination of solvents in chem-
ical processes or performing of the reactions in eco-friendly solvents such as water and
ethanol are the procedures of choice for diminishing the environmental impacts of chemical
reactions.2
Sulfonamides are a very important class of compounds in the pharmaceutical industry,
being widely used as anticancer, anti-inflammatory, and antiviral agents.3,4 Sulfonylazides
are versatile precursors in organic chemistry,5 and their uses in organic synthesis go well
beyond the commonly used diazo6 and azide7 transfer reactions. The search for general
and efficient synthesis of sulfonamides under mild conditions is of continuing interest
for organic chemists. Although recently many efforts have been put into the development
Received 11 March 2010; accepted 21 April 2010.
Support of this work by Research Council of University of Birjand is highly appreciated.
Address correspondence to Maasoumeh Jafarpour and Abdolreza Rezaeifard, Catalysis Research Laboratory,
Department of Chemistry, Faculty of Science, University of Birjand, Birjand, South Khorasan 97179-414, Iran.
E-mail: mjafarpour@birjand.ac.ir; rrezaeifard@birjand.ac.ir
140

SYNTHESIS OF SULFONAMIDES AND SULFONYLAZIDES
141
of novel sulfonamide syntheses,8 the conventional synthesis from amino compounds and
sulfonyl chlorides is still the method of choice because of the reactivity and simplicity of
the method.9 Most of the reported methods for the preparation of sulfonamides suffer from
drawbacks such as formation of a bis-sulfonylation byproduct or hydrolysis of sulfonyl
chlorides as the major competing reaction, which requires the use of excess of sulfonyl
chloride. Thus, the isolation and purification of the sulfonamide products are not always
straightforward in these protocols, resulting in diminishing yields.
According to the literature in a few reports that are available regarding the synthesis
of sulfonamides in water under catalyst-free conditions, the pH control with Na2CO3 is
necessary, and the isolation of the product involved acidification up to pH 2 with HCl8g and
limited sulfonyl chlorides have been used.8q
In continuation of our ongoing research on the development of new eco-friendly
organic reactions,10 we utilized water and ethanol as green solvents to present a novel
catalyst-free method for the synthesis of sulfonamides and sulfonylazides affording the
desired products in excellent yields with a practical and easy workup procedure (Scheme 1).
O
R1
R2
R1
R2
Water or Ethanol
Water or Ethanol
NH
N
S
X
SO2Cl
O
+
O
S
X
N3
NaN3
X
O
X= H, Me, NO2, Br
R1, R2 = H, Alkyl, Aryl
Scheme 1 Catalyst-free of synthesis of sulfonamides and sulfonylazides.
RESULTS AND DISCUSSION
To find the best reaction conditions for the synthesis of sulfonamides, the condensation
of 4-toluenesulfonyl chloride with aniline was used as a model reaction. It was found that
temperature changes (25◦C to 80◦C) did not affect the reaction yield under neat conditions,
and the desired product was formed in only 50% yield (GC) after 6 h. Elongation of
the reaction time also did not affect the yield of the product. Then, a similar reaction
was performed in various solvents in the absence of any catalyst at a temperature range
from 25◦C to 80◦C. The desired yields and conversion rates have been obtained at room
temperature in the presence of water and ethanol, both of which are standard green media.
In addition, the pronounced effect of the solvent quantity on the reaction rates has been
observed. Under the optimized conditions using 4-toluenesulfonyl chloride (1 mmol) and
aniline (2 mmol), the optimum yields were obtained in 2 mL of water (92%) or ethanol
(96%) at room temperature.
In order to show the general applicability of this method, the reaction of structurally
and electronically diverse amines and sulfonyl chlorides was examined. The results, which

142

143

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M. JAFARPOUR ET AL.
Table 2 Catalyst-free azidolysis of sulfonylchloridesa
Time (yield%)c
Time (yield%)c
in EtOH
Entry
1
Sulfonyl chloride
Productb
in H2O
30 min (93)
8 min (95)
2
120 min (94)
12 min (96)
3
4
5
20 min (93)
15 min (94)
60 min (93)
5 min (95)
3 min (96)
8 min (96)
aThe reactions were run the molar ratio of sulfonyl chloride:sodium azide was 1:2.5 in 2 mL water (at reflux)
or ethanol (at r.t).
bStructural assignments of the products are based on their spectral data.5c
cIsolated yield.
are summarized in Table 1, indicate that all reactions proceeded efficiently, and the de-
sired sulfonamides were obtained in excellent yields in relatively short reaction times. It
was observed that electronic factors play a significant role in these reactions. Aromatic
amines substituted with electron-donating groups reacted faster than those having electron-
withdrawing groups and provided the sulfonamides in high yields (Table 1, entries 3–8).
Encouraged by the promising results obtained in the synthesis of sulfonamides, the
azidolysis of sulfonyl chlorides has also been examined by this green reaction system. The
results, which are summarized in Table 2, indicate the high efficiency of this methodology
for the preparation of sulfonylazides in ethanol and water under mild and reflux conditions
respectively.
In order to highlight the efficiency of the presented methodology, we have compared
the results obtained for the synthesis of sulfonamides in water and ethanol with some of
those reported in the literature (Table 3).
In conclusion, an operationally simple and environmentally benign protocol for sul-
fonylation of amines and azidolysis of sulfonyl chlorides in the absence of any catalyst is
described. The mildness and eco-friendly nature of the reaction, short reaction times, and
impressive yields are the considerable advantages that make the present method superior
to the existing methods for the preparation of sulfonamides and sulfonylazides.

145

146

SYNTHESIS OF SULFONAMIDES AND SULFONYLAZIDES
147
EXPERIMENTAL
Amines, sulfonyl chlorides, and NaN3 were purchased from Merck or Fluka chemical
companies. The progress of the reactions was monitored by TLC using silica-gel SIL G/UV
254 plates and also by GC on a Shimadzu GC-16A instrument using a 25 m CBP1-S25
(0.32 mm ID, 0.5 µm coating) capillary column. NMR spectra were recorded on a Bruker
Avance DPX 250 MHz and 500 MHz instruments. Mass spectra were recorded on a
Shimadzu GC-MS-QP 5050A.
General Procedure for the Synthesis of Sulfonamides in Water
To a suspension of sulfonyl chloride (1 mmol) in distilled water (2 mL), amine
(2 mmol) was added at room temperature, and vigorous stirring was continued until the
reaction was completed (followed by TLC). The reaction mixture was extracted with ethyl
acetate, and the organic phase was separated, which was dried over CaCl2. After filtration
and evaporation of the solvent, surplus amine was removed by plate chromatography eluted
with n-hexane/EtOAc (Table 1).
General Procedure for the Synthesis of Sulfonamides in Ethanol
To a solution of sulfonyl chloride (1 mmol) in ethanol (2 mL), amine (2 mmol) was
added at room temperature, and stirring was continued until the reaction was completed
(followed by TLC). After completion of the reaction, the mixture was concentrated under
reduced pressure, and surplus amine was removed by plate chromatography eluted with
n-hexane/EtOAc (Table 1).
General Procedure for Synthesis of Sulfonylazides in Water
To a suspension of sulfonyl chloride (1 mmol) in distilled water (2 mL), NaN3
(2.5 mmol) was added under reflux conditions, and vigorous stirring was continued until
the reaction was completed (followed by TLC). The reaction mixture was extracted with
ethyl acetate, and the organic phase was separated, which was dried over CaCl2. After
filtration and evaporation of the solvent, the desired product was secured in high purity
(Table 2).
General Procedure for Synthesis of Sulfonylazides in Ethanol
To a solution of sulfonyl chloride (1 mmol) in ethanol (2 mL), NaN3 (2.5 mmol) was
added at room temperature, and stirring was continued until the reaction was completed
(followed by TLC). After completion of the reaction, the mixture was concentrated under
reduced pressure, and further purification was performed by plate chromatography. The
desired product was secured in high purity (Table 2).
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