A practical and efficient method for the preparation of sulfonamides utilizing Cl3CCN/PPh3

Article abstract of DOI:10.1016/j.tetlet.2006.08.036

Cl₃CCN in combination with PPh₃ proved to be a highly reactive reagent for the conversion of sulfonic acids to the corresponding sulfonyl chlorides in refluxing CH₂Cl₂. Upon reaction with amines, the corresponding sulfonamides were obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.08.036

Tetrahedron Letters 47 (2006) 7489–7492
A practical and efficient method for the preparation of
sulfonamides utilizing Cl CCN/PPh
3
3
a
b,
a,
*
*
Oraphin Chantarasriwong, Doo Ok Jang and Warinthorn Chavasiri
a
Natural Products Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
b
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
Received 8 June 2006; revised 2 August 2006; accepted 10 August 2006
Abstract—Cl
3 3
CCN in combination with PPh proved to be a highly reactive reagent for the conversion of sulfonic acids to the
corresponding sulfonyl chlorides in refluxing CH Cl . Upon reaction with amines, the corresponding sulfonamides were obtained
2
2
in good to excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Sulfonamides have long been the subject of pharmaceu-
tical interest as a result of their potent biological activi-
ties. They are used in the prevention and treatment of
reagent and that highly toxic and corrosive by-products
are formed. Alternatively, sulfonamides can be prepared
by reacting sulfinic acid salts with an electrophilic nitro-
1
1
3
bacterial infections, diabetes mellitus, oedema, hyper-
tension and gout. Some have proved to be useful as her-
gen source such as hydroxylamine-O-sulfonic acid or
1
4
bis-(2,2,2-trichloroethyl)-azodicarboxylate.
However,
2
3
bicides and plaguicides. Arylsulfonyl substituents have
been used as protecting groups for oxygen and nitrogen
the success of the process lies in the availability of the
required sulfinic acid salt. The existing synthetic ap-
proaches to sulfinic acid salts either involve the use of
organolithium or Grignard reagents, which are incom-
patible with a host of functional groups, or tedious,
multi-step syntheses. Furthermore, the purity of the sul-
finates is usually insufficiently high due to the inability to
isolate the hygroscopic salt. Although several synthetic
methods for sulfonamides have been developed, there
remains a need for a straightforward and general meth-
odology towards accessing sulfonamides under mild
conditions in the absence of a strong base or competing
nucleophile. Recently, it has been reported that the
4
functionalities. Sulfonamide derivatives of azo dyes
have been reported to improve light stability and fibre
5
fixation.
The most commonly used synthetic methods to manipu-
late sulfonamides involve the nucleophilic attack by
ammonia, or primary or secondary amines, with sulfon-
yl chlorides in the presence of a base. Although this
method is efficient, it requires the availability of sulfonyl
chlorides, some of which are hard to prepare and diffi-
cult to store or handle. Side reactions are also possible
due to the presence of base or liberated nucleophilic
chloride, particularly under harsh conditions with rela-
tively non-nucleophilic substrates. Sulfonyl chlorides
are generally prepared from the corresponding sulfonic
1
5
PPh /Cl CCN system could be used for the conversion
3
3
of carboxylic acids to acid chlorides, which were subse-
quently transformed into the corresponding amide, ester
or acid anhydride. Herein, we report the utilization of
Cl CCN and PPh for the efficient synthesis of
6
7
8
acids using SOCl , POCl or PCl . The use of triphos-
2
3
5
3
3
9
10
11
gene, PPh /SO Cl , or SO Cl has been reported for
sulfonamides.
3
2
2
2
2
the preparation of carbohydrate sulfonyl chlorides. A
recent transformation of sulfonic acids or their salts into
sulfonyl chlorides using cyanuric chloride has also been
reported. In addition, there are disadvantages in that
these methods necessitate an excess of chlorinating
Benzenesulfonic acid and cyclohexylamine were used as
model substrates. When the former was treated with
selected halogenated reagents and PPh in CH Cl at
reflux, followed by a treatment with the latter in the
presence of 4-picoline as base, N-cyclohexylbenzenesul-
fonamide was obtained. The type and amount of haloge-
nated reagents were investigated and the results are
given in Table 1.
1
2
3
2
2
*
Corresponding authors. Tel.: +66 2 218 7625; fax: +66 2 218 7598
W.C.); e-mail: warintho@yahoo.com
(
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.036

7490
O. Chantarasriwong et al. / Tetrahedron Letters 47 (2006) 7489–7492
Table 1. Effect of the type and amount of halogenated reagent on the
formation of N-cyclohexylbenzenesulfonamide
ing sulfonamide quantitatively (entry 3) whereas the de-
sired sulfonamide was obtained only in moderate yield
at room temperature (entry 4). However, when the ratio
was increased to 6:6:1, the yield of the desired product
was decreased (entry 5). Other halogenated reagents
were investigated such as Cl CCO Et, Cl CCONH
2
Entry
Halogenated reagent
Amount (mmol)
PPh
3
% Isolated
(
mmol) yield
Type
1
2
3
4
5
Cl
3
CCN
1
2
3
3
6
1
2
3
3
6
21
67
3
2
3
and Br CCO Et; however, the desired sulfonamide was
3
2
Quant
a
obtained in only poor yields (entries 6–11).
57
23
The effect of solvent was next examined. The reaction of
6
7
Cl
Cl
3
3
CCO
2
Et
3
6
3
3
14
23
benzenesulfonic acid and the adduct of Cl CCN and
PPh3 in common organic solvents such as CHCl3,
3
CH CN, THF, EtOAc and 1,2-DCE gave N-cyclohexyl-
3
8
9
0
CCONH
2
3
6
6
3
6
3
20
Trace
43
benzenesulfonamide in low to moderate yields. The
reaction performed in CH Cl was the most efficient
2
2
1
yielding the desired sulfonamide in quantitative yield.
1
1
Br
3
CCO
2
Et
3
3
4
The generality and scope of this method was thoroughly
investigated (Table 2). All primary and secondary, alkyl
and aryl amines gave excellent yields of sulfonamides.
Alkyl amines such as n-butylamine, iso-butylamine and
phenethylamine furnished the corresponding sulfona-
mides in high yields (71–87%, entries 1, 2 and 4). The
secondary amine diethylamine was converted into the
corresponding sulfonamide in 74% yield (entry 5). In
the case of arylamine aniline, the corresponding sulfon-
amide was isolated in 93% yield (entry 6). Gratifyingly,
there was no limit for simple amine substrates, and the
Reaction conditions: benzenesulfonic acid (1 mmol), CH
cyclohexylamine (3 mmol), 4-picoline (9 mmol).
Reaction time: step I, at reflux for 1 h; step II, at room temperature for
h.
2 2
Cl (6 mL),
1
a
Room temperature (28–30 °C) for step I.
At refluxing temperature, when the ratio of
Cl CCN:PPh :sulfonic acid was 1:1:1 and 2:2:1, the
3
3
yields of sulfonamide were low to moderate (entries 1
and 2). Increasing the ratio to 3:3:1 gave the correspond-
Table 2. Effect of various amines on the synthesis of sulfonamides
O
1) Cl CCN, PPh , CH Cl , reflux, 1 h
O
S
3
3
2
2
H
Ph S OH
Ph
N R
2
) RNH , 4-picoline, CH Cl , rt, 1 h
2 2 2
O
O
Entry
1
Amine
Sulfonamide
% Isolated yield
83
O
S
NH2
O
O
S
2
3
71
NH2
O
O
S
NH2
Quant
O
O
S
NH2
4
O
87
O
S
5
6
7
NH
74
93
46
O
O
H
NH2
S N
O
O
H
S N
O
H CO C
NH2
3
2
CO CH3
2

O. Chantarasriwong et al. / Tetrahedron Letters 47 (2006) 7489–7492
7491
reaction also occurred with an amino acid derivative
entry 7).
ride was confirmed as the reaction intermediate. The IR
spectra of benzenesulfonyl chloride (Fig. 1b) and the
reaction mixture (Fig. 1c) both displayed two strong
(
À1
A diverse range of sulfonic acids were then tested under
optimized reaction conditions. Phenethylamine was
reacted with a number of common sulfonic acids and
the results are summarized in Table 3.
bands at 1370 and 1185 cm due to S@O stretching
vibrations of sulfonyl chloride. The IR spectrum of benz-
enesulfonic acid (Fig. 1a) revealed a strong absorption
À1
band at 1129 cm assigned to S@O stretching vibra-
1
7
tions. These results endorsed sulfonyl chloride as a
reactive intermediate in the reaction.
The reaction was not limited by sulfonic acid; however,
the reaction conditions needed to be altered to improve
the yields of the desired sulfonamides such as increasing
the time at reflux in step I (the reaction of methanesulf-
onic acid) from 1 to 3 h and then to 8 h to provide the
corresponding sulfonamide in 51%, 75% and 89% yields,
respectively (entries 1–3). In the case of benzenesulfonic
acid, the corresponding sulfonamide was obtained in
high yield (87%, entry 4). In the reaction of 4-toluene-
sulfonic acid monohydrate, the hydrate reacted with
In summary, a simple and convenient method for the
synthesis of sulfonamides utilizing Cl CCN/PPh has
3
3
been established.
A typical experimental procedure is as follows: PPh3
(3 mmol, 0.79 g) in CH Cl (3 mL) was added to a mix-
2
2
ture of sulfonic acid (1 mmol, 0.16 g) and a selected hal-
ogenated reagent (3 mmol) in CH Cl (3 mL) at reflux.
2
2
PPh resulting in only 33% yield of the sulfonamide.
However, increasing the amount of PPh3 from 3 to
The mixture was stirred for approximately 1 h. A mix-
ture of amine (3 mmol) and 4-picoline (9 mmol, 0.84 g)
was added to the above mixture. The reaction mixture
was stirred for another 1 h at room temperature and
was monitored using TLC. When the reaction was com-
plete, the organic layer was extracted with 1 N HCl and
3
6
mmol and the reaction time in step I from 1 to 3 h im-
proved the yield almost quantitatively (entries 5 and 6).
Interestingly, this method proved to be very useful even
for sterically hindered compounds such as camphor-10-
sulfonic acid, the corresponding sulfonamide was
saturated by aqueous NaHCO , dried over anhydrous
3
1
6
obtained in 77% yield (entry 7).
Na SO and evaporated in vacuo. The residue was
2
4
separated by silica gel column chromatography eluting
with hexane/EtOAc (9:1). Further purification by
recrystallization from a mixture of CH Cl and hexane
The mechanism for the reaction of sulfonic acid,
Cl CCN and PPh was studied by IR and sulfonyl chlo-
3
3
2
2
Table 3. Effect of various sulfonic acids on the synthesis of sulfonamides
O
S
1) Cl CCN, PPh , CH Cl , reflux
O
S
3
3
2
2
H
R
OH
R
N
2
) Ph(CH ) NH , 4-picoline, CH Cl , rt, 1 h
Ph
O
2 2
2
2
2
O
Entry
Sulfonic acid
Sulfonamide
Time for step I
% Isolated yield
O
O
1
2
3
1
3
8
51
75
89
H C S OH
3
H C S
3
O
O
O
S
O
S OH
4
O
1
87
O
O
S
O
5
6
S OH
O
O
1
3
33
a
96
O
O
7
1
77
O
S NH
O
S OH
O
O
a
6
3
equiv of PPh was used.

7492
O. Chantarasriwong et al. / Tetrahedron Letters 47 (2006) 7489–7492
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1
2
Figure 1. The IR spectra of (a) benzenesulfonic acid, (b) benzenesulfo-
nyl chloride and (c) the reaction mixture of benzenesulfonic acid, PPh
and Cl CCN.
3
3
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Acknowledgements
1
6. N-Phenethyl-10-camphorsulfonamide:
77%), R 0.52 (50% EtOAc/hexane). IR (neat): 3295,
956, 1598, 1431, 1326, 1143 and 1065 cm ; H NMR
CDCl , 400 MHz) d (ppm): 0.80–3.40 (15H, m, camphor
yellow
liquid
(
2
(
f
This work was supported by a joint research project un-
der the NRCT-KOSEF international cooperative pro-
gram (KO 47/2547). O.C. and W.C. are also indebted
to the Graduate school, Chulalongkorn University, for
financial support.
À1
1
3
group), 2.93 (2H, m, CH
2
Ar), 3.44 (2H, m, NHCH
2
), 5.04
1H, br s, NH) and 7.20–7.40 (5H, m, ArH). C NMR
CDCl , 100 MHz) d (ppm): 19.5, 19.9, 26.2, 26.9, 36.5,
2.7, 42.9, 44.8, 48.7, 49.3, 58.9, 126.7, 128.7, 128.9, 138.1
13
(
(
3
4
and 216.6. LC–MS (EI) m/z (relative intensity, assign-
ment) 336.2 (41.0, [M+H] ), 212.3 (100).
+
References and notes
1
7. Pavia, D. L.; Lampman, G. M.; Kriz, G. S. Introduction to
Spectroscopy, 2nd ed.; Harcourt Brace College: United
States of America, 1996, pp 81–82.
1
. (a) Harter, W. G.; Albrect, H.; Brady, K.; Caprathe, B.;
Dunbar, J.; Gilmore, J.; Hays, S.; Kostlan, C. R.; Lunney,