Synthesis of novel aryl(heteroaryl)sulfonyl ureas of possible biological interest

Article abstract of DOI:10.3390/molecules15031113

The course of reaction of aryl and heteroaryl sulfonamides with diphenylcarbonate (DPC) and 4-dimethylaminopyridine (DMAP) was found to depend on the pKa of the sulfonamide used. Aryl sulfonamides with pK_a ～ 10 gave 4-dimethylaminopyridinium ar

Full text of DOI:10.3390/molecules15031113

Molecules 2010, 15, 1113-1126; doi:10.3390/molecules15031113
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Novel Aryl(heteroaryl)sulfonyl Ureas of Possible
Biological Interest
Franciszek Sączewski 1,*, Anna Kuchnio 1, Monika Samsel 1, Marta Łobocka 1,
Agnieszka Kiedrowska 1, Karolina Lisewska 1, Jarosław Sączewski 1, Maria Gdaniec 2
and Patrick J. Bednarski 3
1
Department of Chemical Technology of Drugs, Faculty of Pharmacy, Medical University of
Gdańsk, 80-416 Gdańsk, Poland
2
Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznań, Poland
3
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of
Greifswald, D-17487 Greifswald, Germany
* Author to whom correspondence should be addressed; E-Mail: saczew@gumed.edu.pl.
Received: 19 January 2010; in revised form: 26 February 2010 / Accepted: 26 February 2010 /
Published: 26 February 2010
Abstract: The course of reaction of aryl and heteroaryl sulfonamides with
diphenylcarbonate (DPC) and 4-dimethylaminopyridine (DMAP) was found to depend on
the pKa of the sulfonamide used. Aryl sulfonamides with pKa ~ 10 gave 4-dimethylamino-
pyridinium arylsulfonyl-carbamoylides, while the more acidic heteroaryl sulfonamides
(pKa ~ 8) furnished 4-dimethylaminopyridinium heteroarylsulfonyl carbamates. Both the
carbamoylides and carbamate salts reacted with aliphatic and aromatic amines with the
formation of appropriate aryl(heteroaryl)sulfonyl ureas, and therefore, can be regarded as
safe and stable substitutes of the hazardous and difficult to handle aryl(heteroaryl)sulfonyl
isocyanates.
Keywords: 4-dimethylaminopyridinium arylsulfonylcarbamoylides; 4-dimethylamino-
pyridinium arylsulfonyl carbamates; arylsulfonyl ureas; heteroarylsulfonyl ureas;
arylsulfonyl isocyanate substitutes

Molecules 2010, 15
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1. Introduction
Arylsulfonyl ureas constitute a well known class of compounds which exhibit a wide range of
biological activities. The most important include: antidiabetic drugs (e.g., glibenclamide) [1], diuretic
drugs (e.g., torasemide) [2], inhibitors of thromboxane synthase and thromboxane A2 receptor
antagonists with antithrombotic properties [3,4] and inhibitors of acetohydroxyacid synthase (AHAS)
which are used as herbicides (e.g., chlosulfuron) or agents active against Mycobacterium tuberculosis
[5,6] as well as antiischemic [7], antimalarial [8], antifungal [9] and oncolytic (e.g., sulofenur) [10]
agents. Of special interest are antagonists of chemokine receptors (CXCR2 receptors) which are
potential drugs for the treatment of acute respiratory distress syndrome, asthma, chronic bronchitis,
pulmonary fibrosis and cystic fibrosis [11]. Therefore, for medicinal chemistry purposes an easy
access to arylsulfonylureas is of great importance.
Recently, we have described a facile method for the preparation of arylsylfonyl ureas of general
formula C (Scheme 1) using 4-dimethylaminopyridinium arylsulfonyl-carbamoylides B, which
constitute non-hazardous substitutes of arylsulfonyl isocyanates [12,13]. As shown in Scheme 1, the
method consists in the reaction of aromatic sulfonamides A with diphenyl carbonate (DPC) in the
presence of 4-dimethylaminopyridine (DMAP), followed by the reaction with primary or secondary
aliphatic or aromatic amine. The above procedure worked well with phenylsulfonamide and its
para-substituted congeners, such as p-alkyl, p-methoxy- and p-chloro-phenylsulfonamide as the
substrates. The unique structure of the carbamoylides obtained were confirmed by IR and NMR
spectra as well as single crystal X-ray structure analysis [13]. Carbamoylides B compose of an
appropriate arylsulfonyl isocyanate and a DMAP molecule. The stability of these highly polarizable
adducts is mainly due to the delocalization of the positive charge on the pyridine ring and the negative
charge on the arylsulfonylcarbamoyl moiety.
Scheme 1. 4-Dimethylaminopyridinium arylsulfonyl carbamoylides as stable substitutes of
arylsulfonyl isocyanates.
R
R
O
O
O
DPC, DMAP
O
R
SO2NH2
S
O
S
O
C
N
N
N
N(CH3)2
A
B
sulfonamide
carbamoylide
R1
isocyanate
R = H, CH3, i-Pr, OCH3, Cl
N H
R2
- DMAP
R
O
O
S
R1
N
N
R2
C
arylsulfonyl urea
O
H

Molecules 2010, 15
1115
In order to explore the scope of this procedure, an analogous previously not attempted reaction
sequence starting from variously substituted phenylsulfonamides, naphthylsulfonamide as well as
heteroarylsulfonamides, such as 2-thienyl- and benzothiazol-2-yl-sulfonamide has now
been attempted.
2. Results and Discussion
The results of the investigations are presented in Scheme 2. First, it was found that the reaction of
variously substituted phenylsulfonamides 1a-c (including p-nitrophenyl-, o-chlorophenyl- and
2-naphthylsulfonamide) with DPC in the presence of DMAP proceeded smoothly at room temperature
to give appropriate carbamoylides 3a-c in good yields. The reactions of these stable arylsulfonyl
isocyanates substitutes carried out in CH3CN with both aliphatic and aromatic amines at elevated
temperature afforded the desired arylsulfonyl ureas, which could be easily separated from the reaction
mixtures upon treatment with 1% aqueous HCl.
However, when 2-thienyl and benzothiazol-2-yl-sulphonamides 1d-f were treated with DPC in the
presence of DMAP, the pyridinium carbamates 4a-c were obtained as the sole products. Neither
prolonged reaction times nor elevated temperatures changed the reaction course.
The structures of pyridinium carbamoylides 3 and pyridinium carbamates 4 were confirmed by IR
and NMR spectroscopic data as well as X-ray single crystal structure analysis of 4b and 4c (Figure 1).
The compounds 4b and 4c are organic salts with the proton transferred from the sulfonylcarbamate
group to 4-dimethylaminopyridine. In the crystal the anions and the pyridinium cations form ionic
pairs via N-H+···N- hydrogen bonds. The anions assume similar conformation with one of the SO2
group O atoms approximately in the plane of benzothiazole moiety and the bond lengths and angles
are as expected. The crystal packing is, to a large extent, governed by electrostatic interactions, with a
pair of 4-dimethylaminopyridinium cations stacked in anti-parallel manner and completely surrounded
by the anions.
The major difference between the two classes of sulfonamide derivatives studied lies in their
relative acidity, hence, it was reasoned that the more acidic heteroarylsulfonyl sulfonamides 1d-f (pKa
~ 8) [14] formed the more acidic carbamates 2d-f which, in turn, suffered proton abstraction by DMAP
to give pyridinium salts of carbamates 4a-c, while the less acidic arylsulfonamides 1a-c (pKa ~ 10)
[15] gave rise to the formation of less acidic carbamates 2a-c which underwent nucleophilic
substitution reaction with DMAP to give the desired carbamoylides 3a-c.
In order to confirm the above hypothesis the reaction of DPC/DMAP couple with 4-chloropyridin-
3-yl-sulfonamide (1g), characterized by a pKa value of 8.9 [16], was performed. As shown in Scheme
3, the above reaction carried out at ambient temperature afforded two products: the carbamate
pyridinium salt 4d and the carbamoylide 3d which could be separated from the reaction mixture by
fractional crystallization in 48% and 39% yield, respectively. Interestingly enough, while the desired
aryl(heteroaryl)sulfonyl ureas 5 and 6 were obtained in good yields from the reactions of either 3a-c or
4a-c with aliphatic, aromatic and heteroaromatic amines, upon treatment of both the carbamate 4d and
carbamoylide 3d with an excess of a secondary amine, 3-(indolin-1-yl)pyrido[3,4-e][1,4,3]oxathiazine
1,1-dioxide (8) was obtained. This might be formed as a result of an intramolecular nucleophilic
substitution reaction in the transiently formed arylsulfonyl ureidate 7 (Scheme 3).

Molecules 2010, 15
1116
All the newly prepared compounds 5, 6 and 8, including benzothiazol-2-yl analogues of sulofenur,
were screened in vitro for their potential cytotoxic activity using human urinary bladder cancer 5637,
small cell lung cancer A-427 and large cell lung cancer LCLC-103H cell lines. None of these
compounds exhibited cytotoxic activity at concentrations below 20 μM.
Scheme 2. Synthesis of compounds 3-6.
Ar(Het)SO2NH2
1a, Ar = 4-NO2-Ph,
1b
1c, Ar = 2-naphthyl (pKa ~10)
1d, Het = 5-Cl-2-thienyl,
1e
, Het = benzothiazol-2-yl,
, Ar = 2-Cl-Ph,
1f
, Het = 6-EtO-benzthiazol-2-yl (pKa ~8)
DPC, DMAP, MeCN, r.t.
- PhOH
Ar(Het)SO2-NH-COOPh
DMAP
2a-f
nucleophilic substitution
- PhOH
proton abstraction
O
O
O
Ar
O
S
O
N
Het S N
O
O
N
- PhOH
H N
N(CH3)2
N(CH3)2
4a c
pyridinium carbamate ( - )
carbamoylide (3a-c)
4a
, Het = 5-Cl-2-thienyl,
3a
, Ar = 4-NO2-Ph,
3b, Ar = 2-Cl-Ph,
4b, Het = benzothiazol-2-yl,
4c
, Het = 6-EtO-benzthiazol-2-yl
3c
, Ar = 2-naphthyl
1. R1R2NH
2. 1% HCl
Δ
1. R1R2NH
2. 1% HCl
O
O
Ar(Het) S NH N R1
N(CH3)2
O
Ar
+
S
N C O
O
R2
O
N
5a j
arylsulfonyl isocyanate + DMAP
arylsulfonyl ureas ( - ),
heteroarylsulfonyl ureas (6a-i)
Cmpd. 5, Ar =
a, 4-NO2-Ph,
R1R2NH =
Cmpd. 6, Het =
R1R2NH =
pyrrolidine
4-phenylpiperazine
a, 5-Cl-2-thienyl,
b
, 5-Cl-2-thienyl,
indoline
tetrahydroisiquinoline
b
, 4-NO2-Ph,
c
c
, 5-Cl-2-thienyl,
d, benzothiazol-2-yl,
e, benzothiazol-2-yl,
, 4-NO2-Ph,
d, 4-NO2-Ph,
e, 2-Cl-Ph,
4-Cl-aniline
4-OCH3-aniline
pyrrolidine
1-aminoindane
pyrrolidine
1,3-thiazoline
f
f
,
,
2-Cl-Ph,
2-aminopyrimidine
pyrrolidine
benzothiazol-2-yl,
g, benzothiazol-2-yl,
4-Cl-aniline
2-aminopyrimidine
g, 2-naphthyl,
h, 2-naphthyl,
4-phenylpiperazine
h, 6-EtO-benzothiazol-2-yl, tetrahydroisoquinoline
i
i
, 6-EtO-benzothiazol-2-yl, 4-Cl-aniline
,
2-naphthyl,
4-ethoxycarbonylpiperazine
2-aminopyrimidine
j, 2-naphthyl,

Molecules 2010, 15
Figure 1. ORTEP drawings of (a) 4c and (b) two symmetry independent molecules of 4b
1117
with the atom labeling scheme. Displacement ellipsoids are drawn at the 50%
probability level.
Scheme 3. Synthesis of compound 8.
O
N
O
N
Cl
N
O
DPC, DMAP
MeCN, r.t.
S N
O
O
O
SO2NH2
S
O
+
N
Cl
N
Cl
H N
N(CH3)2
N(CH3)2
1g
, ( pKa = 8.9)
4d
pyridinium carbamate ( , 48% yield)
3d
carbamoylide ( , 39% yield)
CH3CN, b.p., 3h
N
H
O
O
N
N
S N
O
N
O
N
N
S
O
- DMAP x HCl
O
Cl
H N
N(CH3)2
8
7
arylsulfonyl ureidate ( )
pyrido[3,4- ][1,4,3]oxathiazine 1,1-dioxide ( )
e

Molecules 2010, 15
3. Experimental
3.1. General
1118
Melting points were measured on a Boetius 545 apparatus and are not corrected. The IR spectra
were obtained on a Nicolet 380 FTIR spectrometer using potassium bromide pellets and the
1
frequencies were quoted in cm-1. The H-NMR spectra were recorded on a Varian Gemini
spectrometer at 200 MHz or a Varian Unity Plus apparatus at 500 MHz. The chemical shifts (δ) are
expressed in ppm in relation to tetramethylsilane as a standard and the coupling constants (J) are given
in Hz. The starting substrates were commercial reagents.
3.2. General procedure for the preparation of 4-dimethylaminopyridinium arylsulfonyl carbamoylides
3a-c and 4-dimethylaminopyridinium heteroarylsulfonyl carbamates 4a-c
A solution of appropriate arylsulfonamide 1a-c (33 mmol) in acetonitrile (40 mL) was treated with
4-dimethylaminopyridine (DMAP, 4.1 g, 66 mmol) and the reaction mixture was stirred at room
temperature until sufonamide 1 had dissolved. Then diphenyl carbonate (DPC, 2.3 g, 37 mmol) was
added and the reaction mixture was left overnight at room temperature. The solid that precipitated was
separated by suction, washed with dry acetonitrile and dried to give pure carbamoylides 3a-d or
carbamates 4a-d.
According to the above procedure the following compounds were obtained:
4-Dimethylaminopyridinium 4-nitrophenylsulfonyl carbamoylide (3a). Yield 56%; m.p. 175–177 °C
(dec); IR (KBr) ν = 3099, 2937, 2683, 1691, 1645, 1578, 1520, 1349, 1294, 1257, 1215, 1159, 1072,
1078 cm-1; 1H-NMR (DMSO-d6) δ = 3.33 (s, 6H, CH3), 6.97 (d, 2H, CH, J = 7.2 Hz), 8.31 (d, 2H, CH,
J = 8.7 Hz), 8.71 (d, 2H, CH, J = 8.7 Hz), 8.95 (d, 2H, CH, J = 7.2 Hz); Anal. Calcd. for C14H14
N4O5S (350.35) C, 47.99%; H, 4.03%; N, 15.99%; Found C, 47.72%; H, 3.87%; N, 15.83%.
4-Dimethylaminopyridinium 2-chlorophenylsulfonyl carbamoylide (3b). Yield: 54%; m.p.
112–115 °C; IR (KBr) ν = 3072, 2924, 1697, 1644, 1560, 1293, 1255, 1215, 1184, 1150, 1128, 1110,
1
1028 cm-1; H-NMR (DMSO-d6) δ = 3.16 (s, 6H, CH3), 6.96 (d, 2H, CH, J = 7.6 Hz), 7.60 (d, 1H,
CH), 7.20-7.47 (m, 2H, CH), 7.95 (d, 1H, CH), 8.65 (d, 2H, CH, J = 7.6 Hz); Anal. Calcd. for
C14H14ClN3O3S (339.80) C, 49.49%; H, 4.15%; N, 12.37%; Found C, 49.18%; H, 4.29%; N, 12.31%.
4-Dimethylaminopyridinium naphth-2-ylsulfonyl carbamoylide (3c). Yield: 53%; m.p. 153–156 °C
(dec); IR (KBr) ν = 3087, 1707, 1648, 1572, 1289, 1253, 1217, 1150, 1090, 1065, 862, 834, 768 cm-1;
1H-NMR (DMSO-d6) δ = 3.22 (s, 6H, CH3), 6.95 (d, 2H, CH, Ј = 7.3 Hz), 7.60-7.69 (m, 2H, CH),
7.88-8.14 (m, 4H, CH), 8.43 (s, 1H, CH), 8.74 (d, 2H, CH, Ј = 7.3 Hz); Anal. Calcd. for C18H17N3O3S
(355.41) C, 60.83%; H, 4.82%; N, 11.82%; Found C, 60.58%; H, 4.77%; N, 11.59%.

Molecules 2010, 15
1119
4-Dimethylaminopyridinium (4-chloropyridin-3-ylsulfonyl carbamoylide (3d). Yield: 39%; m.p.
151–153 °C (dec); IR (KBr) ν = 3097, 2934, 1702, 1645, 1572, 1559, 1449, 1395, 1296, 1260, 1089,
1
842, 824, 766, 596 cm-1; H-NMR (DMSO-d6) δ = 3.25 (s, 6H, CH3), 7.00 (d, 2H, CH, J = 8.1 Hz),
7.64 (d, 1H, CH, J = 5.2 Hz), 8.64 (d, 1H, CH, J = 5.2 Hz), 8.73 (d, 2H, CH, J = 8.1 Hz), 9.07 (s, 1H,
CH); Anal. Calcd. for C13H13ClN4O3S (340.79) C, 45.82%; H, 3.85%; N, 16.44%; Found C, 45.61%;
H, 3.90%; N, 16.16%.
4-(Dimethylamino)pyridinium (5-chlorothiophen-2-ylsulfonyl)(phenoxycarbonyl)amide (4a). Yield:
54%; m.p. 144–146 °C (dec); IR (KBr) ν = 3077, 2924, 2611, 1964, 1645, 1562, 1409, 1295, 1262,
1
1210, 1186, 1173, 1024, 988, 924, 887, 807, 626 cm-1; H-NMR (DMSO-d6) δ = 3.18 (s, 6H, CH3),
6.96-7.38 (m, 8H, CH), 7.42 (d, 1H, CH, J = 3.9 Hz), 8.21 (d, 2H, CH, J = 7.6 Hz), 12.6 (bs, 1H, NH);
Anal. Calcd. for C18H18ClN3O4S2 (439.94) C, 49.14%; H, 4.12%; N, 9.55%; Found C, 48.93%; H,
4.26%; N, 9.19%.
4-(Dimethylamino)pyridinium (benzothiazol-2-ylsulfonyl)(phenoxycarbonyl)amide (4b). Yield: 73%;
m.p. 135–138 °C (dec); IR (KBr) ν = 3060, 2924, 1685, 1646, 1559, 1271 cm-1; 1H-NMR (DMSO-d6)
δ = 3.14 (s, 6H, CH3), 6.92-6.96 (m, 4H, CH), 7.02-7.12 (t, 1H, J = 7.4 Hz), 7.25-732 (t, 2H, CH,
J = 7.4 Hz), 7.45-7.62 (m, 2H, CH), 8.04-8.16 (m, 2H, CH), 8.29 (d, 2H, CH, J = 7.6 Hz); Anal. Calcd.
for C21H20N4O4S2 (456.54) C, 55.25%; H, 4.42%; N, 12.27%; Found C, 55.21%; H, 4.62%; N,
11.92%. Upon treatment of the above pyridinium salt with aqueous 1% HCl at room temperature the
free carbamate 4b’ was obtained; m.p. 206-208 °C; IR (KBr) ν = 3007, 2851, 2799, 1758, 1458, 1222,
1
1096, 922, 767, 634 cm-1; H-NMR (DMSO-d6) δ = 6.75 (d, 2H, CH, J = 7.8 Hz), 7.16 (t, 1H, CH,
J = 7.8 Hz), 7.35 (t, 2H, CH, J = 7.8 Hz), 7.60-7.72 (m, 2H, CH), 8.16-8.30 (m, 2H, CH), 8.35 (s, 1H,
NH); Anal. Calcd. for C14H10N2O4S2 (334.37) C, 50.29%; H, 3.01%; N, 8.38%; Found C, 50.22%; H,
3.32%; N, 8.61%.
4-(Dimethylamino)pyridinium (6-ethoxybenzothiazol-2-ylsulfonyl)(phenoxy-carbonyl)amide (4c).
1
Yield: 29.7%; m.p. 251–255 °C; IR (KBr) ν = 3223, 3066, 2924, 1681, 1645, 1557, 1296 cm-1; H-
NMR (DMSO-d6) δ = 1.35 (t, 3H, CH3, J = 8.1 Hz), 3.14 (s, 6H, CH3), 4.09 (q, 2H, CH2, J = 8.1 Hz),
6.92-6.96 (m, 4H, CH), 7.05-7.15 (dd, 1H, CH, Jortho = 6.75, Jmeta = 2.3 Hz), 7.22-7.30 (t, 2H, CH,
J = 7.4 Hz), 7.65 (d, 1H, CH, Jmeta = 2.3 Hz), 7.93 (d, 1H, CH, Jortho = 6.75 Hz), 8.19 (d, 2H, CH,
J = 7.7 Hz); Anal. Calcd. for C23H24N4O5S2 (500.59) C, 55.18%; H, 4.83%; N, 11.19%; Found C,
54.97%; H, 5.11%; N, 10.98%. Upon treatment of the above pyridinium salt with aqueous 1% HCl the
free carbamate 4c’ was obtained; m.p. 206-208 °C; IR (KBr) ν = 2989, 2859, 2787, 2663, 1756, 1599,
1
1485, 1375, 1262, 1217, 1168, 1080, 1042, 842, 759, 688, 627 cm-1; H-NMR (DMSO-d6) δ = 1.37
(t, 3H, CH3, J = 8.2 Hz), 4.12 (q, 2H, CH2, J = 8.2 Hz), 6.75 (m, 1H, CH), 7.00-7.45 (m, 5H, CH),
7.80-7.95 (m, 1H, CH), 8.00-8.15 (m, 1H, CH), 8.75 (bs, 1H, NH); Anal. Calcd. for C16H14N2O5S2
(378.42) C, 50.78%; H, 3.73%; N, 7.40%; Found C, 50.53%; H, 3.89%; N, 7.06%.
4-(Dimethylamino)pyridinium (4-chloropyridin-3-ylsulfonyl)(phenoxycarbonyl)amide (4d). Yield:
48%; m.p. 191–193 °C; IR (KBr) ν = 3215, 3082, 2922, 1688, 1646, 1561, 1397, 1263, 1191, 1149,
1
1028, 916, 887, 806, 797 cm-1; H-NMR (DMSO-d6) δ = 3.16 (s, 6H, CH3), 6.88-6.93 (m, 2H, CH),

Molecules 2010, 15
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6.96 (d, 2H, CH, J = 7.7 Hz), 7.06 (t, 1H, CH, J = 7.1 Hz), 7.22-7.30 (m, 2H, CH), 7.56 (d, 1H, CH,
J = 5.3 Hz), 8.20 (d, 2H, CH, J = 7.7 Hz), 8.53 (d, 1H, CH, J = 5.3 Hz), 8.96 (s, 1H, CH), 12.60 (bs,
1H, NH); Anal. Calcd. for C19H19ClN4O4S (434.90) C, 52.47%; H, 4.40%; N, 12.88%; Found C,
52.19%; H, 4.71%; N, 12.60%.
3.3. General procedure for preparation of arylsulfonyl ureas 5 and heteroarylsulfonyl ureas 6.
Reaction of carbamoylides 3a-c and carbamates 4a-c with aliphatic and aromatic amines
A mixture of carbamoylide 3 or carbamate 4 (2.8 mmol) and appropriate aliphatic or aromatic
amine (3 mmol) in acetonitrile (10 mL) was heated at reflux for 10 min (in case of aliphatic) or 1 h (in
case of aromatic) amine. The reaction mixture was cooled to room temperature and the solvent was
evaporated under reduced pressure to dryness. The oily residue was suspended in methanol and treated
with 10% aqueous hydrochloric acid. The sulphonylureas 5 or 6 that precipitated were separated by
suction, washed with methanol and water and re-crystallized from suitable solvent.
According to the above procedure the following sulphonylureas were obtained:
N-(4-Nitrophenylsulfonyl)pyrrolidine-1-carboxamide (5a). Yield: 17%; m.p. 187–193 °C (methanol);
IR (KBr) ν = 3466, 3271, 3109, 2990, 2788, 1670, 1529, 1348, 1313, 1167, 1091, 1067 cm-1;
1H-NMR (DMSO-d6) δ = 1.60-1.90 (m, 4H, CH2CH2), 3.15-3.45 (m, 4H, N-CH2), 8.15 (d, 2H, CH,
J = 5.2 Hz), 8.42 (d, 2H, CH, J = 5.2 Hz), 11.05 (bs, 1H, NH); Anal. Calcd. for C11H13N3O5S (299.30)
C, 44.14%; H, 4.38%; N, 14.04%; Found C, 44.08%; H, 4.52; N, 13.96%.
N-4-Nitrophenylsulfonyl)-4-phenylopiperazine-1-carboxamide (5b). Yield: 31%; m.p. 105–107 °C
(ethanol); IR (KBr) ν = 3419, 3105, 2882, 1669, 1600, 1529, 1494, 1350, 1235, 1166, 1091 cm-1;
1H-NMR (DMSO-d6) δ = 2.90-3.20 (m, 4H, CH2), 3.30-3.60 (m, 4H, CH2), 6.80 (t, 1H, CH, J = 7.4
Hz), 6.90 (d, 2H, CH, J = 7.4 Hz), 7.20 (t, 2H, CH, J = 7.4 Hz), 8.50 (d, 2H, CH, J = 9.7 Hz), 8.43 (d,
2H, CH, J = 9.7 Hz), 11.45 (bs, 1H, NH); Anal. Calcd. for C17H18N4O5S (390.41) C, 52.30%; H,
4.65%; N, 14.35%; Found C, 52.05%; H, 4.83%; N, 14.16%.
N-4-Chlorophenylcarbamoyl)-4-nitrophenylsulfonamide (5c). Yield: 42%; m.p. 165–170 °C (ethanol);
IR (KBr) ν = 3438, 3351, 3112, 2890, 1715, 1607, 1542, 1351, 1158, 1086, 1039, 1013 cm-1; 1H-NMR
(DMSO-d6) δ = 7.32 (d, 2H, CH, J = 8.8 Hz), 7.38 (d, 2H, CH, J = 8.8 Hz), 8.22 (d, 2H, CH,
J = 8.8 Hz), 8.46 (d, 2H, CH, J = 8.8 Hz), 9.80 (bs, 1H, NH), 11.20 (bs, 1H, NH); Anal. Calcd. for
C13H10ClN3O5S (355.75) C, 43.89%; H, 2.83%; N, 11.81%; Found C, 44.17%; H, 3.12%; N, 11.57%.
N-(4-Methoksyphenylcarbamoyl)-4-nitrophenylsulfonamide (5d). Yield: 46%; m.p. 148–152 °C
(ethanol); IR (KBr) ν = 3482, 3316, 3117, 3071, 3013, 2959, 2836, 1698, 1530, 1514, 1436, 1348,
1
1311, 1252, 1163, 1089, 1023 cm-1; H-NMR (DMSO-d6) δ = 3.68 (s, 3H, OCH3), 6.84 (d, 2H, CH,
J = 9 Hz), 7.24 (d, 2H, CH, J = 9 Hz), 8.20 (d, 2H, CH, J = 9 Hz), 8.45 (d, 2H, CH, J = 9 Hz); 8.93
(bs, 1H, NH), 11.2 (bs, 1H, NH); Anal. Calcd. for C14H13N3O6S (351.33) C, 47.86%; H, 3.73%; N,
11.96%; Found C, 47.74%; H, 3.95%; N, 11.71%.

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N-(2-Chlorophenylsulfonyl)pyrrolidine-1-carboxamide (5e). Yield: 37%; m.p. 175–190 °C (methanol);
IR (KBr) ν = 3400, 3271, 3102, 3068, 1694, 1575, 1487, 1436, 1255, 1236, 1185, 1168, 1132,
1115 cm-1; 1H-NMR (DMSO-d6) δ = 1.64-1-94 (m, 4H, CH2), 3.15-45 (m, 4H, N-CH2), 7.54-7.58 (m,
1H, CH), 7.60-7.68 (m, 2H, CH), 8.03 (d, 1H, CH, J = 7.7 Hz), 11.06 (s, 1H, NH); Anal. Calcd. for
C11H13ClN2O3S (288.75) C, 45.75%; H, 4.54%; N, 9.70%; Found C, 45.61%; H, 4.82%; N, 9.47%.
2-Chloro-N-(pyrimidin-2-ylcarbamoyl)benzenesulfonamide (5f). Yield: 68%; m.p. 178–182 °C; IR
(KBr) ν = 3148, 3067, 2970, 2920, 1715, 1582, 1470, 1449, 1402, 1353, 1282, 1155, 1130, 1075,
1
1006, 914, 866, 812 cm-1; H-NMR (DMSO-d6) δ = 7.42-7.50 (m, 1H, CH), 7.65-7.80 (m, 3H, CH),
7.97-8.03 (d, 1H, CH, J = 7.6 Hz), 8.70-8.77 (m, 2H, CH), 10.69 (s, 1H, NH), 12.63 (bs, 1H, NH);
Anal. Calcd. for C11H9 ClN4O3S (312.73); C, 42.25%; H, 2.90%; N, 17.92%; Found C, 41.89%; H,
3.27%; N, 17.65%.
N-(Naphthalene-2-ylsulfonyl)pyrrolidine-1-carboxamide (5g). Yield: 48%; m.p. 203–208 °C (ethanol);
IR (KBr) ν = 3266, 2975, 2870, 1692, 1441, 1328, 1157, 1057, 861, 748, 658 cm-1; 1H-NMR (DMSO-
d6) δ = 1.60-1.90 (m, 4H, CH2), 3.15-3.45 (m, 4H, N-CH2), 7.62-7.75 (m, 2H, CH), 7.91-8.21 (m, 4H,
CH), 8.57 (s, 1H, CH), 10.77 (s, 1H, NH); Anal. Calcd. for C15H16N2O3S (304.36) C, 59.19%; H,
5.30%; N, 9.20%; Found C, 58.98%; H, 5.43%; N, 9.01%.
N-(Naphthalene-2-ylsulfonyl)-4-phenylpiperazine-1-carboxamide (5h). Yield: 98%; m.p. 119–123 °C
(ethanol); IR (KBr) ν = 3277, 3059, 3016, 2959, 2936, 1676, 1484, 1338, 1252, 1162, 1125, 1070,
1
1021, 876, 745 cm-1; H-NMR (DMSO-d6) δ = 3.28-3.36 (m, 4H, CH2), 3.66-3.74 (m, 4H, CH2),
7.11-7.17 (m, 1H, CH), 7.30-7.40 (m, 4H, CH), 7.64-7.76 (m, 2H, CH), 7.92-8.22 (m, 4H, CH), 8.59
(s, 1H, CH), 11.35 (bs, 1H, NH); Anal. Calcd. for C21H21N3O3S (395.47) C, 63.78%; H, 5.35%; N,
10.63%; Found C, 63.56%; H, 5.50%; N, 10.33%.
Ethyl 4-(naphthalen-2-ylsulfonylcarbamoyl)piperazine-1-carboxylate (5i). Yield: 48%; m.p.
143–147 °C; IR (KBr) ν = 3196, 3060, 2978, 2930, 2868, 1709, 1677, 1469, 1441, 1257, 1230, 1163,
1072 cm-1; 1H-NMR (DMSO-d6) δ = 1.16 (t, 3H, CH3, Ј = 7 Hz), 3.20-3.42 (m, 8H, CH2), 4.02 (q, 2H,
CH2, Ј = 7 Hz), 7.67-7.73 (m, 2H, CH), 7.88-7.93 (m, 1H, CH), 8.02-8.21 (m, 3H, CH), 8.55 (s, 1H,
CH), 11.20 (bs, 1H, NH); Anal. Calcd. for C18H21N3O5S (391.44) C, 55.23%; H, 5.41%; N, 10.73%;
Found C, 54.94%; H, 5.72%; N, 10.66%.
N-(Pyrimidin-2-ylcarbamoyl)naphthalene-2-sulfonamide (5j). Yield: 68%; m.p. 177–182 °C; IR (KBr)
1
ν = 3148, 3067, 2971, 2920, 1716, 1583, 1471, 1449, 1354, 1283, 1156, 1075 cm-1; H-NMR
(DMSO-d6) δ = 7.20-7.24 (m, 1H, CH), 7.66-7.78 (m, 2H, CH), 7.98-8.26 (m, 4H, CH), 8.70-8.72 (m,
3H, CH), 10.70 (s, 1H, NH), 12.65 (bs, 1H, NH); Anal. Calcd. for C15H12N4O3S (328.35) C, 54.87%;
H, 3.68%; N, 17.06%; Found C, 55.02%; H, 3.84%; N, 16.81%.
N-(5-Chlorothiophen-2-ylsulfonyl)indoline-1-carboxamide (6a). Yield: 73%; m.p. 182–184 °C; IR
(KBr) ν = 3635, 3450, 2920, 1659, 1486, 1464, 1400, 1348, 1165, 1137, 1091, 998, 808, 871, 679,
620, 604 cm-1; 1H-NMR (DMSO-d6) δ = 3.11 (t, 2H, CH2, J = 8.4 Hz), 4.03 (t, 2H, CH2, J = 8.4 Hz),

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6.92-7.01 (m, 1H, CH), 7.08-7.23 (m, 2H, CH), 7.27 (d, 1H, CH, J = 4.2 Hz), 7.69 (d, 1H, CH,
J = 4.2 Hz), 10.9 (bs, 1H, NH); Anal. Calcd. for C13H11ClN2O3S2 (342.82) C, 45.55%; H, 3.23%; N,
8.17%; Found C, 45.38%; H, 3.59%; N, 7.93%.
N-(5-Chlorothiophen-2-ylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (6b). Yield: 61%;
m.p. 169–172 °C; IR (KBr) ν = 3107, 3020, 2896, 2805, 2751, 1646, 1481, 1410, 1344, 1235, 1167,
1001, 757, 616, 572 cm-1; 1H-NMR (DMSO-d6) δ = 2.81-2.82 (m, 2H, CH2), 3.59-3.61 (m, 2H, CH2),
4.53 (s, 2H, CH2), 7.16-7.20 (m, 4H, CH), 7.25 (d, 1H, CH, J = 3.9 Hz), 7.64 (d, 1H, CH, J = 3.9 Hz),
11.44 (bs, 1H, NH); Anal. Calcd. for C14H13ClN2O3S2 (356.85) C, 47.12%; H, 3.67%; N, 7.85%;
Found C, 46.84%; H, 3.73%; N, 7.57%.
5-Chloro-N-(2,3-dihydro-1H-inden-1-ylcarbamoyl)thiophene-2-sulfonamide (6c). Yield: 49%, m.p.
144–148 °C; IR (KBr) ν = 3353, 3094, 1687, 1650, 1541, 1466, 1409, 1367, 1168, 995, 752, 679 cm-1;
1H-NMR (DMSO-d6) δ = 1.71-1.86 (m, 1H, CH), 2.30-2.48 (m, 1H, CH), 2.68-2.96 (m, 2H, CH),
5.00-5.18 (m, 1H, CH, J = 8.0 Hz), 6.99 (d, 1H, NH, J = 8.0 Hz), 7.10-7.24 (m, 4H, CH), 7.29 (d, 1H,
CH, J = 4.1 Hz), 7.65 (d, 1H, CH, J = 4.1 Hz), 10.90 (bs, 1H, NH); Anal. Calcd. for C14H13ClN2O3S2
(356.85) C, 47.12%; H, 3.67%; N, 7.85%; Found C, 46.97%; H, 3.95%; N, 7.82%.
N-(Benzothiazol-2-ylsulfonyl)pyrrolidine-1-carboxamide (6d). Yield: 80%; m.p. 220–222 °C; IR
1
(KBr) ν = 3277, 2877, 1690, 1454, 1168, 1056, 860, 765, 625 cm-1; H-NMR (DMSO-d6)
δ = 1.60-1.95 (m, 4H, CH2), 3.25-3.65 (m, 4H, CH2), 7.61-7.73 (m, 2H, CH), 8.16-8.32 (m, 2H, CH),
11.80 (bs, 1H, NH); Anal. Calcd. for C12H13N3O3S2 (311.38); C, 46.29%; H, 4.21%; N, 13.49%;
Found C, 45.97%; H, 4.53%; N, 13.42%.
N-(Benzothiazol-2-ylsulfonyl)thiazolidine-1-carboxamide (6e). Yield: 79%; m.p. 240–241 °C; IR
1
(KBr) ν = 3068, 2887, 2791, 1681, 1455, 1181, 1385, 1092, 859, 626 cm-1; H-NMR (DMSO-d6)
δ = 2.98-3.04 (m, 2H, CH2), 3.59-3.63 (m, 2H, CH2), 4.42 (s, 2H, CH2), 7.61-7.74 (m, 2H, CH), 8.16-
8.22 (m, 1H, CH), 8.26-8.33 (m, 1H, CH), 11.20 (bs, 1H, NH); Anal. Calcd. for C11H11N3O3S3
(329.42) C, 40.11%; H, 3.37%; N, 12.76%; Found C, 39.87%; H, 3.42%; N, 12.40%.
N-(4-Chlorophenylcarbamoyl)benzothiazole-2-sulfonamide (6f). Yield: 81%, m.p. 182–184 °C; IR
1
(KBr) ν = 3281, 1709, 1597, 1532, 1367, 1166, 1028, 923, 673 cm-1; H-NMR (DMSO-d6)
δ = 7.28 (d, 1H, CH, J = 7.6 Hz,), 7.38 (d, 2H, CH, J = 7.6 Hz), 7.62-7.72 (m, 2H, CH), 8.16-8.23 (m,
1H, CH), 8.25-8.34 (m, 1H, CH), 9.39 (bs, 1H, NH), 12.6 (bs, 1H, NH); Anal. Calcd. for
C14H10ClN3O3S2 (367.83) C, 45.71%; H, 2.74%; N, 11.42%; Found C, 45.34%; H, 3.11%; N, 11.10%.
N-(Pyrimidin-2-ylcarbamoyl)benzothiazole-2-sulfonamide (6g). Yield: 70%; m.p. 312–314 °C; IR
(KBr) ν = 3067, 2972, 2919, 1646, 1583, 1449, 1374, 1161, 1028, 917, 761 cm-1; 1H-NMR (DMSO-d6)
δ = 7.27-7.32 (m, 1H, CH), 7.56-7.69 (m, 2H, CH), 8.10-8.16 (m, 1H, CH), 8.19-8.27 (m, 1H, CH),
8.73-8.76 (m, 2H, CH), 11.43 (bs, 2H, NH); Anal. Calcd. for C12H9N5O3S2 (335.36) C, 42.98%; H,
2.70%; N, 20.88%; Found C, 42.71%; H, 3.02%; N, 20.57%.

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N-(6-Ethoxybenzothiazol-2-ylsulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (6h). Yield: 87%;
m.p. 203–206 °C; IR (KBr) ν = 3145, 3088, 2956, 2876, 1648, 1555, 1432, 1386, 1145, 1128,
1034, cm-1; 1H-NMR (DMSO-d6) δ = 1.37 (t, 3H, CH3, J = 7.8 Hz), 2.80 (t, 2H, CH2, J = 6.8 Hz), 3.60
(t, 2H, CH2, J = 6.8 Hz), 4.12 (q, 2H, CH2, J = 7.8 Hz), 4.51 (s, 2H, CH2), 7.05-7.2 (m, 4H, CH), 7.23
(dd, 1H, CH, Jortho = 6.8 Hz, Jmeta = 2.0 Hz), 7.80 (d, 1H, CH, Jortho = 6.8 Hz), 8.05 (d, 1H, CH,
Jmeta = 2.0 Hz), 11.30 (bs, 1H, NH); Anal. Calcd. for C19H19N3O4S2 (417.50) C, 54.66%; H, 4.59%; N,
10.06%; Found 54.56%; H, 4.85%; N, 10.03%.
N-(4-Chlorophenylcarbamoyl)-6-ethoxybenzothiazol-2-ylsulfonamide (6i). Yield: 75%; m.p.
238–240 °C; IR (KBr) ν = 3326, 3194, 3088, 2967, 2902, 2887, 1642, 1558, 1442, 1390, 1148, 1148,
1
1142, 1044 cm-1; H-NMR (DMSO-d6) δ = 1.37 (t, 3H, CH3, J = 7.7 Hz), 4.16 (q, 2H, CH2,
J = 7.7 Hz), 7.26 (dd, 1H, CH, Jortho = 6.9 Hz, Jmeta = 2.1 Hz), 7.30 (d, 2H, CH, J = 7.0 Hz), 7.38 (d,
2H, CH, J = 7.0 Hz), 7.80 (d, 1H, CH, J = 2.1 Hz), 8.06 (d, 1H, CH, J = 6.9 Hz), 9.30 (s, 1H, NH),
11.80 (bs, 1H, NH); Anal. Calcd. for C16H14ClN3O4S2 (411.88) C, 46.66%; H, 3.43%; N, 10.20%;
Found C, 46.73%; H, 3.68%; N, 9.83%.
3.4. Preparation of 3-(indolin-1-yl)-pyrido[3,4-e][1,4,3]oxathiazine 1,1-dioxide 8
A mixture of carbamoylide 3d or pyridinium carbamate 4d (2.8 mmol) and indoline (3 mmol) in
acetonitrile (10 mL) was heated at reflux for 3 h under reflux. The reaction mixture was cooled to
room temperature and solvent was evaporated under reduced pressure to dryness. The crude residue
triturated with methanol and water to give product 8 which was then separated by suction, washed with
methanol and water and purified by crystallization from DMF. Yield: 33% and 29%, respectively; m.p.
248–250 °C; IR (KBr) ν = 2919, 1633, 1586, 1488, 1472, 1315, 1301, 1173, 1151, 1104, 1011, 765,
1
595 cm-1; H-NMR (DMSO-d6) δ = 3.25 (t, 2H, CH2, J = 7.8 Hz), 4.39 (t, 2H, CH2, J = 7.8 Hz),
7.18-7.21 (m, 1H, CH), 7.34-7.39 (m, 2H, CH), 7.62 (d, 1H, CH, J = 5.4 Hz), 8.07-8.09 (m, 1H, CH),
8.88 (d, 1H, CH, J = 5.4 Hz), 9.13 (s, 1H, CH); Anal. Calcd. for C14H11N3O3S (301.32) C, 55.80%; H,
3.68%; N, 13.95%; Found C, 55.74%; H, 3.78%; N, 14.13%.
3.5. X-ray structure analysis
The diffraction data were collected with a KumaCCD diffractometer using graphite monochromated
Mo Kα radiation. The intensity data were collected and processed using Oxford Diffraction CrysAlis
Software [17]. The crystal structures were solved by direct methods with the program SHELXS-97
[18] and refined by full-matrix least-squares method on F2 with SHELXL-97 [18].
Crystal data for C14H9N2O4S2·C7H11N2 (4b): Triclinic, space group P-1, a = 11.2168(5),
b = 12.0651(6), c = 16.3837(8) Å, α = 79.042(4), β = 85.852(4), γ = 83.798(4)°, V = 2161.02(18) Å3,
Z = 4, dx = 1.403 g.cm-3, T=130K. Data were collected for a crystal with dimensions 0.4x0.4x0.3 mm.
Final R indices for 5697 reflections with I>2σ(I) and 582 refined parameters are: R1 = 0.0319,
wR2 = 0.0764 (R1 = 0.0490, wR2 = 0.0864 for all 7589 data). The benzothiazole ring of one of the
symmetry independent molecules is disordered over two strongly overlapping positions.

Molecules 2010, 15
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Crystal data for C16H13N2O5S2·C7H11N2 (4c): Monoclinic, space group P21/n, a = 12.3446(2),
b = 12.5528(2), c = 15.6694(3) Å, β = 99.7467(18)°, V = 2393.07(7) Å3, Z = 4, dx = 1.389 g.cm-3,
T = 130K. Data were collected for a crystal with dimensions 0.5x0.5x0.1 mm. Final R indices for 4467
reflections with I > 2σ(I) and 314 refined parameters are: R1 = 0.0291, wR2 = 0.0721 (R1 = 0.0391,
wR2 = 0.0832 for all 5320 data).
Crystallographic data for compounds 4b and 4c have been deposited with Cambridge
Crystallographic Data Centre (CCDC deposition numbers CCDC 742624-742625). Copies of the data
can be obtained upon request from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, quoting the
deposition numbers.
3.6. In vitro cytotoxicity assay
The following primary screening of the new compounds was done to indicate whether a substance
possesses enough activity at the concentration of 20 μM to inhibit human tumor cell growth by 50%
(GI50 < 20 μM).
The in vitro cytotoxic activity of all arylsulfonylureas 5a-j and heteroarylsulfonylureas 6a-i were
evaluated [19,20] using human urinary bladder cancer 5637, small cell lung cancer A-427 and large
cell lung cancer LCLC-103H cell lines. The assay was carried out in 96-well microtiter plates. When
the cells were putted into the plates after 24 h cells were treated with appropriate drug solutions. The
cytotoxic effects of the compounds were measured after a 96 h continuous exposure to the substances.
The cell growth inhibition values were estimated by staining the adherent cells with crystal violet.
Only viable cells remained attached to the plastic surface of the wells and bind the dye. The unbound
dye was washed out with water and stain remaining in the wells was redissolved with 70% ethanol.
Finally, the optical density (OD) was measured with a microplate reader set at λ = 570 nm.
4. Conclusions
The current work has addressed the use of environmentally non hazardous
aryl(heteroaryl)sulfonamides and diphenyl carbonate (DPC) in the synthesis of 4-dimethylamino-
pyridinium N-[aryl(heteroaryl)sulfonyl] carbamoylides of type 3, the stable and easy-to-handle
substitutes of aryl(heteroaryl)sulfonyl isocyanates. The comparison of the existing literature methods
for the preparation of arylsulfonyl/heteroaryl carbamates and ureas from arylsulfonamides suggests
that the DPC/DMAP approach is superior. Some of the advantages include mild reaction conditions,
the ease of preparation and product separation and the extended shelf-life of the parent ylides.
Moreover, a very high reactivity of pyridinium carbamoylides renders them suitable for the syntheses
of arylsulfonyl ureas. It should be emphasized, however, that in the above procedure diphenyl
carbonate (DPC) could not be replaced by the less reactive diethyl or dimethyl carbonates.
It has been also found that the course of the reaction between sulphonamide and DPC/DMAP
couple depends on pKa of the substrate. Thus, arylsulphonamides with pKa in the range of 9-10 give
the desired carbamoylides 3, while the more acidic heteroarylsulfonamides (pKa ~ 8) react
preferentially with the formation of pyridinium salts of the intermediary formed carbamates 4.

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Although none of the compounds described in this work exhibited pronounced cytotoxic activity
against selected human tumor cell lines, yet the biological potential of these derivatives incorporating
aryl(heteroaryl)sulfonylurea pharmacophoric group presented in Introduction remains to be explored.
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Sample Availability: Samples of the compounds 3, 4 and 8 are available from the authors.
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).