A new and simple synthesis of sulfonyl ureas from sulfonamides and N-alkyl-1,2,4-dithiazolidine-3,5-diones

Article abstract of DOI:10.1055/s-0029-1217960

A new, short, and simple synthetic approach to sulfonyl ureas is reported. The method involves the transformation of readily synthesized N-alkyl-1,2,4-dithiazolidine-3,5-diones by reaction with primary sulfonamides. Sulfonyl ureas were obtained in moderat

Full text of DOI:10.1055/s-0029-1217960

LETTER
2839
A New and Simple Synthesis of Sulfonyl Ureas from Sulfonamides and
N-Alkyl-1,2,4-dithiazolidine-3,5-diones
S
ynthesis of Sulf
i
U
r
eas hard K. Gessner,a Kelly Chibale*a,b
a
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Fax +27(21)6897499; E-mail: Kelly.Chibale@uct.ac.za
b
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
Received 17 July 2009
sulfonyl isocyanates 7 in situ via treatment with triphen-
ylphosphine (Scheme 2).
Abstract: A new, short, and simple synthetic approach to sulfonyl
ureas is reported. The method involves the transformation of readily
synthesized N-alkyl-1,2,4-dithiazolidine-3,5-diones by reaction
with primary sulfonamides. Sulfonyl ureas were obtained in moder-
ate to high yields.
As previously described in the literature,5,7 the predicted
approach to the N-acyl imides 2 was to react the NH imide
with an acid chloride in the presence of a base (pyridine
was chosen as the base and solvent for this type of reac-
tion) following studies of the reaction of phthalimide with
benzoyl chloride.11 Following this protocol as well as us-
ing other bases such as Hünig’s base, cesium carbonate,
and potassium tert-butoxide, the various efforts were un-
successful. Eventually success was achieved by perform-
ing the reaction in dichloromethane and using poly(4-
vinylpyridine) as an insoluble base.7
Key words: sulfonyl ureas, isocyanates, sulfonamides, heterocy-
cles, protecting group
Isocyanates and acyl isocyanates are important and useful
agents for the preparation of N-acyl ureas and N-acyl car-
bamates, as well as, for the synthesis of a variety of het-
erocycles.1–4
Recent studies have shown that N-alkyl-1,2,4-dithiazoli-
dine-3,5-diones5,6 1 and N-aroyl-1,2,4-dithiazolidine-3,5-
diones7 2 can be prepared relatively easily by the reaction
of alkyl halides and acid chlorides with the heterocyclic
scaffold 3.8–10 These compounds are regarded as protected
isocyanates, as upon treatment with triphenylphosphine
under anhydrous conditions, the respective isocyanate 4 is
formed in situ. In the case of protected acyl isocyanates 5,
it has recently been demonstrated that the reaction with
the desired amine and alcohol nucleophiles proceeds in
the absence of triphenylphosphine (Scheme 1).7
O
O
S
O
O
O
S
S
O
C
S
N
N
Ar
Ar
O
6
7
Scheme 2 N-Arylsulfonyl-1,2,4-dithiazolidine-3,5-dione as a hypo-
thetical protected isothiocyanate
Our initial attempts to generate the equivalent N-sulfonyl
imide followed a similar strategy. Various weak bases, in-
cluding pyridine, N,N-dimethylaminopyridine, sodium bi-
carbonate, potassium carbonate, cesium carbonate, as
well as solvent systems, including N,N-dimethylform-
amide (DMF), dichloromethane, and pyridine were at-
tempted but to no avail. Our lack of success was attributed
to the possible high instability of the desired N-sulfonyl
imide product. Several other observations already record-
ed in the literature may help explain the failure of these at-
tempts. Decomposition of 1,2,4-dithiazolidine-2,5-dione
in reactions with alkyl halides using DMF and dimethyl-
sulfoxide as solvent, as well as at elevated temperatures
(>40 °C) had been documented.5 The reactivity and de-
composition of 1,2,4-dithiazolidine-2,5-diones in the
presence of amines (and amine bases), respectively, is
also well described in the literature.10
O
O
O
S
S
S
S
C
X
N
X
NH
N
R
R
4 X = CH2
5 X = C=O
O
O
1 X = CH2
2 X = C=O
3
Scheme 1 N-Alkyl- and N-aroyl-1,2,4-dithiazolidine-3,5-diones as
isocyanate and acyl isocyanate equivalents
As part of a medicinal chemistry program, we have been
investigating new synthetic methods for accessing sulfo-
nyl ureas. In this regard the use of N-alkyl- and/or N-
aroyl-1,2,4-dithiazolidine-3,5-diones appealed to us. We
had originally envisaged proceeding via N-arylsulfonyl-
1,2,4-dithiazolidine-3,5-diones 6 which would generate
In view of the failure of our initial approach, an alternative
route to access the desired target compounds was consid-
ered. The reaction of 1,2,4-dithiazolidine-2,5-dione 3
with alkyl halides is well documented (Scheme 3,
Table 1).5 The resulting N-alkyl-1,2,4-dithiazolidine-2,5-
diones 1, in the presence of triphenylphosphine, were con-
verted into isocyanates and reacted with amines to give
SYNLETT 2009, No. 17, pp 2839–2843
x
x
.x
x
.2
0
0
9
Advanced online publication: 09.09.2009
DOI: 10.1055/s-0029-1217960; Art ID: D19009ST
© Georg Thieme Verlag Stuttgart · New York

2840
R. K. Gessner, K. Chibale
LETTER
the corresponding ureas. Based on this, we proposed that A number of the N-alkyl-1,2,4-dithiazolidine-3,5-diones
reaction of protected isocyanates 1 with primary sulfon- 1 were chosen and successfully reacted with 4-chloroben-
amides in the presence of triphenylphosphine and a weak zene sulfonamide in the presence of triphenylphosphine
base would give the desired corresponding sulfonyl ureas.
Thus, following the optimized protocol5 using acetonitrile
as the solvent and sodium bicarbonate as the base, a range
of N-alkyl-1,2,4-dithiazolidine-3,5-diones 1 were synthe-
sized by the coupling of 1,2,4-dithiazolidine-3,5-dione 3
with various alkyl bromides.
Table 2 Synthesis of Sulfonyl Ureas from N-Alkyl-1,2,4-dithiazo-
lidine-3,5-diones
Entry R1
R2
Product Yield
(%)
1
2
CO2Et
8a
8b
48
65
O
O
Cl
Cl
S
S
S
S
+
NH
N
R
Br
R
O
O
3
1
Scheme 3 Alkylation of 1,2,4-dithiazolidine-3,5-dione. Reagents
and conditions: NaHCO3 (2 equiv), MeCN, 20 °C, 16 h.
3
8c
52
Cl
Cl
Br
Table 1 Synthesis of N-Alkyl-1,2,4-dithiazolidine-3,5-diones
4
5
6
8d
8e
8f
58
79
67
Entry
1
R
Product
Yield (%)
65
Br
CO2Et
1a
2
3
4
1b
1c
1d
74
94
79
Br
Br
Br
Br
7
8
8g
8h
67
32
Cl
OMe
OMe
5
6
7
1e
1f
92
68
76
Br
MeO
1g
9
8i
8j
71
80
Cl
8
1h
78
10
NH
O
Br
O
Cl
O
O
O
O
O
S
S
+
S
N
R1
N
N
R2
H2N
R2
S
R1
H
H
OMe
O
Cl
H
1
8
O
N
Scheme 4 Reaction of N-alkyl-1,2,4-dithiazolidine-3,5-diones with
sulfonamides Reagents and conditions: Ph3P (1 equiv), K2CO3
(1 equiv), PhMe, reflux, 24 h.
11
8k
47
CO2Et
Br
Synlett 2009, No. 17, 2839–2843 © Thieme Stuttgart · New York

LETTER
Synthesis of Sulfonyl Ureas
2841
4-(2-Bromobenzyl)[1,2,4]dithiazolidine-3,5-dione (1c)
and potassium carbonate in toluene. As a result of the suc-
cess of this reaction, a number of structurally diverse sul-
fonamides were then used to emphasize the broad scope
of the reaction. Yields for target sulfonyl ureas 8 ranged
from moderate to good (30–80%; Scheme 4, Table 2).
Yield 94% (211 mg); white needlelike crystals; Rf = 0.21; mp 80–
81 °C. IR (film): 3060 (w), 1655 (s), 1603 (m), 1477 (m), 1312 (s),
749 (s), 555 (w) cm–1. 1H NMR (400 MHz, CDCl3): d = 7.59 (dd, 1
H, J = 7.8, 1.3 Hz, ArH), 7.29 (td, 1 H, J = 7.6, 1.3 Hz, ArH), 7.18
(td, 1 H, J = 7.8, 1.7 Hz, ArH), 7.07 (dd, 1 H, J = 7.7, 1.7 Hz, ArH),
5.05 (s, 2 H, CH2). 13C NMR (100.6 MHz, CDCl3): d = 162.77 (2
C), 133.25, 132.78, 129.62, 127.86, 127.72, 122.85, 49.21. HRMS
(EI): m/z = 302.90180 [M+].
In summary, all attempts to develop a method to produce
sulfonyl ureas via a N-arylsulfonyl-1,2,4-dithiazolidine-
3,5-dione intermediate (protected sulfonyl isocyanate)
were unsuccessful. However, a new method using readily
available, diverse alkyl halides and sulfonamides (via the
relatively easily accessible intermediate N-alkyl-1,2,4-
dithiazolidine-3,5-diones 1) has been demonstrated. This
method clearly provides a simple approach to new and
Anal. Calcd for C9H6BrNO2S2: C, 35.5; H, 1.99; N, 4.60; S, 21.1.
Found: C, 34.9; H, 1.86; N, 4.18; S, 20.0.
4-(3-Bromobenzyl)[1,2,4]dithiazolidine-3,5-dione (1d)
Yield 79% (178 mg); white needlelike crystals; Rf = 0.30; mp 95–
97 °C. IR (film): 3000 (w), 1652 (s), 1572 (m), 1474 (m), 1303 (s),
novel classes of sulfonyl ureas. It is clear that this meth- 708 (s), 544 (w) cm–1. 1H NMR (400 MHz, CDCl3): d = 7.56 (s, 1
H, ArH), 7.47 (d, 1 H, J = 7.8 Hz, ArH), 7.34 (d, 1 H, J = 7.7 Hz,
odology has its limitations as, to date, only N-alkyl-1,2,4-
ArH), 7.21 (t, 1 H, J = 7.8 Hz, ArH), 4.86 (s, 2 H, CH2). 13C NMR
dithiazolidine-3,5-diones 1 have been used. Further work
(100.6 MHz, CDCl3): d = 167.34 (2 C), 136.17, 132.03, 131.96,
to extend this methodology via the generation of possible
130.38, 127.73, 122.81, 48.57. HRMS (EI): m/z = 302.90191 [M+].
N-aryl-1,2,4-dithiazolidine-3,5-dione
intermediates
Anal. Calcd for C9H6BrNO2S2: C, 35.5; H, 1.99; N, 4.60; S, 21.1.
Found: C, 35.0; H, 1.84; N, 3.98; S, 19.8.
would be important in order to extend this methodology to
include the vast number of commercially available aryl
halides.
4-(4-Bromobenzyl)[1,2,4]dithiazolidine-3,5-dione (1e)
Yield 92% (207 mg); white crystals; Rf = 0.21; mp 93–97 °C. IR
(film): 2995 (w), 1645 (s), 1486 (m), 1301 (s), 724 (s), 525 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47 (d, 2 H, J = 8.4 Hz, 2 × ArH),
7.29 (d, 2 H, J = 8.30 Hz, 2 × Ar2), 4.85 (s, 2 H, CH2). 13C NMR
(100.6 MHz, CDCl3): d = 167.38 (2 C), 133.08, 132.03 (2 C),
130.86 (2 C), 123.02, 48.65. HRMS (EI): m/z = 302.90176 [M+].
Anal. Calcd for C9H6BrNO2S2: C, 35.5; H, 1.99; N, 4.60; S, 21.1.
Found: C, 35.1; H, 1.96; N, 4.09; S, 19.7.
All commercially available chemicals were purchased from either
Sigma-Aldrich or Merck. All solvents were dried by appropriate
techniques. Unless otherwise stated, all solvents used were anhy-
drous. Reactions were monitored by TLC using Merck silica gel
plates (60 F-254), and were visualized by the ultraviolet light. Silica
gel chromatography was performed using Merck kieselgel 60: 70–
230 mesh for gravity columns. Melting points were determined on
a Reichert-Jung Thermovar hotstage microscope and are uncorrect-
ed. Infrared spectra were recorded on a Thermo Nicolet FTIR in-
strument in the 4000–500 cm–1 range using KBr discs.
Microanalyses were determined using a Fisons EA 1108 CHNO-S
instrument. Mass spectra were recorded at the School of Chemistry,
University of the Witwatersrand. NMR spectra were recorded on ei-
ther a Varian Mercury-300 (1H NMR: 300.13 MHz; 13C NMR: 75.5
MHz) or a Varian Unity-400 (1H NMR: 400.13; 13C NMR: 100.6
MHz) spectrometer. Chemical shifts (d) are given in ppm downfield
from TMS as the internal standard.
4-Allyl[1,2,4]dithiazolidine-3,5-dione (1f)
Yield 68% (88 mg); clear, yellow oil; Rf = 0.31 (EtOAc–hexane,
1:19). 1H NMR (400 MHz, CDCl3): d = 5.79 (m, 1 H, CH), 5.28 (m,
2 H, CH2), 4.33 (dt, 2 H, J = 6.0, 1.4 Hz, CH2). 13C NMR (100.6
MHz, CDCl3): d = 169.35 (2 C), 129.18, 120.20, 47.96. HRMS (EI):
m/z = 174.97561 [M+].
4-(4-Methoxybenzyl)[1,2,4]dithiazolidine-3,5-dione (1g)
Yield 76% (143 mg); white, crystalline solid; Rf = 0.23 (EtOAc–
hexane, 1:19); mp 62–63 °C. 1H NMR (400 MHz, CDCl3): d = 7.26
(t, 1 H, J = 8.3 Hz, ArH), 6.97 (m, 2 H, 2 × ArH), 6.87 (d, 1 H, J =
8.3 Hz, ArH), 4.87 (s, 2 H, CH2), 3.80 (s, 3 H, OCH3). 13C NMR
(100.6 MHz, CDCl3): d = 167.42 (2 C), 159.85, 135.53, 129.85,
121.20, 114.51, 114.28, 55.27, 49.27. HRMS (EI): m/z = 255.00182
[M+]. Anal. Calcd for C10H9NO3S2: C, 47.0; H, 3.55; N, 5.49; S,
25.1. Found: C, 46.9; H, 3.60; N, 5.31; S, 24.9.
General Procedure for the Synthesis of Alkyl/Aryl-[1,2,4]dithi-
azolidine-3,5-diones (1a–h)5
1,2,4-Dithiazolidine-3,5-dione 3 (100 mg, 0.74 mmol) was dis-
solved in MeCN (1.5 mL). NaHCO3 (120 mg, 1.43 mmol) was add-
ed with stirring to the solution at r.t. (19 °C). The alkyl bromide
(0.87 mmol) was added, and the mixture was left to stir for 16 h. The
solvent was removed under reduced pressure with adsorption of the
residue onto silica gel for purification by flash chromatography
(EtOAc–hexane, 1:9).
4-(Biphenyl-2-ylmethyl)[1,2,4]dithiazolidine-3,5-dione (1h)
Yield 78% (174 mg); white, crystalline solid; Rf = 0.38 (EtOAc–
1
hexane, 1:19); mp 92–95 °C. H NMR (400 MHz, CDCl3): d =
7.43–7.14 (m, 9 H, 9 × ArH), 4.88 (s, 2 H, CH2). 13C NMR (100.6
MHz, CDCl3): d = 167.12 (2 C), 141.87, 140.20, 131.27, 130.41,
129.13 (2 C), 128.40 (2 C), 127.88, 127.85, 127.49, 126.49, 47.28.
HRMS (EI): m/z = 301.02259 [M+]. Anal. Calcd for C15H11NO2S2:
C, 59.8; H, 3.68; N, 4.65; S, 21.3. Found: C, 59.9; H, 3.61; N, 4.58;
S, 21.1.
Ethyl {3,5-Dioxo-[1,2,4]dithiazolidin-4-yl}acetate (1a)
1
Yield 65% (106 mg); yellow oil; Rf = 0.26. H NMR (400 MHz,
CDCl3): d = 4.46 (s, 2 H, CH2), 4.25 (q, 2 H, J = 7.1 Hz, CH2), 1.29
(t, 3 H, J = 7.2 Hz, CH3).
4-Benzyl[1,2,4]dithiazolidine-3,5-dione (1b)
Yield 74% (124 mg); white crystals; mp 87–91 °C. 1H NMR (400
MHz, CDCl3): d = 7.41 (m, 2 H, 2 × ArH), 7.43 (m, 3 H, 3 × ArH),
4.91 (s, 2 H, CH2). 13C NMR (100.6 MHz, CDCl3): d = 167.47 (2
C), 136.18, 129.06 (2 C), 128.82 (2 C), 128.71, 49.38.
General Procedure for the Synthesis of Sulfonyl Ureas 8a–k
One equiv of 4-chlorobenzene sulfonamide was added to a solution
of alkylated 1,2,4-dithiazolidine-3,5-dione (50 mg for 8a–d and 60
mg for 8e–k) and Ph3P (1 equiv) dissolved in toluene (2.0 mL).
K2CO3 (1 equiv) was added, and the reaction was stirred under re-
flux for 24 h. The reaction mixture was allowed to cool to r.t. The
HRMS (EI): m/z = 224.99127 [M+]. Anal. Calcd for C9H7NO2S2: C,
48.0; H, 3.13; N, 6.22; S, 28.5. Found: C, 47.8; H, 3.14; N, 6.10; S,
28.0.
Synlett 2009, No. 17, 2839–2843 © Thieme Stuttgart · New York

2842
R. K. Gessner, K. Chibale
LETTER
suspended material was filtered off and washed with deionised H2O
and toluene.
7.08 (t, 1 H, J = 8.0 Hz, ArH), 4.05 (s, 2 H, CH2). 13C NMR (100.6
MHz, DMSO): d = 145.74, 133.75, 132.89, 132.62, 132.48, 129.25,
129.13, 128.68, 128.12, 127.90, 127.71, 127.42, 126.99, 126.17,
124.98, 122.55, 44.10. MS (EI): m/z = 418.0 [M+]. Anal. Calcd for
C18H15BrN2O3S: C, 51.6; H, 3.61; N, 6.68; S, 7.65. Found: C, 51.1;
H, 3.28; N, 6.72; S, 6.30.
Ethyl 2-[3-(4-Chlorophenylsulfonyl)ureido]acetate (8a)
Purified by column chromatography (EtOAc–hexane, 1:9; adjust-
ing to EtOAc–hexane, 2:3). Yield 48% (30.6 mg); yellow oil;
Rf = 0.05 (EtOAc–hexane, 2:3). 1H (400 MHz, DMSO): d = 8.17 (s,
1 H, NH), 7.58 (m, 4 H, 4 × ArH), 4.12 (q and s overlapping, 3 H,
J = 7.1 Hz, CH2 and NH), 4.00 (s, 2 H, CH2), 1.18 (t, 3 H, J = 7.1
Hz, CH3). 13C NMR (100.6 MHz, DMSO): d = 171.43, 167.37,
131.45 (2 C), 128.97, 128.72 (2 C), 127.53, 45.99, 38.90, 13.90. MS
(EI): m/z = 320.0 [M+].
4-Chloro-N-(3-methoxybenzylcarbamoyl)benzenesulfonamide
(8g)
Yield 67% (47.6 mg); white solid; mp 232–234 °C. 1H NMR (400
MHz, DMSO): d = 7.75 (d, 2 H, J = 8.4 Hz, 2 × ArH), 7.35 (d, 2 H,
J = 8.5 Hz, 2 × ArH), 7.13 (t, 1 H, J = 7.8 Hz, ArH), 6.76 (m, 3 H,
3 × ArH), 4.07 (d, 2 H, J = 6.5 Hz, CH2), 3.70 (s, 3 H, OCH3). 13
C
N-(Benzylcarbamoyl)-4-chlorobenzenesulfonamide (8b)
Yield 65% (46.1 mg); white powder; mp 248–252 °C. IR (film):
3378 (s), 3028 (w), 1603 (s), 1476 (w), 1458 (s), 1344 (s), 1220 (s),
1134 (s), 728 (s) cm–1. 1H NMR (400 MHz, DMSO): d = 7.72 (d, 2
H, J = 8.3 Hz, 2 × ArH), 7.37 (d, 2 H, J = 8.4 Hz, 2 × ArH), 7.22 (t,
2 H, J = 7.9 Hz, 2 × ArH), 7.14 (m, 3 H, 3 × ArH), 4.05 (s, 2 H,
CH2). 13C NMR (100.6 MHz, DMSO): d = 160.50, 146.73, 133.53,
128.35 (2 C), 127.79 (2 C), 127.33 (2 C), 126.83 (2 C), 125.95,
123.46, 43.06. MS (EI): m/z = 324.0 [M+]. Anal. Calcd for
C14H13N2O3SCl: C, 51.8; H, 4.03; N, 8.63; S, 9.87. Found: C, 51.3;
H, 3.73; N, 8.08; S, 9.24.
NMR (100.6 MHz, DMSO): d = 160.58, 159.07, 146.76, 143.57,
133.45, 128.75, 128.34 (2 C), 127.28 (2 C), 119.02, 112.31, 111.52,
54.74, 42.82. MS (EI): m/z = 354.0 [M+]. Anal. Calcd for
C15H15ClN2O4S: C, 50.8; H, 4.26; N, 7.90; S, 9.04. Found: C, 50.2;
H, 3.87; N, 6.76; S, 8.17.
2,4,6-Triisopropyl-N-(3-methoxybenzylcarbamoyl)benzene-
sulfonamide (8h)
Purified by column chromatography (EtOAc–hexane, 1:4); yield
1
32% (28.4 mg); white solid; Rf = 0.17); mp 135–137 °C. H NMR
(300 MHz, acetone): d = 7.29 (s, 2 H, 2 × ArH), 7.13 (t, 1 H, J = 7.8,
ArH), 6.79 (m, 3 H, 3 × ArH), 4.36 (sept, 2H, J = 6.8 Hz, 2 × CH),
4.29 (s, 2 H, CH2), 3.71 (s, 3 H, OCH3), 2.96 (sept, 1 H, J = 6.9 Hz,
CH), 2.06 (m, 3 H, 3 × CH), 1.25 (m, 18 H, 6 × CH3). 13C NMR
(75.5 MHz, acetone): d = 160.17, 159.54, 153.19, 150.98 (2 C),
141.07, 133.78, 129.56, 123.91 (2 C), 119.43, 112.89, 112.74,
54.74, 43.15 (2 C), 34.15, 29.28, 24.29 (4 C), 23.15 (2 C). HRMS
(EI): m/z = 446.22338 [M+]. Anal. Calcd for C24H34N2O4S: C, 64.5;
H, 7.67; N, 6.27; S, 7.18. Found: C, 63.9; H, 6.87; N, 6.76; S, 8.17.
N-(3-Bromobenzylcarbamoyl)-4-chlorobenzenesulfonamide
(8c)
Yield 52% (46.1 mg); white powder; mp 240–244 °C. IR (film):
3386 (s), 3022 (w), 2933 (w), 1599 (s), 1458 (s), 1334 (s), 1214 (s),
1
1130 (s), 783 (s), 520 (s) cm–1. H NMR (400 MHz, DMSO): d =
7.71 (d, 2 H, J = 8.2 Hz, 2 × ArH), 7.36 (m, 4 H, 4 × ArH), 7.16 (m,
2 H, 2 × ArH), 4.03 (s, 2 H, CH2). 13C NMR (100.6 MHz, DMSO):
d = 160.65, 145.08, 133.54, 130.28, 129.94, 129.48, 128.74, 128.30
(2 C), 127.35 (2 C), 125.83, 121.35, 42.32. MS (EI): m/z = 400.9
[M+]. Anal. Calcd for C14H12BrN2O3SCl: C, 41.7; H, 3.00; N, 6.94;
S, 7.94. Found: C, 41.2; H, 2.69; N, 6.32; S, 7.18.
N-(Biphenyl-2-ylmethylcarbamoyl)-4-chlorobenzene-
sulfonamide (8i)
Yield 71% (56.9 mg); white solid; mp 192–195 °C. 1H NMR (400
MHz, DMSO): d = 7.70 (d, 2 H, J = 8.4 Hz, 2 × ArH), 7.48–7.11 (m,
11 H, 11 × ArH), 6.49 (t, 1 H, J = 5.8 Hz, CH2NH), 4.05 (d, 2 H,
J = 5.7 Hz, CH2), 3.70 (s, 3 H, OCH3). 13C NMR (100.6 MHz, DM-
SO): d = 160.58, 146.72, 140.41, 140.07, 137.65, 133.48, 129.13,
128.89 (2 C), 128.41, 128.30 (2 C), 128.07 (2 C), 127.31 (2 C),
127.03, 126.83, 125.99, 40.83. MS (EI): m/z = 400.0 [M+]. Anal.
Calcd for C20H17ClN2O3S: C, 59.9; H, 4.27; N, 6.99; S, 8.00. Found:
C, 59.2; H, 3.99; N, 6.76; S, 7.17.
N-(4-Bromobenzylcarbamoyl)-4-chlorobenzenesulfonamide
(8d)
Yield 58% (51.5 mg); white powder; mp 243–247 °C. IR (film):
3378 (s), 3039 (w), 2882 (w), 1603 (s), 1574 (m), 1462 (s), 1343 (s),
1218 (s), 1133 (s), 755 (s), 521 (s) cm–1. 1H NMR (400 MHz, DM-
SO): d = 7.70 (d, 2 H, J = 8.3 Hz, 2 × ArH), 7.38 (m, 4 H, 4 × ArH),
7.10 (d, 2 H, J = 8.0 Hz, 2 × ArH), 4.00 (s, 2 H, CH2). 13C NMR
(100.6 MHz, DMSO): d = 160.75, 141.27, 133.70, 130.94, 130.62
(2 C), 129.10 (2 C), 128.34 (2 C), 127.39 (2 C), 118.90, 42.29. MS
(EI): m/z = 400.9 [M+]. Anal. Calcd for C14H12BrN2O3SCl: C, 41.7;
H, 3.00; N, 6.94; S, 7.94. Found: C, 41.2; H, 2.44; N, 6.18; S, 7.57.
N-{4-[N-(2-Bromobenzylcarbamoyl)sulfamoyl]-phenethyl}-5-
chloro-2-methoxybenzamide (8j)
Yield 80% (92.6 mg); white powder; mp 206–210 °C. IR (film):
3363 (s), 3285 (s), 2902 (w), 1638 (s), 1615 (s), 1535 (s), 1508 (s),
1462 (s), 1342 (s), 1295 (s), 1227 (s), 1163 (s), 743 (s), 572 (s)
cm–1. 1H NMR (400 MHz, DMSO): d = 8.20 (t, 1 H, J = 5.5 Hz, NH-
CO), 7.65 (m, 3 H, 3 × ArH), 7.48 (m, 2 H, 2 × ArH), 7.23 (m, 2 H,
2 × ArH), 7.21 (d, 2 H, J = 8.1 Hz, 2 × ArH), 7.12 (m, 2 H,
2 × ArH), 4.07 (s, 2 H, CH2), 3.78 (s, 3 H, OCH3), 3.51 (m, 2 H,
CH2), 2.82 (t, 2 H, J = 7.0 Hz, CH2). 13C NMR (75.5 MHz, DMSO):
d = 163.36, 160.44, 155.70, 145.84, 140.35, 132.15, 131.71, 131.43,
129.52, 128.93, 128.47, 127.91, 127.61, 127.16, 126.41, 125.56,
124.28, 122.14, 121.83, 114.11, 56.22, 43.34, 40.45, 34.52. MS
(EI): m/z = 579.0 [M+]. Anal. Calcd for C24H23BrN3O5SCl: C, 49.6;
H, 3.99; N, 7.23; S, 5.52. Found: C, 49.0; H, 3.54; N, 6.25; S, 5.22.
N-(2-Bromobenzylcarbamoyl)benzenesulfonamide (8e)
Yield 79% (58.6 mg); white powder; mp 214–216 °C. IR (film):
3334 (s), 3054 (w), 2905 (w), 1623 (s), 1588 (m), 1532 (s), 1443 (s),
1366 (s), 1293 (m), 1133 (s), 753 (s), 579 (s) cm–1. 1H NMR (400
MHz, DMSO): d = 7.71 (m, 2 H, 2 × ArH), 7.49 (d, 1 H, J = 7.5 Hz,
ArH), 7.32 (m, 3 H, 3 × ArH), 7.23 (m, 2 H, 2 × ArH), 7.10 (t, 1 H,
J = 7.6 Hz, ArH), 4.07 (s, 2 H, CH2). 13C NMR (100.6 MHz, DM-
SO): d = 166.42, 141.04, 132.90, 132.50, 129.70, 129.17, 128.71,
128.11 (2 C), 127.96, 126.98 (2 C), 122.57, 44.10. MS (EI):
m/z = 368.0 [M+]. Anal. Calcd for C14H13BrN2O3S: C, 45.5; H,
3.55; N, 7.59; S, 8.68. Found: C, 45.0; H, 2.96; N, 7.66; S, 8.04.
N-(2-Bromobenzylcarbamoyl)naphthalene-2-sulfonamide (8f)
Yield 67% (56.5 mg); white powder; mp 166–170 °C. IR (film):
3371 (s), 1624 (s), 1590 (s), 1453 (s), 1337 (s), 1260 (m), 1182 (s),
744 (s) cm–1. 1H NMR (400 MHz, DMSO): d = 8.24 (s, 1 H, ArH),
7.92 (m, 2 H, 2 × ArH), 7.84 (m, 2 H, 2 × ArH), 7.54 (m, 2 H,
2 × ArH), 7.47 (d, 1 H, J = 8.1 Hz, ArH), 7.18 (m, 2 H, 2 × ArH),
Ethyl 3-[N-(4-Bromobenzylcarbamoyl)sulfamoyl]-4-chloro-5-
[2-(naphthalene-1-yl)acetamido]benzoate (8k)
Yield 47% (50.7 mg); white powder; mp 213–217 °C. IR (film):
3366 (s), 3262 (s), 2978 (w), 1706 (s), 1673 (s), 1599 (s), 1512 (s),
1443 (s), 1315 (s), 1285 (s), 1243 (s), 1160 (s), 778 (s), 573 (s) cm–
1. 1H NMR (400 MHz, DMSO): d = 8.30 (d, 1 H, J = 2.1 Hz, ArH),
Synlett 2009, No. 17, 2839–2843 © Thieme Stuttgart · New York

LETTER
Synthesis of Sulfonyl Ureas
2843
8.27 (d, 1 H, J = 2.1 Hz, ArH), 8.16 (d, 1 H, J = 8.3 Hz, ArH), 7.94
(d, 1 H, J = 7.7 Hz, ArH), 7.85 (d, 1 H, J = 8.1 Hz, ArH), 7.53 (m,
3 H, 3 × ArH), 7.48 (d, 2 H, J = 8.5 Hz, 2 × ArH), 7.38 (d, 1 H, J =
8.3 Hz, ArH), 7.18 (d, 2 H, J = 8.5 Hz, 2 × ArH), 4.29 (m, 4 H, CH2
and OCH2), 3.97 (s, 2 H, CH2), 1.28 (t, 3 H, J = 7.1 Hz, OCH2CH3).
13C NMR (100.6 MHz, DMSO): d = 170.68, 170.37, 165.51,
147.25, 141.17, 134.10, 132.81, 132.65, 131.70 (2 C), 131.33 (2 C),
129.88, 129.80, 129.13, 128.79, 128.09, 127.93, 127.60, 126.85,
126.44, 126.24, 124.86, 120.14, 119.57, 62.29, 61.78, 43.06, 14.83.
MS (EI): m/z = 657.0 [M+]. Anal. Calcd for C29H25BrN3O6SCl: C,
52.9; H, 3.82; N, 6.38; S, 4.87. Found: C, 51.5; H, 3.47; N, 5.76; S,
4.17.
References
(1) Arbuzov, B. A.; Zobova, N. N. Synthesis 1974, 461.
(2) Arbuzov, B. A.; Zobova, N. N. Synthesis 1982, 433.
(3) Hari, Y.; Iguchi, T.; Aoyama, T. Synthesis 2004, 1359.
(4) Hari, Y.; Iguchi, T.; Aoyama, T. Synthesis 2005, 2147.
(5) Wood, M. E.; Cane-Honeysett, D. J.; Dowle, M. D.; Coles,
S. J.; Hursthouse, M. B. Org. Biomol. Chem. 2003, 1, 3015.
(6) Cane-Honeysett, D. J.; Dowle, M. D.; Wood, M. E.
Tetrahedron 2005, 61, 2141.
(7) Wood, M. E.; Annis, V. M.; Jones, C. D. Org. Biomol.
Chem. 2008, 6, 4099.
(8) Davies, W.; MacLauren, J. A. J. Chem. Soc. 1951, 1434.
(9) Zumach, G.; Kühle, E. Angew. Chem., Int. Ed. Engl. 1970,
9, 54.
(10) Chen, L.; Thompson, T. R.; Hammer, R. P.; Barany, G.
J. Org. Chem. 1996, 61, 6639.
Acknowledgment
We thank the National Research Foundation of South Africa (DoL),
GlaxoSmithKline and the University of Cape Town for funding. We
would further like to make special mention of Dr Jerome Dauvergne
for useful discussions.
(11) Titherly, A. W.; Hicks, W. L. J. Chem. Soc. 1906, 89, 708.
Synlett 2009, No. 17, 2839–2843 © Thieme Stuttgart · New York

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