A convenient synthesis of sulfonylureas from carboxylic acids and sulfonamides via an in situ Curtius rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.10.046

A one-pot reaction of carboxylic acids with sulfonamides to afford sulfonylureas is described.

Full text of DOI:10.1016/j.tetlet.2007.10.046

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8878–8882
A convenient synthesis of sulfonylureas from carboxylic acids
and sulfonamides via an in situ Curtius rearrangement
Christopher A. Luckhurst,* Ian Millichip, Beth Parker, James Reuberson and Mark Furber
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire,
England LE11 5RH, United Kingdom
Received 2 August 2007; revised 4 October 2007; accepted 11 October 2007
Available online 14 October 2007
Abstract—A one-pot reaction of carboxylic acids with sulfonamides to afford sulfonylureas is described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
COCl2
S
N
R
SO2NH2
R
SO2NCO
H2N
As part of a medicinal chemistry programme, targeting
the zinc metalloproteinase endothelin converting
enzyme (ECE-1), a range of thiazole sulfonylureas were
synthesised to profile their biological activity.
S
N
COCl2 OCN
O
R
SO2NH2
S
O
S
O
N
Sulfonylureas are employed in a variety of applications
including that of the treatment of type II diabetes (for
example, tolbutamide and glibenclamide, Fig. 1), and
as plant growth regulators or herbicides.
R
N
N
H
H
S
N
H2N
O
S
N
R
SO2Cl
H2N
N
NaOCN
H
The limited availability of isocyanates meant that a
number of the methodologies known in the literature
to generate sulfonylureas were explored (Scheme 1).1
Scheme 1. Some early attempts at the synthesis of thiazole
sulfonylureas.
Neither the reaction of a pre-formed sulfonyl isocyanate
with an amino thiazole, nor that of a thiazole isocyanate
with a sulfonamide was successful (Scheme 1). Further-
more, the formation of a primary urea from the amino
thiazole using sodium cyanate followed by reaction with
a sulfonyl chloride met with little success. The procedure
shown in Scheme 2, via an activated sulfonyl carbamate,
was also dropped in the quest for a more direct method
O
O O
S
O
OMe O
Cl
N
N
O O
S
H
H
S
N
N
N
N
H
H
H
H2N
O
S
Tolbutamide
R'OCOCl
O
Glibenclamide
O
O
O O
S
N
S
R
SO2NH2
R
N
N
R
N
OR'
Figure 1. Sulfonylurea drugs used in the treatment of type II diabetes.
H
H
H
refluxing
toluene
*
Corresponding author. Tel.: +44 1509 644542; fax: +44 1509
645571; e-mail: chris.luckhurst@astrazeneca.com
Scheme 2. Sulfonylureas from sulfonyl carbamates.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.046

C. A. Luckhurst et al. / Tetrahedron Letters 48 (2007) 8878–8882
8879
Table 1. Reaction of sulfonamides with 2-methyl-4-phenyl-1,3-thia-
zole-5-carboxylic acid to give sulfonylureas
that would enable a large number of compounds to be
synthesised in a very short time.
Et3N or iPr2NEt (1-2 Eq)
DPPA (1.2 Eq)
H
H
R1
R1
N
N
S
S
N
+
SO2NH2
S
N
HO2C
2. Results and discussion
O O
O
°
PhH, 85 C, 2-3 h
Generally, the wide range of methodologies1 for the syn-
thesis of sulfonylureas are much more cumbersome than
the procedure described in this Letter. As outlined
above, the application of some of these methods to the
thiazole system described proved unsuccessful. Their
failure may in part be a consequence of the instability
of the thiazole isocyanate present as an intermediate in
some of these methods. The method presented in this
Letter avoids this problem by generating and reacting
the isocyanate in situ.
R1
Product
Isolated yielda (%)
67
N
S
1
EtO
Cl
S
S
2
62
3
4
48b
41
S
The sulfonylureas were accessed conveniently from the
corresponding sulfonamides and carboxylic acids via
the generation of isocyanates in situ. Diphenylphos-
phoryl azide (DPPA) was employed to form the acyl
azide from the acid, and then the isocyanate via Curtius
rearrangement, in the presence of a sulfonamide. This
clearly obviates the requirement to isolate isocyanates
or other intermediates and attempts to limit the problem
of competing isocyanate hydrolysis. A wide range of
carboxylic acids are available commercially, and those
that are not are much easier to obtain through synthesis
than their isocyanate counterparts. The reactions were
initially carried out at 85 °C in the presence of triethyl-
amine or diisopropylethylamine as base, in benzene.
The product sulfonylureas were isolated either by silica
gel chromatography, by trituration with acetonitrile or
ethyl acetate, or by reverse phase HPLC. The main
byproduct was the symmetrical urea, and accordingly
some sulfonamide was recovered.
O
MeO2C
5
6
41
30
OMe
a >95% chemical purity as determined by analytical HPLC.
b More carboxylic acid (0.3 equiv) was added after 3 h, heating con-
tinued for a further 2 h.
Table 2. Reaction of sulfonamides with benzoic acid
iPr2NEt (2 Eq)
DPPA (1.2 Eq)
H
H
R1
N
N
R1
+
S
SO2NH2
O O
O
HO2C
°
PhH, 85 C, 2-3 h
R1
Product
Isolated yield (%)
77
The scope of the reaction is illustrated by the
compounds in Table 1. Heteroaromatic and benzylic
sulfonamides underwent reaction with 2-methyl-4-
phenyl-1,3-thiazole-5-carboxylic acid in synthetically
useful isolated yields.
7
Me
MeO
8
9
43
33
To explore the chemistry more generally and investigate
steric and electronic effects in the sulfonamide and
carboxylic acid, a small range of simple sulfonylureas
was synthesised. The reaction of methanesulfonamide
with benzoic acid to furnish sulfonylurea 7 was more
successful than those with aryl sulfonamides and
benzoic acid, reflecting the reactivity of the sulfonamide
(Table 2).
10
31
ortho-Substitution on the aromatic acid resulted in lower
yields than para-substitution. Not illustrated in the
table, electron-rich heterocyclic acids fared poorly;
2-furoic acid gave a yield of only 18% under the
diisopropylamine-benzene conditions and no conversion
with potassium carbonate–dioxane. No conversion to
sulfonylurea was observed for pyrrole-2-carboxylic acid
with either method.
Attention was next turned to the reaction of methane-
sulfonamide with a range of aromatic carboxylic acids,
as illustrated in Table 3. An alternative procedure was
attempted, whereby the starting materials were heated
at 85 °C in the presence of potassium carbonate in
dioxane.
Generally, the yields obtained with this method were
similar to those from the N,N-diisopropylethylamine-
benzene method described above; in Table 3, the method
with the higher yield is shown for each example.
For aliphatic acids, the alternative potassium carbon-
ate–dioxane conditions proved to be far superior to
the procedure using diisopropylamine-benzene (Table

8880
C. A. Luckhurst et al. / Tetrahedron Letters 48 (2007) 8878–8882
Table 3. Reactions of methanesulfonamide with benzoic acids
1H-pyrazole-5-carboxylic acid gave lower yields of the
sulfonylureas; one example, 25, is shown in Table 5.
Base
DPPA (1.2 Eq)
H
H
+
Me
The reaction was also attempted with an amide in the
place of the sulfonamide as shown in Scheme 3, furnish-
ing acyl urea 27 in a useful 32% yield.
Me
N
N
Ar
SO2NH2
S
HO2C
Ar
Solvent, 85 °C, 2-3 h
O O
O
Ar
Product
Basea
Solvent
Isolated
yield (%)
Many of the sulfonamides that we wished to use in the
programme of work directed towards ECE inhibitors
11
12
13
14
i-Pr2NEt
K2CO3
C6H6
62
OMe
CN
Table 5. Formation of sulfonylureas from heterocyclic acids
Dioxane
C6H6
51
Et3N or iPr2NEt (1-2 Eq)
DPPA (1.2 Eq)
H
H
R2
R1
R1
N
N
i-Pr2NEt
K2CO3
36b
34
HO2C
R2
+
SO2NH2
S
O O
O
°
PhH, 85 C, 2-3 h
NO2
R1
R2
Product
Isolated
Dioxane
yielda (%)
30
OH
15
16
i-Pr2NEt
i-Pr2NEt
C6H6
C6H6
32
22
S
N
Cl
21
S
OMe
a 2 equiv of i-Pr2NEt, or 3 equiv of K2CO3 were used.
b For example, using K2CO3, dioxane, the yield of 13 was 29%.
Table 4. Reaction of aliphatic acids with benzenesulfonamide
22
23
30
29
N
S
NMe2
N
Cl
Cl
K2CO3 (3 Eq)
DPPA (1.2 Eq)
H
H
R2
+
N
N
R2
HO2C
SO2NH2
S
°
Dioxane, 85 C, 2-3 h
O O
O
NMe2
N
S
R2
Product
Isolated yield (%)
52
Cl
Cl
24
27
17
18
19
50
40
Boc
OH
N
N
N
N
25
26
25
15
20
23
S
N
H
4). Entry 20 demonstrates that an unprotected hydroxyl
group can be tolerated, albeit in lower yield.
a >95% chemical purity as determined by analytical HPLC.
As illustrated by some of the examples in Table 5, yields
were lower when certain functionalities were present,
but this methodology clearly allows examples incorpo-
rating nitrogen atoms and hydroxyl groups to be syn-
O
O
i-Pr2NEt (2 Eq)
CONH2
HO2C
N
thesised. This route was
a
convenient, if only
S
DPPA (1.2 Eq)
S
N
N
N
moderate-yielding method to access these more func-
tionalised compounds. Evidently, a multi-step route
involving isolation of the isocyanate would be incom-
patible with some of the functionality in the desired
products. In general, the reaction of sulfonamides with
the more electron-rich heterocycle 3-methyl-1-phenyl-
H
H
N
°
+
PhH, 85 C, 2-3 h
N
27
(32%)
Scheme 3. Formation of an acyl urea.

C. A. Luckhurst et al. / Tetrahedron Letters 48 (2007) 8878–8882
8881
are unavailable commercially and are needed to be syn-
thesised. Alkylsulfonamides were generated from the
corresponding halide via the sulfinate salt using sodium
3-methoxy-3-oxopropane-1-sulfinate (SMOPS)2,3 and
subsequent treatment with hydroxylamine-O-sulfonic
acid as an electrophilic nitrogen source. For aromatic
and heteroaromatic sulfonamides, lithiation followed
by quenching with sulfur dioxide and then hydroxyl-
amine-O-sulfonic acid also proved to be efficient.
Scheme 4 describes the synthesis of an aminoalkyl ben-
zenesulfonamide from SMOPS, used in the synthesis of
zwitterionic sulfonylurea 23.
are underway to explore the use of solid-supported
DPPA5 to expedite removal of phosphorus-containing
byproducts.
3. Procedures for the synthesis of sulfonylureas
3.1. The synthesis of sulfonylureas using triethylamine or
N,N-diisopropylethylamine-benzene
3.1.1. Preparation of 6-ethoxy-N-{[(2-methyl-4-phenyl-
1,3-thiazol-5-yl)amino]carbonyl}-1,3-benzothiazole-2-sul-
fonamide (1). To a stirred mixture of 2-methyl-4-phen-
yl-1,3-thiazole-5-carboxylic acid (0.132 g), 6-ethoxy-1,3-
benzothiazole-2-sulfonamide (0.163 g) and triethylamine
(0.100 mL) in benzene (5 mL) was added diphenylphos-
phoryl azide (0.155 mL) under nitrogen. The mixture
was then heated at 85 °C for 2 h. The cooled mixture
was concentrated in vacuo, dissolved in a small volume
of acetonitrile and subjected to reverse phase HPLC
(SunFireÒ, 5% to 90% acetonitrile in 0.1% v/v aqueous
trifluoroacetic acid). The appropriate fractions were
concentrated in vacuo to give 1 (0.190 g, 67%) as a white
Scheme 5 shows a facile synthesis of indole-2-sulfon-
amide en route to 26, based upon methodology from
Katritzky,4 avoiding the requirement for protection of
the indole nitrogen, with, for example, a phenyl sulfonyl
group.
In summary, this methodology enabled a wide variety of
sulfonylureas to be obtained that would not have been
accessed conveniently by other means. The reactivity
of both the sulfonamide and acid were the key determi-
nants to the product yield. Isocyanate trapping is the
major constraint to the methodology with the weak sul-
fonamide nucleophile. The main byproduct seen was the
symmetrical urea which was presumably formed from
reaction of the in situ-formed isocyanate with its amine
hydrolysis product; however, the addition of molecular
sieves failed to provide a significant improvement in
the yield of the sulfonylureas. Additionally, performing
the reaction up to the same temperature under micro-
wave irradiation in a sealed tube offered no enhance-
ment in yield versus the thermal conditions described
above. It appears unlikely that the sulfonamide is react-
ing directly with DPPA, or competing with azide in the
reaction with the activated acid moiety. Efforts
1
solid; mp 174–176 °C; H NMR (400 MHz, DMSO) d
9.34 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.81 (d,
J = 2.6 Hz, 1H), 7.70 (d, J = 7.4 Hz, 2H), 7.43 (t,
J = 7.8 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.26 (dd,
J = 9.2, 2.6 Hz, 1H), 4.14 (q, J = 6.9 Hz, 2H), 2.56 (s,
3H), 1.38 (t, J = 6.9 Hz, 3H); one NH resonance absent;
13C NMR (125.7 MHz, DMSO) d 159.9, 158.2, 145.7,
138.2, 133.3, 132.6, 128.6, 128.4, 127.5, 126.8, 125.2,
121.3, 118.0, 114.8, 105.1, 63.9, 18.5, 14.4; LRMS
(ESI) m/z 475 [M+H]+, 473 [MÀH]À; Elemental Anal.
Calcd for C20H18N4O4S3: C, 50.62; H, 3.82; N, 11.81;
S, 20.27. Found: C, 50.57; H, 4.11; N, 11.82; S, 19.99.
3.1.2. Preparation of 5-[(4-chlorophenyl)thio]-N-{[(2-
methyl-4-phenyl-1,3-thiazol-5-yl)amino]carbonyl}thioph-
ene-2-sulfonamide (2). To
2-methyl-4-phenyl-1,3-thiazole-5-carboxylic
a
stirred mixture of
acid
Br
Br
MeO2C
O
S
(0.150 g), 5-[(4-chlorophenyl)thio]thiophene-2-sulfon-
amide (0.20 g) and triethylamine (0.120 mL) in benzene
CO2Me
ONa
S
O
Br
O
Cl
(5 mL)
was
added
diphenylphosphoryl
azide
Cl
DMSO, RT
Cl
Cl
(0.180 mL) under nitrogen. The mixture was then heated
at 85 °C for 2 h. The cooled mixture was concentrated in
vacuo and acetonitrile (3 mL), water (3 mL) and a few
drops of trifluoroacetic acid were added. The resulting
white solid was filtered off to give analytically pure 2
(0.220 g, 62%); mp 130–133 °C (dec); 1H NMR
(400 MHz, DMSO) d 9.17 (s, 1H), 7.74 (d, J = 3.8 Hz,
1H), 7.66 (dm, J = 7.4 Hz, 2H), 7.48–7.39 (m, 7H),
7.36–7.31 (m, 1H), 2.59 (s, 3H); one NH resonance ab-
sent; 13C NMR (100.5 MHz, DMSO) d 158.9, 149.9,
142.5, 140.9, 140.8, 134.2, 133.6, 133.6, 133.5, 133.0,
131.5, 131.5, 129.7, 128.5, 127.9, 127.6, 18.7; LRMS
(ESI) m/z 522, 524 [M+H]+, 520, 522 [MÀH]À; Elemen-
tal Anal. Calcd for C21H16N3O3S4Cl. H2O: C, 46.70; H,
3.36; N, 7.78; S, 23.74. Found: C, 47.04; H, 3.43; N,
8.07; S, 23.51.
HNMe2
in THF, RT
NMe2
1. NaOMe, MeOH, RT
2. H2NOSO3H, NaOAc,
NMe2
SO2NH2
CO2Me
S
O
Cl
O
Cl
(22% overall)
Cl
H2O, RT
Cl
Scheme 4.
°
C
n
-BuLi, -78
H2NOSO3H
CO2(g), to RT
SO2Li
SO2NH2
N
H
N
N
NaOAc, H2O
H
°
C
CO2Li
t
-BuLi, -78
3.1.3. Preparation of N-(anilinocarbonyl)-4-methoxyben-
zenesulfonamide (8). To a stirred mixture of benzoic
acid (0.122 g), 4-methoxybenzenesulfonamide (0.187 g)
SO2(g), to RT
(90%, 2 steps)
Scheme 5.

8882
C. A. Luckhurst et al. / Tetrahedron Letters 48 (2007) 8878–8882
and N,N-diisopropylethylamine (0.350 mL) in benzene
(4 mL) was added diphenylphosphoryl azide
3.2. The synthesis of sulfonylureas using a typical
potassium carbonate–dioxane procedure
(0.260 mL) under nitrogen. The mixture was then heated
at 85 °C for 2 h. The cooled mixture was concentrated in
vacuo and the residue was subjected to flash column
chromatography (SiO2, 10% to 25% ethyl acetate in iso-
hexane) then to reverse phase HPLC (SunFireÒ, 5% to
90% acetonitrile in 0.1% v/v aqueous trifluoroacetic
acid). The appropriate fractions were concentrated in
vacuo to leave a colourless gum. This was triturated
with diethyl ether to give 8 (0.132 g, 43%) as a white so-
lid; mp 154–157 °C; 1H NMR (400 MHz, DMSO) d
10.57 (s, 1H), 8.76 (s, 1H), 7.90 (d, J = 9.6 Hz, 2H),
7.32 (d, J = 8.7 Hz, 2H), 7.25 (dd, J = 8.9, 7.5 Hz,
2H), 7.14 (d, J = 9.4 Hz, 2H), 7.01 (t, J = 7.5 Hz, 1H),
3.85 (s, 3H); 13C NMR (100.5 MHz, DMSO) d 162.9,
149.4, 138.1, 131.4, 129.8, 128.9, 123.2, 118.9, 114.2,
55.7; LRMS (APCI) m/z 307 [M+H]+, 305 [MÀH]À;
Elemental Anal. Calcd for C14H14N2O4S.1/2H2O: C,
53.32; H, 4.79; N, 8.88; S, 10.17. Found: C, 53.23; H,
4.46; N, 9.37; S, 10.66.
3.2.1. Preparation of N-{[(4-methoxyphenyl)amino]car-
bonyl}-methanesulfonamide (12). To a stirred solution of
4-methoxybenzoic acid (0.152 g) and methanesulfonam-
ide (0.095 g) in 1,4-dioxane (4 mL) was added diphenyl-
phosphoryl azide (0.26 mL) and potassium carbonate
(0.41 g) under nitrogen. The reaction mixture was then
heated at 85 °C for 2 h. The cooled mixture was concen-
trated in vacuo. Water was added to dissolve the solid
material and the pH adjusted to 4–5 with a few drops of
concentrated HCl. Thesolid was then collected by vacuum
filtration and triturated with diethyl ether to yield 12
(0.139 g, 51%) as a white solid; mp 176–180 °C (dec); 1H
NMR (300 MHz, DMSO) d 10.17 (s, 1H), 8.72 (s, 1H),
7.32 (dm, J = 9.2 Hz, 2H), 6.89 (dm, J = 9.2 Hz, 2H),
3.72 (s, 3H), 3.28 (s, 3H); 13C NMR (100.5 MHz, DMSO)
d 155.3, 150.1, 130.9, 120.8, 113.9, 55.1, 41.3; LRMS (ESI)
m/z 245 [M+H]+, 243 [MÀH]À; Elemental Anal. Calcd
for C9H12N2O4SÆ1/10(C2 H5)2O: C, 44.86; H, 5.21; N,
11.13; S 12.74. Found: C, 44.85; H, 4.99; N, 10.96; S 12.52.
3.1.4. Preparation of 4-chloro-N-({[2-(dimethylamino)-
4-phenyl-1,3-thiazol-5-yl]amino}carbonyl)benzenesulfon-
amide (24). To a stirred mixture of N2,N2-dimethyl-4-
phenyl-1,3-thiazole-2,5-diamine (1.00 g), 4-chloroben-
zene-sulfonamide (0.924 g) and N,N-diisopropylethyl-
amine (0.80 mL) in benzene (50 mL) was added
diphenylphosphoryl azide (1.05 mL) under nitrogen.
The mixture was then heated at 85 °C for 2 h. The
cooled mixture was diluted with ethyl acetate (200 mL)
and washed with saturated aqueous sodium hydrogen
carbonate (100 mL). The organic phase was dried over
sodium sulfate, filtered and concentrated in vacuo. The
residue was subjected to flash column chromatography
(SiO2, 5% triethylamine in ethyl acetate, then acetoni-
trile) then reverse phase HPLC (XTerraÒ, 5% to 95%
acetonitrile in 0.1% v/v aqueous trifluoroacetic acid).
The appropriate fractions were concentrated in vacuo
to give 24 (0.580 g, 27%) as a white solid; mp 120–
References and notes
1. (a) GB 692,360, 1953, CAN 47:51633; (b) King, C. J. Org.
Chem. 1960, 25, 352; (c) Meyer, W.; Foery, W.; Toepfl, W.
U.S. patent 4,518,776, 1984, CAN 100:191911; (d) Kris-
tinsson, H.; Toepfl, W. U.S. patent 4,521,597, 1984, CAN
101:130720; (e) Szczepanski, H.; Foery, W.; Meyer, W.;
Toepfl, W. EP 101,670, 1984, CAN 101:38480; (f) Kimura,
F.; Haga, T.; Sakashita, N.; Honda, C.; Hayashi, K.; Seki,
T.; Minamida, K. EP 184,385, 1986, CAN 107:35159; (g)
Burger, K.; Hoss, E.; Geith, K. Synthesis 1990, 360; (h)
Howbert, J. J.; Grossman, C. S.; Crowell, T. A.; Rieder, B.
J.; Harper, R. W.; Kramer, K. E.; Tao, E. V.; Aikins, J.;
Poore, G. A.; Rinzel, S. M.; Grindey, G. B.; Shaw, W. N.;
Todd, G. C. J. Med. Chem. 1990, 33, 2393; (i) Gilman, J.
W.; Otonari, Y. A. Synth. Commun. 1993, 23, 335; (j)
Englert, H. C.; Gerlach, U.; Goegelein, H.; Hartung, J.;
Heitsch, H.; Mania, D.; Scheidler, S. J. Med. Chem. 2001,
44, 1085; (k) Yuriev, E.; Kong, D. C. M.; Iskander, M. N.
Eur. J. Med. Chem. 2004, 39, 835.
2. Baskin, J. M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479.
3. SMOPS could be synthesised in one step, on a 25 g scale,
from 3-(chlorosulfonyl)-propionic acid methyl ester, with
buffered sodium sulfite: Crowell, T. A.; Halliday, B. D.;
McDonald, J. H.; Indelicato, J. M.; Pasini, C. E.; Wu, E. C.
Y. J. Med. Chem. 1989, 32, 2436.
4. Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985,
26, 5935.
5. Lu, Y.; Taylor, R. T. Tetrahedron Lett. 2003, 44, 9267.
1
125 °C (dec); H NMR (400 MHz, DMSO) d 8.89 (s,
1H), 7.93 (dm, J = 8.5 Hz, 2H), 7.71 (dm, J = 8.5 Hz,
2H), 7.62 (dm, J = 8.1 Hz, 2H), 7.41–7.29 (m, 3H),
3.04 (s, 6H); one NH resonance absent; 13C NMR
(125.7 MHz, DMSO) d 165.6, 158.9, 158.6, 151.0,
139.2, 134.1, 129.9, 129.8, 128.8, 128.1, 117.2, 114.8,
39.9; LRMS (APCI) m/z 437, 439 [M+H]+; Elemental
Anal. Calcd for C18H17N4O3S2ClÆC2HO2F3Æ1/2H2O: C,
42.90; H, 3.42; N, 10.01; S, 11.45. Found: C, 42.88; H,
3.18; N, 10.11; S, 11.88.