A convenient procedure for the preparation of sulfonamidoureas using triphosgene

Article abstract of DOI:10.1515/znb-2007-0516

An efficient method for the preparation of sulfonamidourea using triphosgene in organic solvents is reported. Sulfonylhydrazides and acetylsulfanilylhydrazide were transformed into the corresponding intermediates using triphosgene in 1,4-dioxane/water or tetrahydrofuran as solvents. These intermediates were converted in situ into symmetrical and unsymmetrical sulfonamidoureas in high yields and shorter periods of time related to previous methods.

Full text of DOI:10.1515/znb-2007-0516

A Convenient Procedure for the Preparation of Sulfonamidoureas Using
Triphosgene
Javad Safaei-Ghomi, Abdolhamid Bamoniri, and Aboalfazl Abbaszadeh-Nooshabady
Department of Chemistry, Faculty of Science, University of Kashan, 51167 Kashan, Iran
Reprint requests to Dr. Javad Safaei-Ghomi. Fax: (+98) 361 5552932. E-mail: safaei@kashanu.ac.ir
Z. Naturforsch. 2007, 62b, 721 – 724; received December 12, 2006
An efficient method for the preparation of sulfonamidourea using triphosgene in organic solvents is
reported. Sulfonylhydrazides and acetylsulfanilylhydrazide were transformed into the corresponding
intermediates using triphosgene in 1,4-dioxane/water or tetrahydrofuran as solvents.These interme-
diates were converted in situ into symmetrical and unsymmetrical sulfonamidoureas in high yields
and shorter periods of time related to previous methods.
Key words: Sulfonamidourea, Triphosgene, Sulfonylhydrazides
Introduction
Table 1. The preparation of symmetrical sulfonamidoureas
using triphosgene.
Sulfonamidoureas, in contrast to sulfonylureas, have
received but little consideration [1]. Both the paucity of
information regarding the series of sulfonamidoureas
and the possibility of useful pharmacological activity
of some members of this series motivated this inves-
tigation. Some sulfonamidourea derivatives are impor-
tant compounds as blowing agents in cellular rubber
and cellular plastic [2]. Sulfonylureas have found ap-
plications as oral antidiabetic drugs [3] and as herbi-
cides [4, 5]. Therefore, it seemed of interest to deter-
mine the extent to which sulfonamidoureas might also
possess such activities.
2, 3 Ar
Time (min) Yield (%) M.p. (◦C)
a
b
c
Ph
10
10
95
93
93
230 – 232
225 – 227
218 – 220
4-Me-C6H4
4-CH3CONH-C6H4 15
placed its gaseous congener, phosgene, in terms of its
reactivity and safe handling.
Herein we wish to report a simple one-pot method
for the preparation of sulfonamidoureas from sulfonyl-
hydrazide and aryl or alkyl amines utilizing commer-
cially available triphosgene in organic and aqueous sol-
vents.
The classical methods for the preparation of sulfon-
amidoureas involve the reaction of sulfonylhydrazides
with isocyanates [6], or the reaction of sulfonylchlo-
rides with semicarbazides in an inert solvent [6, 7]. In
some of these methods the yields of products are not
high and the starting materials such as isocyanates are
toxic. These compounds are usually prepared by bub-
bling phosgene gas through a solution of an amine
Results and Discussion
Treatment of two molar equivalents of a sulfonylhy-
drazide with triphosgene (1) in THF at r. t. produced
symmetrical sulfonamidoureas as indicated in Table 1
(Scheme 1).
We have now extended the observed different re-
at elevated temperature [8]. The hazards of handling activity of triphosgene toward amines and sulfonylhy-
of phosgene and the drastic conditions detract from drazides to a facile one-pot synthesis of unsymmetri-
these procedures. Over the last few years triphosgene cally substituted sulfonamidoureas by sequential addi-
[bis(trichloromethyl)carbonate] has emerged as a ver- tion of two different amine components (sulfonylhy-
satile synthetic reagent for the synthesis of a large va- drazide and amine) to a solution of triphosgene in THF.
riety of organic compounds [9, 10]. It was success- In a typical procedure, intermediate 4 was first formed
fully used for the sequential synthesis of unsymmet- from slow addition of a sulfonylhydrazide to a cooled
◦
rical ureas by Pavel [11], Weiberth [12], Lopez [13], solution of triphosgene at −5 C. The amine compo-
and also by Suzuki [14] for the preparation of sulfonyl- nent 5 was then added as the hydrochloride 5 · HCl to
amidoureas. This white crystalline compound has re- this solution in one portion to provide an unsymmetri-
0932–0776 / 07 / 0500–0721 $ 06.00 © 2007 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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J. Safaei-Ghomi et al. · Preparation of Sulfonamidoureas Using Triphosgene
Table 2. The preparation of un-
symmetrical sulfonamidoureas us-
ing triphosgene.
6
Ar
5
Yield
(%)
90
80
93
60
92
95
89
M.p.
(◦C)
a
b
c
d
e
f
4-CH3CONHPh
4-CH3CONHPh
Ph
Ph
Ph
Ph
4-MePh
4-MePh
NH3
HN(CH2CH2)2O
NH3
H2NCH2CH2NH2
PhCH2NH2
HN(CH2CH3)2
NH3
227 – 228 (227 [4])
196 – 198
220 – 222 (222 [15])
216 – 218
182 – 184
160 – 162
g
h
235 – 237 (234 – 236 [15])
192 – 195
PhCH2NH2
87
Scheme 1.
Scheme 2. (For the amine com-
ponents 5, used as hydrochlo-
rides, see Table 2).
i
cal sulfonamidourea 6 (Scheme 2). Pr2EtN was used sired products. The reactions are operationally simple,
as an auxiliary base.
offer high yields and short reaction times.
In order to prevent the production of undesirable
products (symmetrical sulfonamidoureas), a less re-
active sulfonylhydrazide was used in the first step of
the above procedure. The generality of this reaction
was established by preparing various unsymmetrical
sulfonamidoureas from the corresponding sulfonylhy-
drazides and amines (Table 2). Importantly, excellent
transformations were obtained when 1 reacted with
a water-soluble acetamidosulfonylhydrazide (Table 2,
entries a and b).
In conclusion, we have provided a convenient, one-
pot procedure for the preparation of symmetrical and
unsymmetrical sulfonamidoureas utilizing easily ac-
cessible triphosgene. This compound reacts rapidly
with various sulfonylhydrazides and amines in anhy-
Experimental Section
Melting points were determined on a Kofler block
and are uncorrected. FT-IR spectra were recorded on a
Nicolet Magna 550 spectrometer (KBr). 1H NMR and
13C NMR spectra were determined on a Bruker DRX-500
AVANCE (1H: 500 MHz; 13C: 125 MHz) spectrometer us-
ing [D6]DMSO as a solvent and TMS as internal standard.
Mass spectra were obtained on a QP 1100 EX spectrome-
ter. Elemental analyses were determined on a Carlo ERBA
model EA 1108. Starting materials were either commercially
available or prepared according to literature procedures [16].
General procedure for the preparation of symmetrical sul-
fonamidoureas (3a – c)
To a stirred solution of triphosgene (0.148 g, 0.5 mmol)
drous or hydrous organic solvents to provide the de- in THF (2 mL) was added a solution of sulfonylhydrazide
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J. Safaei-Ghomi et al. · Preparation of Sulfonamidoureas Using Triphosgene
723
(1.1 mmol) in THF (5 mL) at r. t. in one portion. The reac- NH2) cm−1. – 1H NMR: δ = 2.1 (s, 3H, -NHCOCH3), 5.9 (s,
tion mixture was stirred at this temperature until the sulfonyl- 2H, -CONH2), 7.7 (m, 4H, ArH), 7.9 (s, 1H, -NHCONH2),
hydrazide was consumed (as evidenced by TLC). The reac- 9.3 (s, 1H, SO2NH-), 10.3 (s, 2H, -NHCOCH3).
6b: White solid; m. p. 196 – 198 ◦C. – IR (film): ν = 1163,
tion mixture was then evaporated to dryness and the residue
1316 (SO2), 1700 (C=O), 3230, 3324 (NH, NH2) cm−1. –
1H NMR: δ = 2 (s, 3H, -NHCOCH3), 3.1 (t, J = 4.6 Hz,
4H, -NCH2CH2-O), 3.4 (t, J = 4.6 Hz, 4H, -NCH2CH2-O),
7.6 (d, J = 9 Hz, 2H, ArH), 7.7 (d, J = 9 Hz, 2H, ArH),
8.8 (s, 1H, -NHCON), 8.9 (s, 1H, SO2NH-), 10.3 (s, 1H, -
was washed with 5 % aq. HCl and water and dried under re-
duced pressure to give a white powder. The crude product
was recrystallized from ethanol. No additional chromatogra-
phy was needed. For the preparation of 3c the sulfonylhy-
drazide was dissolved in boiling 1,4-dioxane/water (2 : 1.6).
3a: White solid; m. p. 230 – 232 ◦C. – IR (film): ν = NHCOCH3). – 13C NMR: δ = 25.2, 46.9, 67.1, 113.5, 125.3,
1160, 1347 (SO2), 1675 (C=O), 3293, 3375 (NH) cm−1. – 134.4, 137.8, 156.5 (C=O), 169.1 (C=O). – MS (EI): m/z
1H NMR: δ = 7.5 – 7.7 (m, 10H, ArH,), 8.3 (s, 2H, -NH- (%) = 342 (3) [M]+, 229 (14), 187 (28), 154 (100), 93 (100),
CO), 9.4 (s, 2H, SO2-NH-). – 13C NMR: δ = 127.5, 128.8, 87 (10), 43 (57), 65 (80). – Analysis for C13H18N4O5S:
132.9, 138.5, 156.3 (C=O). – MS (EI): m/z (%) = 372 (4) calcd. C 45.61, H 5.30, N 16.36; found C 45.55, H 5.46,
[M]+, 229 (12), 199 (2), 172 (86), 141 (54), 77 (100). – Anal- N 16.55.
◦
◦
ysis for C13H14N4O5S2: calcd. C 42.16, H 3.81, N 15.13;
found C 42.10, H 3.85, N 15.20.
6c: White solid; m. p. 220 – 222 C (220 C [15]). – IR
(film): ν = 1168, 1326 (SO2) 1659 (C=O), 3375, 3457 (NH,
NH2) cm−1. – 1H NMR: δ = 5.9 (s, 2 H, -CONH2), 7.5 – 7.8
3b: White solid; m. p. 225 – 227 ◦C. – IR (film): ν =
1157, 1351 (SO2), 1668 (C=O), 3237, 3360 (NH) cm−1. – (m, 5H, ArH), 7.9 (s, 1H, -NHCO), 9.4 (s, 1H, SO2NH-).
1H NMR: δ = 2.3 (s, 3H, ArCH3), 7.3 (d, J = 7.5 Hz,
4H, ArH), 7.6 (d, J = 7.5 Hz, 4H, ArH), 8.2 (s, 2H, -NH-
CO), 9.3 (s, 2H, SO2-NH-). – 13C NMR: δ = 21.1, 127.7,
129.3, 135.6, 143.2, 156.3 (C=O). – MS (EI): m/z (%) =
398 (2) [M]+, 243 (10), 213 (14), 156 (86), 139 (78),
91 (100). – Analysis for C15H18N4O5S2: calcd. C 45.22,
H 4.55, N 14.06; found C 45.31, H 4.50, N 14.11.
6d: White solid; m. p. 216 – 218 ◦C. – IR (film): ν = 1169,
1352 (SO2), 1644 (C=O), 3129, 3446 (NH, NH2) cm−1. –
1H NMR: δ = 2.8 (s, 4H, CH2CH2), 6.4 (s, 2H, -NHCH2),
7.5 – 7.8 (m, 10 H, ArH,), 8.0 (s, 2H, -NHCO), 9.6 (s,
2H, SO2NH-). – 13C NMR: δ = 42.2, 115, 128.6, 129.7,
139.1, 158.4 (C=O). – MS (EI): m/z (%) = 258 (20) [M–
PhSO2NHNHCO]+, 218 (3), 141 (66), 125 (76), 109 (33), 91
3c: White solid; m. p. 218 – 220 ◦C. – IR (film): ν = 1157, (3), 77 (100), 65 (14). – Analysis for C16H20N6O6S2: calcd.
1337 (SO2), 1670 (C=O), 3370, 3503 (-NH-NH-) cm−1. – C 42.10, H 4.42, N 18.41; found C 42.17, H 4.35, N 18.45.
1H NMR: δ = 2.0 (s, 6H, -NHCOCH3), 7.7 (d, J = 8.4 Hz,
4H, ArH), 7.8 (d, J = 8.4 Hz, 4H, ArH), 8.3 (s, 2H, -NH-
CO), 9.3 (s, 2H, SO2-NH-), 10.3 (s, 2H, -NH-COCH3). –
13C NMR: δ = 24.5, 119.3, 129.8, 132.5, 144.1, 157.3
(C=O), 170 (C=O). – MS (EI): m/z (%) = 484 (2) [M]+, 229
(8), 187 (15), 154 (100), 93 (100), 43 (40), 65 (95). – Anal-
ysis for C17H20N6O7S2: calcd. C 42.14, H 4.16, N 17.35;
found C 42.27, H 4.36, N 17.47.
6e: White solid; m. p. 182 – 184 ◦C. – IR (film): ν =
1170, 1342 (SO2), 1644 (C=O), 3250, 3395 (NH) cm−1. –
1H NMR: δ = 4.1 (bs, 2H, ArCH2), 6.9 (bs, 1H, Ar-CH2NH),
7.1 – 7.3 (m, 5H, ArH,), 7.5 – 7.8 (m, 5H, ArH,), 8.1 (s,
1H, -NHCO), 9.5 (s, 1H, SO2NH-). – 13C NMR: δ =
43.5, 126.9, 127.1, 128.8, 128.9, 129.9, 133.8, 139.6, 141.6,
158.1 (C=O). – MS (EI): m/z (%) = 305 (2) [M]+, 172
(100), 164 (60), 143 (100), 106 (50), 91 (100). – Analysis
for C14H15N3O3S: calcd. C 55.07, H 4.95, N 13.76; found
C 55.25, H 5.11, N 13.45.
General procedure for the preparation of unsymmetrical sul-
fonamidoureas (6a – h)
6f: White solid; m. p. 160 – 162 ◦C. – IR (film): ν =
A solution of sulfonylhydrazide (0.7 mmol) in THF 1163, 1326 (SO2), 1644 (C=O), 3119, 3370 (NH) cm−1. –
(6 mL) was slowly added to the stirred solution of triphos- 1H NMR: δ = 0.9 (t, J = 7 Hz, 6H, CH2CH3), 3.0 (q,
gene (0.148 g, 0.5 mmol in 2 mL of THF) over a period J = 7 Hz, 4H, CH2CH3), 7.5 – 7.7 (m, 5H, ArH,), 8.6 (s,
◦
of 40 min at −5 C. (For 6a and 6b, the sulfonylhydrazide 2H, -NHCO), 8.9 (s, 2H, SO2NH-). – 13C NMR: δ = 14.2,
was dissolved in 1,4-dioxane/water (2 : 1.6)). After a further 41.2, 128.6, 129.3, 133.4, 139.4, 156.5 (C=O). – MS (EI):
5 min of stirring, a solution of the respective amine 5 as hy- m/z (%) = 271 (38) [M]+, 241 (70), 141 (52), 130 (64),
drochloride (1 mmol) and diisopropylethylamine (2 mmol) in 101 (100), 86 (62), 77 (100). – Analysis for C11H17N3O3S:
THF (3 mL) was added in one portion. The reaction mixture calcd. C 48.69, H 6.31, N 15.49; found C 48.59, H 6.24,
was then stirred for 10 min at r. t. and evaporated to dryness. N 15.63.
6g: White solid; m. p. 235 – 237 ◦C (234 – 236 ◦C [15]). –
The residue was washed with 5 % aq. HCl and water and then
dried under reduced pressure to yield the colorless product.
IR (film): ν = 1175, 1337 (SO2), 1654 (C=O), 3375, 3457
(NH, NH2) cm−1. – 1H NMR (60 MHz): δ = 2.1 (s, 3H,
The crude products were recrystallize◦d from et◦hanol.
6a: White solid; m. p. 227 – 228 C (227 C [4]). – IR ArCH3), 5.4 (s, 2H, CONH2,), 6.7 – 7.2 (m, 4H, ArH), 7.3
(film): ν = 1163, 1332 (SO2), 1654 (C=O), 3385, 3482 (NH, (s, 2H, -NHCO), 8.7 (s, 2H, SO2NH-).
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J. Safaei-Ghomi et al. · Preparation of Sulfonamidoureas Using Triphosgene
6h: White solid; m. p. 192 – 195 ◦C. – IR (film): ν = 1168, 13C NMR: δ = 21.9, 43.4, 127.3, 127.6, 128.6, 128.8,
1342 (SO2), 1649 (C=O), 3293, 3411 (NH, NH2) cm−1. – 130.2, 136.2, 141.2, 144.1, 158.4 (C=O). – MS (EI): m/z
1H NMR: δ = 2.3 (s, 3H, ArCH3), 4.1 (bs, 2H, ArCH2- (%) = 319 (6) [M]+, 186 (100), 164 (66), 156 (100), 106
), 6.9 (bs, 1H, Ar-CH2NH), 7.1 – 7.2 (m, 5H, ArH,), 7.3 (40), 91 (100), 65 (94). – Analysis for C15H17N3O3S:
(d, J = 7.6 Hz, 2H, ArH), 7.7 (d, J = 7.6 Hz, 2H, calcd. C 56.41, H 5.36, N 13.16; found C 56.35, H 5.40,
ArH), 8.0 (s, 1H, -NHCO), 9.4 (s, 1H, SO2NH-). – N 13.21.
[9] L. Cotarca, P. Delogu, A. Nardelli, V. Sunjic, Synthesis
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