Facile one-pot synthesis of tetrasubstituted N-sulfonylguanidines from sulfonamides and ureas

Article abstract of DOI:10.1007/s00706-021-02815-6

A facile method for the synthesis of tetrasubstituted N-sulfonylguanidines has been developed via the direct condensation of sulfonamides and ureas in the presence of phosphoryl chloride under basic conditions. Detailed synthetic studies showed that this is a simple protocol for preparing N-sulfonylguanidines at room temperature in a short reaction time with good to excellent yields. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-021-02815-6

Monatshefte für Chemie - Chemical Monthly (2021) 152:993–999
https://doi.org/10.1007/s00706-021-02815-6
ORIGINAL PAPER
Facile one‑pot synthesis of tetrasubstituted N‑sulfonylguanidines
from sulfonamides and ureas
Fei Wang1 · Abulimiti Yumaier2 · Abudureheman Wusiman1,2
Received: 25 February 2021 / Accepted: 5 July 2021 / Published online: 7 August 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
A facile method for the synthesis of tetrasubstituted N-sulfonylguanidines has been developed via the direct condensation
of sulfonamides and ureas in the presence of phosphoryl chloride under basic conditions. Detailed synthetic studies showed
that this is a simple protocol for preparing N-sulfonylguanidines at room temperature in a short reaction time with good to
excellent yields.
Graphic abstract
Keywords Sulfonylguanidines · Urea · Sulfonamide · Phosphoryl chloride · Chloroformamidinium
Introduction
such as arginine, creatine phosphates, and purines [7–11].
Guanidines are widely used in other research areas, such as
coordination chemistry [12, 13], crystal engineering, supra-
molecular chemistry, ionic liquids [14], and food chemistry
[15–17].
Guanidine is among the most important functional groups
in chemistry, and has recently attracted considerable atten-
tion owing to its fascinating chemical, biological, and other
versatile properties [1, 2]. Guanidine is classifed as an orga-
nosuperbase and widely utilized as a base-assisted organo-
catalyst in synthetic organic chemistry and asymmetric syn-
thesis [3–6]. Guanidine is considered a fundamental entity
in medicinal chemistry owing to its occurrence in many bio-
active natural products, and as an essential substructure in
many pharmacologically and biologically active molecules,
Classical protocols for guanidine synthesis rely on trans-
forming the functional groups of thioureas, isothioureas,
amidine sulfonic acids, cyanamides, carbodiimides, pyra-
zole carboximidamides, trifyl guanidines, benzotriazoles,
and other compounds [18]. In recent years, several new pro-
tocols have been developed for preparing mono- [19, 20], di-
[21–29], and trisubstituted N-sulfonylguanidines [30–33].
Synthetic methods for tetrasubstituted analogs have also
received considerable attention (Scheme 1).
Fei Wang and Abulimiti Yumaier contributed equally to this work.
In 1967, Senning frst reported [34] N,N,N’,N’-tetra-
methyltosylguanidine by reacting N-sulfnyl-p-toluenesul-
fonamide with 1,1,3,3-tetramethylthiourea. In 2003, Suo
and coworkers developed [19] a synthesis of the same mol-
ecule using tosyl chloride (TsCl) and excess 1,1,3,3-tetra-
methylguanidine (Scheme 1a). In 2006, the Depreux group
reported [35] tetramethylsulfonylguanidines by the reaction
* Abudureheman Wusiman
arahman@xjnu.edu.cn
1
School of Chemistry and Chemical Engineering,
Xinjiang Normal University, Urumqi 830054,
People’s Republic of China
2
College of Chemistry and Environmental Science, Kashi
University, Kashi 844007, People’s Republic of China
Vol.:(0123456789)
1 3

994
Scheme 1
F. Wang et al.
conditions using tosylamide (TsNH2, 1a), TMU (2a), and
acid chloride (Table 1). To our delight, after screening
diferent acid chlorides, POCl3 aforded 3a in 53% yield
in the presence of triethylamine (TEA, 3.0 equiv.) in CCl4
(entry 3), with other reagents found to be inefective for
this transformation (entries 1, 2, and 4). Subsequently, dif-
ferent solvents were surveyed to determine their efect on
the yield (entries 5–9). The best result was obtained using
dichloromethane (DCM), with 3a isolated in 83% yield in
a shorter reaction time at 40 °C (entry 7). Inferior results
were obtained when the reaction was performed in other
solvents, such as chloroform (CHCl3), dichloroethane
(DCE), chlorobenzene (PhCl), and toluene (PhMe) (entries
5, 6, 8, and 9). Next, diferent organic and inorganic bases
were investigated. TEA was observed to play a crucial role
in this transformation, with the reaction not proceeding in
its absence (entry 10), with DBU afording a much lower
yield (entry 11), while the reaction was fully suppressed
when using other bases (entries 12–14). Furthermore, the
yield of 3a clearly declined when the amount of TEA was
decreased (entry 15). However, increasing the amount
of TEA did not obviously improve the reaction outcome
(entry 16). When the reaction was conducted at room tem-
perature, the highest yield (90%) of 3a was obtained (entry
17). With the other conditions unchanged, increasing the
POCl3 loading to 1.2 equiv. showed no improvement
in yield (entry 18), while decreasing the TMU loading
reduced the yield of 3a and necessitated longer reaction
times (entry 19). The reaction with no chlorinating agent
did not proceed (entry 20). Therefore, the optimal reaction
conditions were sulfonamide 1 (1.0 equiv.) and urea 2 (1.2
equiv.) in the presence of POCl3 (1.0 equiv.) and TEA (3
equiv.) at room temperature in DCM for 1 h.
of sulfonamide with HBTU [O-(1H-benzotriazol-1-yl)-
N,N,N’,N’-tetramethyluronium hexafuorophosphate] in the
presence of diisopropylethylamine (DIEA) (Scheme 1b). In
2018, the Hu group applied [36] a CuI-catalyzed three-com-
ponent method to the synthesis of tetramethyltosylguanidine
using tetramethylurea (TMU), sulfonyl azide, and 3-butyn-
2-one (Scheme 1c). In 2019, Chiba and coworkers reported
[37] a novel coupling strategy of sulfonyl azide and tetrasub-
stituted thiourea to yield sulfonylguanidine (Scheme 1d). In
the same year, Liu and Wei coworkers developed [38] a fac-
ile one-pot method for the synthesis of sulfonylguanidines
by reacting tetrasubstituted ureas with sulfonyl isocyanate
(Scheme 1e).
With optimal conditions in hand, the substrate scopes
of sulfonamides and urea were investigated, as shown in
Table 2. The reactions of aromatic sulfonamides with
TMU were frst investigated. Notably, a range of aro-
matic sulfonamides with electron-donating and electron-
withdrawing groups on the benzene ring were tolerated
in the condensation reaction, providing tetramethyl sul-
fonylguanidines 3a–3g in good to excellent yields. The
exact structure of 3d was established by single-crystal
X-ray difraction analysis (Fig. 1). The X-ray structural
data showed that the bond lengths of N2–C7 [1.350(2)
Å] and N3–C7 [1.349(2) Å] were almost identical, while
the N1–C7 bond length [1.331(2) Å] was signifcantly
shorter, indicating the C=N double bond character of this
N-sulfonylguanidine, as also observed in previous reports
[38]. When pyridyl- and thienyl-sulfonamide were used
as substrates, desired products 3h and 3i were obtained in
69% and 81% yields, respectively. Alkyl sulfonamides also
reacted efciently, afording products 3j–3l in moderate
to good yields.
Although signifcant achievements have been made in this
feld, some limitations remain, including the use of metal
catalysts or specialized reactants (such as sulfonyl azides,
HBTU, sulfonyl isocyanate), tedious workup procedures,
high temperatures, and long reaction times. This highlights
the need for cheaper and simpler procedures to generate sul-
fonylguanidine derivatives using easy-to-handle reagents.
Based on our previous work on the synthesis of N-sulfonyl-
formamidine [39, 40], we now describe our eforts to achieve
the facile synthesis of tetrasubstituted N-sulfonylguanidines
from sulfonamide and urea (Scheme 1f).
Results and discussion
In theory, N-sulfonylguanidines should be prepared by the
direct condensation of sulfonamides and ureas, as the most
straightforward and atom-economic method. To examine
the feasibility of this hypothesis, we explored the reaction
1 3

Facile one‑pot synthesis of tetrasubstituted N‑sulfonylguanidines from sulfonamides and…
995
Table 1 Optimization of
reaction conditionsa
Entry Acid chloride
Base
Solvent
Temp. /°C
t/h
Yield b /%
1
SOCl2
(COCl)2
POCl3
SO2Cl2
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
–
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
–
CCl4
CCl4
60
60
60
60
60
80
40
80
80
40
40
40
40
40
40
40
rt
4
4
4
4
4
4
1
4
1
6
1
1
1
1
1
1
1
1
2
6
NR
NR
53
2
3
CCl4
4
CCl4
NR
60
5
CHCl3
DCE
6
48
7
DCM
PhCl
83
8
41
9
PhMe
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
81
10
11
12
13
14
15c
16d
17
18e
19f
20
NR
20
DBU
Py
trace
trace
trace
60
DMAP
NaOH
TEA
TEA
TEA
TEA
TEA
TEA
82
90
rt
89
rt
82
rt
NR
NR no reaction
aReactions were performed with 1a (1.0 mmol), 2a (1.2 mmol), acid chloride (1.0 mmol), and base
(3.0 mmol) in 5 cm3 of solvent, unless otherwise noted
bIsolated yield after column chromatography
c2.0 equiv. of TEA was used
d5.0 equiv. of TEA was used
e1.2 equiv. of POCl3 was used
f1.0 equiv. of 2a was used
Next, diferent tetrasubstituted ureas were tested as reac-
tolerated, generating 3p in 62% yield. Unfortunately, mono-
methyl-, dimethyl-, and trimethylurea showed poor reactiv-
ity and failed to obtain desired products (3q–3t). Therefore,
the urea structure seemed to be limited to only N,N,N’,N’-
tetrasubstituted derivatives.
tion partners, with tetraethylurea and carbonyldipyrrolidine
found to proceed smoothly, furnishing the corresponding
desired products (3m and 3o) in good yields. Meanwhile,
tetrabutylurea gave a lower yield (3n, 59%). This result
indicated that steric efects were a factor in the reaction
yield. Cyclic urea 1,3-dimethyl-2-imidozolidinone was well
As an extension of this work, we also attempted the syn-
thesis of N-oxysulfonyl- and N-sulfamoylguanidines under
1 3

996
F. Wang et al.
Table 2 Preparation of
N-sulfonylguanidinesa,b
aReactions were performed with sulfonamide 1 (1.0 mmol), urea 2 (1.2 mmol) in 5 cm3 of DCM at room
temperature for 1 h, unless otherwise noted
bIsolated yield after column chromatography
cGram scale reaction in 2 h
dReaction time was 2 h
the optimized conditions (Scheme 2). Phenyl sulfamate and
2,2,2-trichloroethyl sulfamate (TcesNH2) reacted smoothly
with TMU to give corresponding products 5a and 5b in 86%
and 81% yields, respectively. Furthermore, N-phenylsulfa-
mide aforded the corresponding N-sulfamoylguanidine (5c)
in 63% yield.
indicated that 3p was formed via in situ formation of a
chloroformamidinium intermediate, while the involve-
ment of TEA was probably essential after formation of
this active intermediate.
From these results, and previous reports [40, 41], we
have proposed a possible reaction mechanism (Scheme 4).
Initially, urea 2 is activated by POCl3 to form chlorofor-
mamidinium intermediate A. Sulfonamide 1 then reacts
with highly active intermediate A to form B, with TEA then
sequentially capturing HCl and HOPOCl2 to generate C and
fnal product 3. This might explain why this transformation
requires an excess amount of TEA.
To confrm the reaction pathway, 1a was treated with
commercially available reagent 1,3-dimethyl-2-chloro-
imidazolinium chloride (DMCI, Scheme 3), affording
desired compound 3p in 75% yield under the optimal
reaction conditions. As expected, the reaction was com-
pletely suppressed in the absence of TEA. These results
1 3

Facile one‑pot synthesis of tetrasubstituted N‑sulfonylguanidines from sulfonamides and…
997
Fig. 1 X-ray structure of 3d
(CCDC 2058614)
Scheme 2
Conclusion
In summary, we have developed a facile method for the
formation of tetrasubstituted N-sulfonylguanidines from
inexpensive commercially available reagents under mild
conditions. This reaction tolerates (hetero)aromatic and
aliphatic sulfonamides, as well as sulfamates and sulfa-
mides, with the desired products generated in good to
excellent yields. A preliminary mechanistic study sug-
gested that the reaction involved a chloroformamidinium
intermediate.
Scheme 3
Experimental
The sulfamates 4a and 4b [42] and sulfamide 4c [43] are
prepared according to literature procedures. CCl4, DCM,
CHCl3, PhCl and DCE were distilled from CaH2. Other
solvents and commercial reagents were used without addi-
tional purifcation. Purifcation of the reaction products
was carried out by fash column chromatography using
200–300 mesh silica gel. High-resolution mass spectra
were recorded on a Bruker BIO TOF Q mass spectrometer.
Proton and carbon magnetic resonance spectra (1H NMR
and 13C NMR) were recorded on a Varian Inova 400 MHz
(1H NMR at 400 MHz and 13C NMR at 100 MHz) spec-
trometer with solvent resonance as the internal stand-
ard (1H NMR: CDCl3 at 7.26 ppm; 13C NMR: CDCl3 at
77.02 ppm). Single-crystal X-ray difraction was carried
out on a Agilent SuperNova, Dual, Cu at zero, AtlasS2 dif-
fractometer with graphite monochromated Cu Kα radiation
(λ = 0.71073 Å) at 100.00(10) K. The melting point was
determined using BUCHI melting point apparatus.
Scheme 4
1 3

998
F. Wang et al.
J=8.8, 1.6 Hz, 1H),7.37 (dd, J=8.8, 1.6 Hz, 1H), 6.96 (dd,
J=8.8, 4.0 Hz, 1H), 2.95 (s,12H, N-CH3) ppm; 13C NMR
(100 MHz, CDCl3): δ = 161.75, 148.01, 128.84, 128.56,
126.39, 40.56, 38.59 ppm; HRMS (ESI): m/z calculated for
C9H16N3O2S2 ([M+H]+) 262.0678, found 262.0686.
General procedure for preparing
N‑sulfonylguanidines
A solution of 153.3 mg phosphoryl chloride (1.0 mmol, 1.0
equiv.) in 2.0 cm3 of DCM was added dropwise to a solution
of the appropriate urea 2 (1.2 mmol, 1.2 equiv.) in 3.0 cm3
of DCM at room temperature and stirred for 15 min, and
then the sulfonamide 1 (1.0 mmol, 1.0 equiv.) was added
in one portion and 0.3 g TEA (3.0 mmol, 3.0 equiv) was
added dropwise to the reaction mixture and stirred at room
temperature for 1 h. The reaction mixture was poured into
10 cm3 of water and extracted with 30 cm3 of DCM (3 times)
and the combined organic layer was dried over anhydrous
MgSO4 and fltered, the solvent was removed and the crude
reaction mixture was purifed by column chromatography on
silica gel column (ethyl acetate/petroleum ether) chromatog-
raphy to aford the desired products.
N‑[Bis(dimethylamino)methylene]‑1‑phenylmethanesul‑
fonamide (3j, C12H20N3O2S) White solid; Rf = 0.36 (EA:
PE=8:1); m.p.:104–105 °C; 1H NMR (400 MHz, CDCl3):
δ=7.48 (d, J=6.4 Hz, 2H), 7.35–7.29 (m, 3H), 4.31 (s, 2H),
2.86 (s, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ=162.07,
131.27, 130.75, 128.34, 61.98, 40.44, 38.59 ppm; HRMS
(ESI): m/z calculated for C12H20N3O2S ([M+H]+) 270.1271,
found 270.1276.
N‑[Bis(dimethylamino)methylene]methanesulfonamide
(3k, C6H16N3O2S) White solid; Rf = 0.26 (EA: PE = 8:1);
1
m.p.: 109–110 °C; H NMR (400 MHz, CDCl3): δ = 2.99
All new compounds (3d–3e, 3h–3n, and 5a–5c) were
characterized using 1H and 13C NMR and HRMS analysis.
The known compounds (3a–3c, 3f, 3g, 3o, and 3p) have sat-
isfactory melting points and spectral data which are identical
with those reported in the literature [35–38].
(s, 3H), 2.95 (s, 12H) ppm; 13C NMR (100 MHz, CDCl3):
δ=161.94, 44.42, 40.37 ppm; HRMS (ESI): m/z calculated
for C6H16N3O2S ([M+H]+) 194.0958, found 194.0965.
N‑[Bis(dimethylamino)methylene]‑2‑methylpropane‑2‑sul‑
fonamide (3l, C9H22N3O2S) White solid; Rf = 0.24 (EA:
N‑[Bis(dimethylamino)methylene]‑4‑(tert‑butyl)benzene‑
sulfonamide (3d, C15H26N3O2S) White solid; Rf =0.40 (EA:
PE=8:1); m.p.: 108–109 °C; 1H NMR (400 MHz, CDCl3):
δ=7.85 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 2.93
(s, 12H), 1.31 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 161.89, 154.06, 142.94, 125.37, 125.32, 40.50, 34.86,
31.17 ppm; HRMS (ESI): m/z calculated for C15H26N3O2S
([M+H]+) 312.1740, found 312.1747.
1
PE = 5:1); m.p.: 79–80 °C; H NMR (400 MHz, CDCl3):
δ = 2.95 (s, 12H),1.43 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3): δ=162.57, 58.89, 40.53, 24.78 ppm; HRMS (ESI):
m/z calculated for C9H22N3O2S ([M+H]+) 236.1427, found
236.1434.
N‑[Bis(diethylamino)methylene]‑4‑methylbenzenesul‑
fonamide (3m, C16H28N3O2S) White solid; Rf = 0.54 (EA:
PE=3:1); m.p.: 107–109 °C; 1H NMR (400 MHz, CDCl3):
δ=7.80 (d, J=8.4 Hz, 2H), 7.21 (d, J =8.0 Hz, 2H), 3.31
(q, J=7.2 Hz, 8H), 2.37 (s, 3H), 1.11 (t, J =7.2 Hz, 12H)
ppm; 13C NMR (100 MHz, CDCl3): δ = 161.10, 143.07,
140.80, 128.86, 125.62, 43.98, 21.36, 13.09 ppm; HRMS
(ESI): m/z calculated for C16H28N3O2S ([M+H]+) 326.1897,
found 326.1903.
N‑[Bis(dimethylamino)methylene]‑4‑chlorobenzenesul‑
fonamide (3e, C11H17ClN3O2S) White solid; Rf = 0.42 (EA:
PE=8:1); m.p.: 103–104 °C; 1H NMR (400 MHz, CDCl3):
δ=7.87 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 2.93
(s, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ = 161.83,
144.40, 136.83, 128.61, 127.16, 40.53, 38.59 ppm; HRMS
(ESI): m/z calculated for C11H17ClN3O2S ([M + H]+)
290.0725, found 290.0732.
N‑[Bis(dibutylamino)methylene]‑4‑methylbenzenesul‑
fonamide (3n, C24H44N3O2S) White solid; Rf = 0.45 (EA:
N‑[Bis(dimethylamino)methylene]‑5‑methylpyridine‑2‑sul‑
fonamide (3h, C11H19N4O2S) White solid; Rf = 0.21 (EA:
PE=8:1); m.p.: 161–162 °C; 1H NMR (400 MHz, CDCl3):
δ=8.45 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.62 (d, J=9.2 Hz,
1H), 2.98 (s, 12H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 162.23, 158.45, 149.61, 137.91, 135.61,
120.63, 40.69, 18.41 ppm; HRMS (ESI): m/z calculated for
C11H19N4O2S ([M+H]+) 271.1223, found 271.1229.
1
PE = 1:1); m.p.: 59–60 °C; H NMR (400 MHz, CDCl3):
δ=7.78 (d, J=8.4 Hz, 2H), 7.20 (d, J =8.4 Hz, 2H), 3.23
(t, J=7.8 Hz, 8H), 2.36 (s, 3H), 1.49–1.41 (m, 8H), 1.249
(m, 8H), 0.87 (t, J=7.2 Hz, 12H) ppm; 13C NMR (100 MHz,
CDCl3): δ=161.25, 142.99, 140.72, 128.80, 125.73, 49.71,
29.95, 21.31, 20.10, 13.75 ppm; HRMS (ESI): m/z calculated
for C24H44N3O2S ([M+H]+) 438.3149, found 438.3157.
Phenyl [bis(dimethylamino)methylene]sulfamate (5a,
C11H18N3O3S) White solid; Rf =0.30 (EA: PE=3:1); m.p.:
96–97 °C; 1H NMR (400 MHz, CDCl3): δ=7.40–7.38 (m,
N‑[Bis(dimethylamino)methylene]thiophene‑2‑sulfonamide
(3i, C9H16N3O2S) White solid; Rf =0.30 (EA: PE=8:1); m.p.:
1
106–107 °C; H NMR (400 MHz, CDCl3): δ = 7.54 (dd,
1 3

Facile one‑pot synthesis of tetrasubstituted N‑sulfonylguanidines from sulfonamides and…
999
10. Shaw JW, Grayson DH, Rozas I (2015) Guanidines as reagents
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2H), 7.35–7.31 (m, 2H), 7.20–7.16 (m, 1H), 2.92 (s, 12H,
N-CH3) ppm; 13C NMR (100 MHz, CDCl3): δ = 162.66,
151.56, 129.32, 125.64, 121.56, 40.44 ppm; HRMS (ESI):
m/z calculated for C11H18N3O3S ([M+H]+) 272.1063, found
272.1071.
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2,2,2‑Trichloroethyl [bis(dimethylamino)methylene]sulfa‑
mate (5b, C7H15Cl3N3O3S) White solid; Rf = 0.36 (EA:
PE=3:1); m.p.: 108–109 °C; 1H NMR (400 MHz, CDCl3):
δ=4.69 (s, 2H), 3.02 (s, 12H) ppm; 13C NMR (100 MHz,
CDCl3): δ=162.52, 94.38, 78.17, 40.60 ppm; HRMS (ESI):
m/z calculated for C7H15Cl3N3O3S ([M + H]+) 325.9894,
found 325.9907.
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N‑[Bis(dimethylamino)methylene]‑Nʹ‑phenylsulfamide (5c,
C11H19N4O2S) White solid; Rf =0.30 (EA: PE=5:1); m.p.:
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1
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158–159 °C; H NMR (400 MHz, CDCl3): δ = 7.27–7.23
(m, 2H), 7.19–7.17 (m, 2H), 7.03–6.99 (m, 1H), 6.63 (bs,
1H), 2.81 (s, 12H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 162.61, 139.66, 129.01, 123.23, 119.42, 40.21 ppm;
HRMS (ESI): m/z calculated for C11H19N4O2S ([M+H]+)
271.1223, found 271.1231.
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The single crystal of 3d was obtained with suitable quality
from DCM under aerobic conditions. Unit cell parameters:
a=13.1875(8) Å, b=10.7104(6) Å, c=12.6762(9) Å; space
group monoclinic P21/c. Crystal data deposited at the Cam-
bridge Crystallographic Data Centre under CCDC 2058614.
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