A facile synthesis of sulfonylureas: Via water assisted preparation of carbamates

Article abstract of DOI:10.1039/c7ob00872d

A novel and simple approach to the synthesis of sulfonylureas has been reported. It involved the reaction of various amines with diphenyl carbonate to yield the corresponding carbamates, which subsequently reacted with different sulphonamides to produce different sulfonylureas in excellent yields. The first reaction of diphenyl carbonate with amines was carried out in aqueous:organic (H₂O:THF, 90:10) medium at room temperature to produce carbamates that paved a straightforward route to sulfonylureas after reaction with sulfonamides. The above process avoided traditional multistep protocols and the use of hazardous, irritant, toxic and moisture sensitive reagents such as phosgene, isocyanates and/or chloroformates.

Full text of DOI:10.1039/c7ob00872d

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A facile synthesis of sulfonylureas via water assisted preparation
of carbamates
Dinesh Kumar Tanwar,a Anjali Ratan,a Manjinder Singh Gill*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A novel and simple approach to the synthesis of Sulfonylureas has been reported. It involved the reaction of
various amines with diphenyl carbonate to yield the corresponding carbamates, which subsequetly reacted
with different sulphonamides to produce different sulfonylureas in excellent yields. The first reaction of
diphenyl carbonate with amines was carried out in aqueous:organic (H2O:THF, 90:10) medium at room
temperature to produce carbamates that paved a straightforward route to sulfonylureas after reaction with
sulfonamides. Above process avoided traditional multistep protocols and use of hazardous, irritant, toxic and
www.rsc.org/
moisture
sensitive
reagents
such
as
phosgene,
isocyanates
and/or
chloroformates.
Introduction
Although above processes to sulfonylureas have been
optimized/modified to minimize the hazards associated with the
manufacturing of these molecules but a facile, environmentally
benign process deemed desirable for such an important class of
molecules. Increasing regulatory pressure, market competition and
environmental awareness also dictate the development of an
improved manufacturing process of sulfonylureas. One such ideal
process would be devoid of any hazardous reagents/solvents. In the
present paper a novel and simple approach to the synthesis of
sulfonylureas without any use of phosgene, isocyanates and/or
chloroformates has been reported.
Sulfonylurea derivatives were the first oral hypoglycemic agents
that have been in use for the treatment of type II diabetics for
almost eight decades.1 All sulfonylurea hypoglycemic drugs act by
releasing insulin from the β cells of pancreas.2 Along with their
secretogogues action, sulfonylureas are also reported to have
insulin sensitizers activities.3-5 In addition, these molecules
exhibited other therapeutic uses such as their use as diuretic agents
(e.g. torasemide)6, agents active against mycobacterium
tuberculosis,7,8 antimalarial9, antifungal10,11 anticancer agents12,13
and Zinc Metalloenzyme Modulators.14 More interestingly
sulfonylureas are also reported to act as herbicides (e.g.,
chlosulfuron).15-17 Most commonly, sulfonylureas are prepared
either by treatment of a sulphonamide with an isocyanate in the Results and discussion
presence of a base18,19 or by converting the sulfonamides into their
Carbamates of amines have already been used in sulfonylureas
synthesis25 but the process to synthesize above carbamates did
involve the use of either phosgene gas or chloroformates.24
Alkyl26,27 and aryl28 carbonates, both, have also been used to
synthesize carbamates. As compared to aryl carbonates, the
synthesis of alkyl carbonates gave various side products.29 The
reactivity of carbamates with nucleophiles is related to pKa values
of the released alcohols hence O-alkyl carbamates do not react
efficiently30,31 as compare to O-aryl carbamates. Aryl carbonates
have successfully been used for the synthesis O-Aryl carbamates
using aromatic amines only.28 Literature search also revealed that
N-alkyl O-aryl carbamates have been synthesized from reaction of
aliphatic amines with chlorofomates.31 As most of the antidiabetic
sulfonylureas have aliphatic N-side chains therefore N-alkyl O-aryl
carbamates are required for the synthesis of these molecules.
Keeping in view the low cost of aryl carbonate such as diphenyl
carbonate (DPC), it appeared a synthetic challenge to prepare N-
alkyl O-aryl carbamates from the reaction of aryl carbonated with
primary amines. Therefore, our investigation started with the
reaction of diphenyl carbonate with primary aliphatic amines to
produce carbamates as the key intermediates which were then
carbamate derivatives, which upon treatment with amines provide
the corresponding sulfonylureas,20,21 Scheme 1. Isocyanate
synthesis involves the use of phosgene,22 a highly toxic chemical,
which requires special handling on scale.23 Similarly carbamate of
sulfonamides are prepared from chloroformates which are,
subsequently, synthesized from phosgene.24
(a)
O
O
S
R2
H2NO2S
Base
R1
Phosgene
R1 NH2
R1
NCO
N
H
N
H
R2
O
(b)
O
R
O
O
S
O
O
S
R1 NH2
Base
O
Cl
H2NO2S R2
R
R1
Base
O
N
R2
N
N
R2
O
O
H
H
H
Scheme 1. Sulfonylurea synthesis (a) via isocyanate; (b) via
carbamate.
a.Department of Pharmaceutical Technology (Process Chemistry), National Institute
of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab-160062,
India
E-mail address: msingh@niper.ac.in, Tel: +91-172-2214683 ext. 2147
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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converted in to sulfonylureas. The overall process executed to Furthermore, the method worked well for benzyl amine and other
synthesize various sulfonylureas is depicted in Scheme 2.
aralkyl amines, (Table 2, entries 12-14). The reaction of secondary
alkyl amines also proceeded smoothly and the expected
carbamates were obtained in good yields, (Table 2, entries 15-18).
In order to synthesize carbamate of aromatic amine, aniline was
used, but with aniline no detectable amount of carbamate was
produced. Low basicity (pka≈4.6) of aniline as compared to
departing phenol (pka≈9.95) accounts for the observed outcome.
Likewise, other arylamines such as 3-chloroaniline, 4-cyanoaniline
and N-methylaniline and heteroarylamines (2-aminothiazole, 2-
aminopyridine, 2-aminopyrimidine) showed no visible sign of
formation of corresponding carbamates under the reaction
conditions used to generate carbamates of alkyl and aryalkyl
amines.
Scheme 2. New route to sulfonylureas via carbamates.
Our first target was to synthesize Tolbutamide-currently used as an
antidiabetic drug. The synthesis of required intermediate, phenyl
butylcarbamate, was explored as shown in Table 1. The use of
organic solvents gave the desired product (carbamate) in a very low
isolated yield (22-30%). The major side product of the reaction was
identified as
a symmetrical urea i.e. N,N`-dibutylurea. The
formation of symmetrical urea seemed obvious as the carbmate
intermediate was expected to react further with n-butyl amine. In
order to improve the yield of the carbamate formation and/or to
minimize the side reaction i.e. the formation of symmetrical urea,
several solvents and solvent mixtures were tried, and the results
are listed in Table 1. Although, in organic solvents, carbamate yield
was low but the reaction was over within 2 hours. To our surprise,
the yield of carbamate increased to 83% in aqueous medium (Table
1, entry 7), but 8 hours were required for the reaction to go to
completion. The aqueous: organic (Water:THF, 90:10) mixture gave
an optimal yield of carbamate (83%) in 7 hours of reaction time,
(Table 1, entry 8). Further increase in the amount of organic solvent
led to poor yields. The variation in molar ratio of diphenyl
carbonate in a range of 1.0 to 1.5 as compare to amine made no
significant impact on the outcome of the reaction.
Table 2
Entry
1
Amine
Butyl
amine
Carbamates
Time (hrs) Yielda
8
83
2
Methyl
amine
7
88
3
4
5
6
Ethyl amine
7
7
9
9
85
87
78
75
Propyl
amine
Table 1
Isopropyl
amine
Cyclopropyl
amine
entry
Solvent
Acetonitrile, rt
THF, rt
Time (hrs)a
Carbamateb
7
8
9
Pentyl
amine
8
8
8
84
83
85
1
2
2
2
2
2
2
2
8
7
6
5
30
26
22
23
24
28
83
83
78
71
Hexyl
amine
3
Acetone, rt
4
DCM, rt
5
DCE, rt
Cyclohexyl
amine
6
DMF, rt
7
Water, rt
8
Water:THF (90:10), rt
Water:THF (80:20), rt
Water:THF (70:30), rt
10
trans-4-
Methyl
cyclohexyl
amine
Octyl
amine
8
84
9
10
11
12
13
Water:THF (60:40), rt
Water:THF (50:50), rt
Water:THF (40:60), rt
4
3
3
62
51
40
11
12
8
8
84
85
aThe reaction times were obtained from the consumption of amine
Benzyl
amine
as followed by TLC.
bIsolated % yield.
13
14
1-
phenylethyl
amine
8
8
86
85
After establishing the optimal conditions for the preparation of
carbamates, the scope and generality of the procedure was
explored. As given in Table 2, aliphatic cyclic and acyclic (straight
and branched chain) primary amines afforded the desired
carbamates in good to excellent yields, (Table 2, entries 1-11).
2-
phenylethyl
amine
2 | J. Name., 2012, 00, 1-3
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15
16
Dimethyl
amine
8
8
86
84
13
14
TEA, reflux
12
70
80
Acetonitrile, DBU, reflux
4
aThe reaction times were obtained from the consumption of
carbamate as followed by TLC.
bIsolated % yield.
Diethyl
amine
nd=not detected
17
18
Pyrrolidine
Piperidine
7
6
85
78
As shown in Table 4, the above optimized reaction conditions have
successfully been extended to synthesize other sulfonylureas by
reacting different carbamates with a variety of sulphonamides. By
applying present methodology another antidiabetic drug,
Chlorpropamide (33) was also synthesized in an isolated yield of
85%.
aIsolated % yield.
In
order
to
synthesize
the
Tolbutamide
4-methyl
benzenesulfonamide was reacted with phenylbutyl carbamate in
acetonitrile without any base but no product was detected, (Table
3, entry 1). The reaction was also performed in DMF in order to
attain a higher reaction temperature (Table 3, entry 2) but again no
reaction was observed. Then, the reaction was investigated in
various bases (Table 3, entries 3-14). The use of inorganic bases
such as K2CO3, NaOH, Cs2CO3 and LiOH gave poor results, most
likely due to the hydrolysis of carbamate intermediate. Organic
bases such as Pyridine, DMAP, Triethylamine and DBU gave good
yields. Optimal yield was achieved when the reaction was carried
out either in a 1:6 v/v mixture of acetonitrile and triethylamine
(Table 3, entry 12) in 12 hours or in the presence of a catalytic
amount of DBU (Table 3, entry 14) in four hours. The use of
triethylamine alone, as a solvent, for the reaction led to poor yields
of sulfonylurea possibly due to low solubility of reactants and/or
products, (Table 3, entry 13).
Table 4
Entry
1
R1
R2
Sulfonylurea
Yielda
Butyl
CH3
80
2
3
4
Methyl
Ethyl
H
H
H
82
81
85
Benzyl
Table 3
5
1-
H
83
phenylethyl
6
7
Ethyl
Propyl
CH3
CH3
CH3
CH3
CH3
81
82
81
74
83
Entry
Solvent/Base
Time (hrs)a Sulfonylureab
1
2
3
Acetonitrile, reflux
DMF, reflux
12
nd
nd
42
8
Isopropyl
Hexyl
Acetonitrile, K2CO3,
reflux
O
O
S
4
5
6
Acetonitrile, NaOH,
reflux
12
12
12
45
50
50
9
N
N
O
H
H
27
Acetonitrile, Cs2CO3,
reflux
10
Cyclohexyl
Acetonitrile, LiOH,
reflux
11
12
13
14
Benzyl
CH3
CH3
Cl
80
82
81
82
7
8
Acetonitrile, TEA, reflux
Acetonitrile, Pyridine,
reflux
12
12
60
62
1-
9
Acetonitrile, DMAP,
reflux
12
12
12
12
65
63
70
80
phenylethyl
10
11
12
Acetonitrile:TEA (1:2),
reflux
Methyl
Ethyl
Acetonitrile:TEA (1:4),
reflux
Cl
Acetonitrile:TEA(1:6),
reflux
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15
Journal Name
was synthesized on gram scale and the desired product was
obtained in 83% isolated yield (Scheme 4).
Propyl
Isopropyl
Benzyl
Cl
Cl
Cl
Br
Br
85
83
84
83
81
16
17
18
19
O
O
S
Scheme 4. Gram scale synthesis of Tolbutamide.
Methyl
Propyl
N
N
H
O
H
Br
36
Conclusions
In conclusion, an efficient, cost-effective, easy and green
method has been developed for the preparation of
sulfonylureas without any use of hazardous, irritant, toxic and
moisture sensitive reagents such as phosgene, isocyanates
and/or chloroformates. This efficient procedure has a broad
substrate scope, and consistently afforded sulfonylureas in
good to excellent yields. In addition, the procedure is
operationally simple, potentially scalable and significantly
benign as compared to current methodologies available for the
synthesis of these important antidiabetic compounds.
20
21
22
23
Cyclopropyl
Benzyl
Br
Br
Br
Br
80
84
81
79
1-
phenylethyl
2-
phenylethyl
Experimental
24
25
Methyl
Methoxy
Methoxy
85
86
All reagents and solvents were used as received from Sigma Aldrich
and Alfa Aesar. Melting points were determined on a Büchi melting
point apparatus. 1H and 13C NMR spectra were obtained in DMSO-d6
trans-4-
Methyl
cyclohexyl
as solvent using
a 400 MHz and 100 MHz spectrometer,
respectively, with Me4Si as an internal standard. Coupling constants
(J values) are reported in Hz. High resolution mass spectra (HRMS)
were obtained using electron spray ionisation (ESI) technique and
as TOF mass analyser. Thin layer chromatography was performed
on pre coated silica gel plates (F254, Merck). Column
chromatography was performed on silica gel (60-120 mesh).
aIsolated % yield.
After successfully synthesizing the sulfonylureas, we decided to
synthesize trisubstituted sulfonylureas by the reaction of
carbamates of secondary amines (15-18) with different
sulphonamides but no reaction was observed in either case. Based
on above observations on reactions of carbmates of secondary
amines and literature review,32 it seems reasonable to conclude
that above reactions proceed via the formation of an isocynate
intermediate and a base is required to extract hydrogen from the
carbamate to generate it. The resulting isocyanate reacts quickly
with sulphonamide to produce the desired sulfonylurea (Scheme 3).
In carbamates of secondary amines as no proton is available hence
reaction did not proceed even in the presence of a suitable base.
Typical procedure for the synthesis of carbamates (1-18)
Finely powdered diphenyl carbonate (15 mmol) was suspended in a
mixture of THF (4 mL) and water (36 mL). The resulting suspension
was stirred at room temperature followed by dropwise addition of
amine (15 mmol). The reaction continued at room temperature and
was monitored by TLC. After completion of reaction, as indicated by
TLC, the reaction mixture was extracted with ethyl acetate, and the
organic layer was washed with cold aquous NaOH solution (10%)
and then with brine. Organic layer was dried over anhydrours
Na2SO4, concentrated under reduced pressure and purified by
column chromatography using hexane:ethyl acetate mixture as
eluent to afford the desired carbamate.
Phenyl butyl carbamate (1)
White solid, mp 38-40 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.72 (t, J=5.6 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H),
7.08 (d, J=7.5 Hz, 2H), 3.06 (quartet, J=6.9 Hz, 2H), 1.45(quintet,
J=7.5 Hz, 2H), 1.32(sextet, J=7.6 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H). 13C-
NMR (100 MHz, DMSO-d6): 154.8, 151.5, 129.6, 125.2, 122.1, 40.5,
31.8, 19.8, 14.0. HRMS (ESI): calcd. for C11H15NNaO2 [M+Na]+,
216.1000, found: 216.1000.
Scheme 3. Possible routes to sulfonylureas via base catalysed
formation of isocyanates.
Moreover, to further demonstrate the practicality of the above
methodology, Tolbutamide, a marketed antidiabetic sulfonylurea
Phenyl methyl carbamate (2)
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White solid, mp 83-85 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 26.3, 22.5, 14.3. HRMS (ESI): calcd. for C13H19NNaO2 [M+Na]+,
244.1313, found: 244.1309.
7.59 (d, J=4.1 Hz, 1H), 7.37 (t, J=8.3 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H),
7.09 (d, J=7.5 Hz, 2H), 2.67 (d, J=4.6 Hz, 3H). 13C-NMR (100 MHz,
DMSO-d6): 155.3, 151.5, 129.6, 125.3, 122.2, 27.5. HRMS (ESI):
calcd. for C8H9NNaO2 [M+Na]+, 174.0531, found: 174.0536.
Phenyl cyclohexyl carbamate(9)
White solid, mp 138-140 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.69 (d, J=7.8 Hz, 1H), 7.36 (t, J=8.1 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H),
7.08 (d, J=7.5 Hz, 2H), 3.36-3.26 (m, 1H), 1.83-1.54 (m, 5H), 1.28-
1.09 (m, 5H). 13C-NMR (100 MHz, DMSO-d6): 153.9, 151.5, 129.6,
125.2, 122.2, 50.2, 32.9, 25.5, 25.0. HRMS (ESI): calcd. for
C13H17NNaO2 [M+Na]+, 242.1157, found: 242.1154.
Phenyl ethyl carbamate (3)
White solid, mp 48-50 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.71 (t, J=4.8 Hz, 1H), 7.36 (t, J=8.2 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H),
7.08 (d, J=7.6 Hz, 2H), 3.09 (quintet, J=7.1 Hz, 2H), 1.08 (t, J=7.2 Hz,
3H). 13C-NMR (100 MHz, DMSO-d6): 154.6, 151.5, 129.6, 125.2,
122.2, 35.7, 15.3. HRMS (ESI): calcd. for C9H11NNaO2 [M+Na]+,
188.0687, found: 188.0687.
Phenyl ((1r,4r)-4-methylcyclohexyl)carbamate (10)
White solid, mp 175-177 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.68 (d, J=7.9 Hz, 1H), 7.36 (t, J=8.1 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H),
7.08 (d, J=7.6 Hz, 2H), 3.34-3.18 (m, 1H), 1.85 (d, J=10.1 Hz, 2H),
1.67 (d, J=12.2 Hz, 2H), 1.29-1.22 (m, 3H), 1.03-0.91 (m, 2H), 0.86
(d, J=6.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 153.9, 151.5,
129.6, 125.2, 122.2, 50.3, 33.9, 32.8, 31.8, 22.6. HRMS (ESI): calcd.
for C14H19NNaO2 [M+Na]+, 256.1313, found: 256.1309.
Phenyl propyl carbamate (4)
White solid, mp 56-58 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.73 (t, J=5.4 Hz, 1H), 7.36 (t, J=8.3 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H),
7.08 (d, J=7.5 Hz, 2H), 3.03 (quartet, J=6.9 Hz, 2H), 1.48 (sextet,
J=7.2 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6):
154.8, 151.5, 129.6, 125.2, 122.1, 42.6, 22.9, 11.6. HRMS (ESI):
calcd. for C10H13NNaO2 [M+Na]+, 202.0844, found: 202.0840.
Phenyl octyl carbamate (11)
White solid, mp 40-42 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.72 (t, J=5.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 2H), 7.18 (t, J=7.4 Hz, 1H),
7.08 (d, J=7.5 Hz, 2H), 3.04 (quartet, J=6.7 Hz, 2H), 1.46 (quintet,
J=6.8 Hz, 2H), 1.37-1.18 (m, 10H), 0.86 (t, J=7.0 Hz, 3H). 13C-NMR
(100 MHz, DMSO-d6): 154.7, 151.5, 129.6, 125.2, 122.1, 40.8, 31.7,
29.6, 29.2, 29.1, 26.7, 22.5, 14.4. HRMS (ESI): calcd. for
C15H23NNaO2 [M+Na]+, 272.1626, found: 272.1628.
Phenyl isopropyl carbamate (5)
White solid, mp 80-82 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.66 (d, J=7.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H),
7.08 (d, J=7.6 Hz, 2H), 3.71-3.60 (m, 1H), 1.12 (d, J=6.5 Hz, 6H). 13C-
NMR (100 MHz, DMSO-d6): 153.9, 151.5, 129.6, 125.2, 122.2, 43.1,
22.8. HRMS (ESI): calcd. for C10H13NNaO2 [M+Na]+, 202.0846, found:
202.0846.
Phenyl benzyl carbamate (12)
White solid, mp 82-84 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
8.31 (t, J=6.1 Hz, 1H), 7.39-7.24 (m, 7H), 7.19 (t, J=7.8 Hz, 1H), 7.11
(d, J=7.7 Hz, 2H), 4.28 (d, J=6.1 Hz, 2H). 13C-NMR (100 MHz, DMSO-
d6): 155.1, 151.5, 139.7, 129.7, 128.8, 127.6, 127.4, 125.4, 122.2,
44.4. HRMS (ESI): calcd. for C14H13NNaO2 [M+Na]+, 250.0844, found:
250.0838.
Phenyl cyclopropyl carbamate (6)
White solid, mp 73-75 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.92 (br. s, 1H), 7.36 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.09 (d,
J=7.8 Hz, 2H), 2.55 (sextet, J=3.4 Hz, 1H), 0.65-0.51 (m, 4H). 13C-
NMR (100 MHz, DMSO-d6): 155.4, 151.4, 129.6, 125.3, 122.2, 23.5,
6.2. HRMS (ESI): calcd. for C10H11NNaO2 [M+Na]+, 200.0687, found:
200.0687.
Phenyl (1-phenylethyl) carbamate (13)
White solid, mp 105-107 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
8.35 (d, J=8.1 Hz, 1H), 7.39-7.33 (m, 6H), 7.24 (t, J=6.9 Hz, 1H), 7.18
(t, J=7.3 Hz, 1H), 7.08 (d, J=7.8 Hz, 2H), 4.73 (quintet, J=7.4 Hz, 1H),
1.42 (d, J=7.0 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 154.1, 151.4,
145.0, 129.7, 128.8, 127.2, 126.3, 125.3, 122.2, 50.8, 23.2. HRMS
(ESI): calcd. for C15H15NNaO2 [M+Na]+, 264.1000, found: 264.0992.
Phenyl pentyl carbamate (7)
White solid, mp 48-50 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.72 (t, J=5.5 Hz, 1H), 7.37 (t, J=8.2 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H),
7.09 (d, J=7.5 Hz, 2H), 3.05 (quartet, J=6.9 Hz, 2H), 1.47 (quintet,
J=7.1 Hz, 2H), 1.33-1.26 (m, 4H), 0.88 (t, J=7.0 Hz, 3H). 13C-NMR (100
MHz, DMSO-d6): 154.7, 151.6, 129.6, 125.2, 122.1, 40.8, 29.3, 28.9,
22.2, 14.3. HRMS (ESI): calcd. for C12H17NNaO2 [M+Na]+, 230.1157,
found: 230.1160.
Phenyl phenethyl carbamate (14)
White solid, mp 93-95 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.84 (t, J=5.5 Hz, 1H), 7.38-7.29 (m, 4H), 7.25-7.17 (m, 4H), 7.06 (d,
J=7.6 Hz, 2H), 3.29 (quartet, J=6.1 Hz, 2H), 2.79 (t, J=7.1 Hz, 2H). 13C-
NMR (100 MHz, DMSO-d6): 154.7, 151.5, 139.6, 129.6, 129.1, 128.8,
126.6, 125.3, 122.1, 42.4, 35.7. HRMS (ESI): calcd. for C15H15NNaO2
[M+Na]+, 264.1000, found: 264.0991.
Phenyl hexyl carbamate (8)
White solid, mp 44-46 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.72 (t, J=5.4 Hz, 1H), 7.37 (t, J=8.1 Hz, 2H), 7.19 (t, J=7.3 Hz, 1H),
7.08 (d, J=7.6 Hz, 2H), 3.05 (quartet, J=6.8 Hz, 2H), 1.46 (quintet,
J=7.1 Hz, 2H), 1.35-1.22 (m, 6H), 0.87 (t, J=6.9 Hz, 3H). 13C-NMR (100
MHz, DMSO-d6): 154.7, 151.6, 129.6, 125.2, 122.1, 40.9, 31.4, 29.6,
Phenyl dimethylcarbamate (15)
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White solid, mp 43-45 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 127.5, 26.6. HRMS (ESI): calcd. for C8H10N2NaO3S [M+Na]+,
7.38 (t, J=7.5 Hz, 2H), 7.21 (t, J=7.5 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 237.0310, found: 237.0313.
3.03 (s, 3H), 2.90 (s, 3H). 13C-NMR (100 MHz, DMSO-d6): 154.4,
151.8, 129.6, 125.5, 122.3, 36.7, 36.5. HRMS (ESI): calcd. for
C9H12NO2 [M+H]+, 166.0868, found: 166.0865.
N-(ethylcarbamoyl)benzenesulfonamide (21)
White solid, mp 125-127 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.92 (d, J=7.3 Hz, 2H), 7.70 (t, J=7.3 Hz, 1H), 7.63 (t, J=7.2 Hz, 2H),
Phenyl diethylcarbamate (16)
6.56 (t, J=5.1 Hz, 1H), 2.98 (quintet, J=7.1 Hz, 2H), 0.95 (t, J=7.2 Hz,
Viscous liquid; H-NMR (400 MHz, DMSO-d6): δ (ppm) 7.38 (t, J=7.6 3H). 13C-NMR (100 MHz, DMSO-d6): 151.8, 140.3, 133.7, 129.5,
1
Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.5 Hz, 2H), 3.39 (quartet, 127.5, 34.6, 15.1. HRMS (ESI): calcd. for C9H12N2NaO3S [M+Na]+,
J=6.6 Hz, 2H), 3.30 (quartet, J=6.7 Hz, 2H), 1.19 (t, J=5.8 Hz, 3H), 251.0466, found: 251.0469.
1.11 (t, J=6.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 153.7, 151.7,
129.6, 125.4, 122.2, 42.1, 41.9, 14.5, 13.7. HRMS (ESI): calcd. for
C11H16NO2 [M+H]+, 194.1181, found: 194.1177.
N-(benzylcarbamoyl)benzenesulfonamide (22)
White solid, mp 179-181 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.92 (d, J=7.4 Hz, 2H), 7.69 (t, J=7.4 Hz, 1H), 7.60 (t, J=7.2 Hz, 2H),
7.29-7.21 (m, 3H), 7.13 (d, J=7.0 Hz, 2H), 7.04 (t, J=5.7 Hz, 1H), 4.16
Phenyl pyrrolidine-1-carboxylate (17)
White solid; mp 74-76 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) (d, J=5.9 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): 151.4, 140.1,
7.38 (t, J=8.2 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.13 (d, J=7.5 Hz, 2H), 139.0, 133.1, 129.0, 128.2, 127.1, 126.9, 126.8, 42.6. HRMS (ESI):
3.49 (t, J=6.6 Hz, 2H), 3.33 (t, J=6.3 Hz, 2H), 1.93-1.82 (m, 4H). 13C- calcd. for C14H14N2NaO3S [M+Na]+, 313.0623, found: 313.0620.
NMR (100 MHz, DMSO-d6): 152.6, 151.6, 129.6, 125.4, 122.3, 46.6,
46.4, 25.7, 24.9. HRMS (ESI): calcd. for C11H13NNaO2 [M+Na]+,
N-((1-phenylethyl)carbamoyl)benzenesulfonamide (23)
214.0844, found: 214.0838.
White solid, mp 166-168 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.86 (d, J=7.5 Hz, 2H), 7.65 (t, J=7.3 Hz, 1H), 7.56 (t, J=7.3 Hz, 2H),
7.26 (t, J=7.3 Hz, 2H), 7.18 (t, J=7.8 Hz, 3H), 6.95 (d, J=7.7 Hz, 1H),
Phenyl piperidine-1-carboxylate (18)
White solid; mp 78-80 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 4.60 (quintet, J=7.1 Hz, 1H), 1.27 (d, J=6.9 Hz, 3H). 13C-NMR (100
7.38 (t, J=8.2 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.5 Hz, 2H), MHz, DMSO-d6): 151.1, 144.3, 140.3, 133.7, 129.5, 128.8, 127.5,
3.55 (br. s, 2H), 3.40 (br. s, 2H), 1.62-1.55 (m, 6H). 13C-NMR (100 127.3, 126.0, 49.4, 22.9. HRMS (ESI): calcd. for C15H16N2NaO3S
MHz, DMSO-d6): 53.3, 151.8, 129.6, 125.5, 122.3, 45.5, 45.0, 25.9, [M+Na]+, 327.0779, found: 327.0769.
25.5, 24.1. HRMS (ESI): calcd. for C12H15NNaO2 [M+Na]+, 228.1000,
found: 228.0968.
N-(ethylcarbamoyl)-4-methylbenzenesulfonamide (24)
White solid, mp 139-141 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.77 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.45 (t, J=5.3 Hz, 1H),
General procedure for the synthesis of sulfonylureas (19-43)
Sulfonamide (2 mmol) and carbamate (2.2 mmol) were dissolved in 2.96 (quintet, J=7.1 Hz, 2H), 2.37 (s, 3H), 0.93 (t, J=7.1 Hz, 3H). 13C-
acetonitrile (15 mL), then DBU (3 mmole) was added, and the NMR (100 MHz, DMSO-d6): 151.6, 144.0, 137.9, 129.8, 127.6, 34.5,
reaction mixture was refluxed. The reaction was monitored by TLC. 21.4, 15.3. HRMS (ESI): calcd. for C10H14N2NaO3S [M+Na]+,
After completion of the reaction, as indicated by TLC, solvent was 265.0623, found: 265.0628.
evaporated under reduced pressure. The residue was then
dissolved in ethyl acetate and extracted with 0.1N HCl. Organic
4-methyl-N-(propylcarbamoyl)benzenesulfonamide (25)
layer was washed with brine, dried over Na2SO4, and concentrated
again under reduced pressure. The crude product was purified by
crystallization using hexane-ethyl acetate mixture to afford the
desired sulfonylurea.
White solid, mp 152-154 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.78 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 6.45 (t, J=5.3 Hz, 1H),
2.90 (quartet, J=6.7 Hz, 2H), 2.38 (s, 3H), 1.32 (sextet, J=7.2 Hz, 2H),
0.75 (t, J=7.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 151.3, 143.5,
137.4, 129.3, 127.1, 125.5, 40.8, 22.3, 20.9, 10.9. HRMS (ESI): calcd.
for C11H16N2NaO3S [M+Na]+, 279.0779, found: 279.0782.
N-(butylcarbamoyl)-4-methylbenzenesulfonamide (19)
1
White solid, mp 128-130 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.77 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.44 (t, J=5.3 Hz, 1H),
2.93 (quartet, J=6.8 Hz, 2H), 2.37 (s, 3H), 1.28 (quintet, J=7.3 Hz,
2H), 1.15 (sextet, J=7.1 Hz, 2H), 0.80 (t, J=7.3 Hz, 3H). 13C-NMR (100
MHz, DMSO-d6): 151.7, 144.0, 137.8, 129.8, 127.6, 39.2, 31.7, 21.4,
19.7, 13.9. HRMS (ESI): calcd. for C12H18N2NaO3S [M+Na]+,
293.0936, found: 293.0932.
N-(isopropylcarbamoyl)-4-methylbenzenesulfonamide (26)
White solid, mp 171-173 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.77 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 6.27 (d, J=7.5 Hz, 1H),
3.65-3.54 (m, 1H), 2.37 (s, 3H), 0.99 (d, J=6.5 Hz, 6H). 13C-NMR (100
MHz, DMSO-d6): 150.4, 143.5, 137.3, 129.3, 127.1, 41.3, 22.2, 20.9.
HRMS (ESI): calcd. for C11H16N2NaO3S [M+Na]+, 279.0779, found:
279.0779.
N-(methylcarbamoyl)benzenesulfonamide (20)
1
White solid, mp 148-150 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
N-(hexylcarbamoyl)-4-methylbenzenesulfonamide (27)
7.89 (d, J=5.7 Hz, 2H), 7.67-7.60 (m, 3H), 6.41 (br. s, 1H), 2.50 (s,
3H). 13C-NMR (100 MHz, DMSO-d6): 152.3, 140.8, 133.5, 129.4,
6 | J. Name., 2012, 00, 1-3
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White solid, mp 95-97 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 4-chloro-N-(isopropylcarbamoyl)benzenesulfonamide (34)
White solid, mp 153-155 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.90 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 6.37 (d, J=7.4 Hz, 1H),
7.77 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 6.43 (t, J=5.2 Hz, 1H),
2.93 (quartet, J=6.7 Hz, 2H), 2.38 (s, 3H), 1.33-1.13 (m, 8H), 0.82 (t,
J=7.0 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 151.7, 143.9, 137.9,
3.62-3.53 (m, 1H), 1.00 (d, J=6.5 Hz, 6H). 13C-NMR (100 MHz, DMSO-
129.8, 127.6, 39.5, 31.3, 29.5, 26.2, 22.4, 21.4, 14.3. HRMS (ESI):
d6): 150.9, 139.6, 138.4, 129.6, 129.5, 41.9, 22.7. HRMS (ESI): calcd.
calcd. for C14H22N2NaO3S [M+Na]+, 321.1249, found: 321.1249.
for C10H13ClN2NaO3S [M+Na]+, 299.0233, found: 299.0229.
N-(cyclohexylcarbamoyl)-4-methylbenzenesulfonamide (28)
N-(benzylcarbamoyl)-4-chlorobenzenesulfonamide (35)
1
White solid, mp 199-201 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
White solid, mp 171-173 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.77 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 6.32 (d, J=7.6 Hz, 1H),
7.91 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.29-7.21 (m, 3H), 7.13-
7.07 (m, 3H), 4.15 (d, J=5.9 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6):
3.29-3.22 (m, 1H), 2.38 (s, 3H), 1.65-1.42 (m, 5H), 1.22-1.05 (m, 5H).
13C-NMR (100 MHz, DMSO-d6): 150.9, 144.0, 137.9, 129.8, 127.6,
151.9, 139.5, 139.4, 138.6, 129.7, 129.6, 128.7, 127.4, 127.3, 43.1.
HRMS (ESI): calcd. for C14H13ClN2NaO3S [M+Na]+, 347.0233, found:
48.5, 32.7, 25.4, 24.6, 21.4. HRMS (ESI): calcd. for C14H20N2NaO3S
[M+Na]+, 319.1092, found: 319.1097.
347.0233.
N-(benzylcarbamoyl)-4-methylbenzenesulfonamide (29)
4-bromo-N-(methylcarbamoyl)benzenesulfonamide (36)
1
White solid, mp 185-187 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
White solid, mp 176-178 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.80 (s, 4H), 6.45 (d, J=2.9 Hz, 1H), 2.48 (d, J=3.6 Hz, 3H). 13C-NMR
7.78 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.30-7.18 (m, 3H), 7.11
(d, J=6.9 Hz, 2H), 7.01 (t, J=5.7 Hz, 1H), 4.14 (d, J=5.8 Hz, 2H), 2.37
(100 MHz, DMSO-d6): 157.2, 144.6, 137.2, 134.4, 132.3, 31.3. HRMS
(s, 3H). 13C-NMR (100 MHz, DMSO-d6): 152.1, 144.2, 139.5, 137.7,
(ESI): calcd. for C8H9BrN2NaO3S [M+Na]+, 314.9415, found:
129.9, 128.7, 127.6, 127.4, 127.3, 43.1, 21.4. HRMS (ESI): calcd. for
314.9406.
C15H16N2NaO3S [M+Na]+, 327.0779, found: 327.0779.
4-bromo-N-(propylcarbamoyl)benzenesulfonamide (37)
White solid, mp 133-135 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
4-methyl-N-((1-phenylethyl)carbamoyl)benzenesulfonamide (30)
1
White solid, mp 130-132 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.82 (s, 4H), 6.53 (br. s, 1H), 2.89 (quartet, J=6.2 Hz, 2H), 1.32
(sextet, J=7.1 Hz, 2H), 0.75 (t, J=7.2 Hz, 3H). 13C-NMR (100 MHz,
7.77 (d, J=7.4 Hz, 2H), 7.38 (d, J=7.4 Hz, 2H), 7.29-7.22 (m, 5H), 6.89
(d, J=6.5 Hz, 1H), 4.63 (quintet, J=6.3 Hz, 1H), 2.38 (s, 3H), 1.30 (d,
DMSO-d6): 151.2, 139.5, 132.0, 129.2, 126.9, 40.8, 22.3, 11.0. HRMS
J=6.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 151.0, 144.4, 144.0,
(ESI): calcd. for C10H13BrN2NaO3S [M+Na]+, 344.9707, found:
137.8, 129.8, 128.7, 127.7, 127.3, 126.2, 49.3, 23.0, 21.4. HRMS
344.9698.
(ESI): calcd. for C16H18N2NaO3S [M+Na]+, 341.0936, found: 341.0933.
4-bromo-N-(cyclopropylcarbamoyl)benzenesulfonamide (38)
4-chloro-N-(methylcarbamoyl)benzenesulfonamide (31)
White solid, mp 138-140 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
1
White solid, mp 192-194 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.82 (s, 4H), 6.73 (br. s, 1H), 2.40 (sextet, J=2.9 Hz, 1H), 0.55
(quartet, J=5.6 Hz, 2H), 0.34 (br. s, 2H). 13C-NMR (100 MHz, DMSO-
7.90 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 6.45 (quartet, J=3.6 Hz,
1H), 2.51 (d, J=4.5 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 152.2,
d6): 152.6, 139.9, 132.5, 129.8, 127.5, 22.8, 6.4. HRMS (ESI): calcd.
for C10H11BrN2NaO3S [M+Na]+, 340.9571, found: 340.9559.
139.6, 138.4, 129.7, 129.6, 26.6. HRMS (ESI): calcd. for
C8H9ClN2NaO3S [M+Na]+, 270.9920, found: 270.9917.
N-(benzylcarbamoyl)-4-bromobenzenesulfonamide (39)
4-chloro-N-(ethylcarbamoyl)benzenesulfonamide (32)
White solid, mp 201-203 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
1
White solid, mp 147-149 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.83 (s, 4H), 7.32-7.20 (m, 3H), 7.18-7.02 (m, 3H), 4.15 (d, J=5.8 Hz,
2H). 13C-NMR (100 MHz, DMSO-d6): 151.4, 139.3, 138.9, 132.1,
7.91 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 6.53 (t, J=5.2 Hz, 1H),
2.97 (quintet, J=7.1 Hz, 2H), 0.94 (t, J=7.2 Hz, 3H). 13C-NMR (100
129.2, 128.2, 127.1, 126.9, 126.8, 42.7. HRMS (ESI): calcd. for
C14H13BrN2NaO3S [M+Na]+, 392.9707, found: 392.9702.
MHz, DMSO-d6): 151.5, 139.6, 138.4, 129.6, 129.5, 34.6, 15.2. HRMS
(ESI): calcd. for C9H11ClN2NaO3S [M+Na]+, 285.0077, found:
285.0068.
4-bromo-N-((1-phenylethyl)carbamoyl)benzenesulfonamide (40)
White solid, mp 130-132 °C; 1H-NMR (400 MHz, DMSO-d6): δ (ppm)
4-chloro-N-(propylcarbamoyl)benzenesulfonamide (33)
7.82 (s, 4H), 7.31-7.20 (m, 5H), 7.04 (d, J=7.7 Hz, 1H), 4.63 (quintet,
1
J=7.2 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6):
White solid, mp 128-130 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.90 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 6.54 (t, J=5.1 Hz, 1H),
155.7, 149.1, 144.5, 137.3, 134.5, 133.5, 132.3, 132.1, 130.9, 54.2,
27.6. HRMS (ESI): calcd. for C15H15BrN2NaO3S [M+Na]+, 404.9884,
2.89 (quartet, J=6.6 Hz, 2H), 1.32 (sextet, J=7.2 Hz, 2H), 0.74 (t, J=7.4
Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 151.7, 139.5, 138.5, 129.6,
found: 404.9875.
129.5, 41.3, 22.8, 11.5. HRMS (ESI): calcd. for C10H13ClN2NaO3S
[M+Na]+, 299.0233, found: 299.0226.
4-bromo-N-(phenethylcarbamoyl)benzenesulfonamide (41)
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1
White solid, mp 122-124 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.84-7.78 (m, 4H), 7.25 (t, J=7.5 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 7.12
(d, J=7.1 Hz, 2H), 6.51 (t, J=5.2 Hz, 1H), 3.19 (quartet, J=6.8 Hz, 2H),
2.64 (t, J=7.1 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): 151.6, 139.9,
139.3, 132.5, 129.7, 129.0, 128.8, 127.5, 126.6, 41.1, 35.5. HRMS
(ESI): calcd. for C15H15BrN2NaO3S [M+Na]+, 406.9864, found:
406.9854.
6
7
H. Knauf and E. Mutschler, Clin. Pharmacokinet., 1998, 34, 1.
Y. Liu, P. Bao, D. Wang, Z. Li, ,Y. Li, L. Tang, Y. Zhou and W. Zhao,
Jpn. J. Infect. Dis., 2014, 67, 485.
M. Dong, D. Wang, Y. Jiang, L. Zhao, C. Yang and C. Wu, Saudi
Med. J., 2011, 32, 1122.
C. León, J. Rodrigues, N. G. de Domínguez, J. Charris, J. Gut, P. J.
Rosenthal and J. N. Domínguez, Eur. J. Med. Chem., 2007, 42,
735.
8
9
10 W. Chen, Y. Li, Y. Shi, W. Wei, Y. Chen, Y. Li, J. Liu, B. Li, Z. Li,
Chem. Res. Chin. Univ., 2015, 31, 218.
11 Y. T. Lee, C. J. Cui, E. W. L. Chow, N. Pue, T. Lonhienne, J. G.
Wang, J. A. Fraser and L. W. Guddat, J. Med. Chem., 2013, 56,
210.
12 K. Szafrański and J. Sławiński, Molecules, 2015, 20, 12029.
13 B. Żołnowska, J. Sławiński, A. Pogorzelska, J. Chojnacki, D. Vullo
and C. T. Supuran, Eur. J. Med. Chem.,2014, 71, 135.
14 M. Hadianawala and B. Datta, RSC Adv., 2016, 6, 8923.
15 W. C. Guo, X. H. Liu, Y. H. Li, S. H. Wang and Z. M. Li. Chem. Res.
Chin. Univ., 2008, 24, 32.
4-methoxy-N-(methylcarbamoyl)benzenesulfonamide (42)
1
White solid, mp 149-151 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
7.83 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.9 Hz, 2H), 6.37 (quartet, J=4.2 Hz,
1H), 3.84 (s, 3H), 2.50 (d, J=4.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-
d6): 163.0, 152.6, 132.4, 129.9, 114.5, 56.1, 26.6. HRMS (ESI): calcd.
for C9H12N2NaO4S [M+Na]+, 267.0415, found: 267.0407.
4-methoxy-N-(((1r,4r)-4-methylcyclohexyl)carbamoyl)
benzenesulfonamide (43)
1
16 R. Galeazzi, C. Marucchini, M. Orena and C. Zadra, Bioorg. Med.
Chem., 2002, 10, 1019.
17 T. K. James, P. T. Holland, A. Rahman and Y. R. Lu, Weed Res.,
1999, 39, 137.
18 J. Cervelló and T. Sastre, Synthesis, 1990, 1990, 221.
19 D. Tan, V. Štrukil, C. Mottillo and T. Friščić, Chem. Commun.,
2014, 50, 5248.
20 I. G. Rathish, K. Javed, S. Bano, S. Ahmad, M. S. Alam and K. K.
Pillai, Eur. J.Med. Chem., 2009, 44, 2673.
White solid, mp 185-187 °C; H-NMR (400 MHz, DMSO-d6): δ (ppm)
10.25 (br. s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.9 Hz, 2H), 6.25
(d, J=7.5 Hz, 1H), 3.83 (s, 3H), 3.19-3.16 (m, 1H), 1.68 (d, J=10.1 Hz,
2H), 1.59 (d, J=12.1 Hz, 2H), 1.33-1.01 (m, 3H), 0.95-0.75 (m, 5H).
13C-NMR (100 MHz, DMSO-d6): 163.1, 151.0, 132.2, 130.0, 114.5,
56.1, 48.9, 33.8, 32.7, 31.6, 22.5. HRMS (ESI): calcd. for
C15H22N2NaO4S [M+Na]+, 349.1198, found: 349.1185.
21 A. S. Thakur, R. Deshmukh, A. K. Jha and P. S. Kumar, Saudi
Pharm. J., 2015, 23, 475.
Gram scale synthesis of Tolbutamide
4-methylbenzenesulfonamide (20 mmol, 3.424 g) and phenyl
butylcarbamate (22 mmol, 4.251 g) were dissolved in acetonitrile
(150 mL), then DBU (30 mmole, 4.49 mL) was added, and the
reaction mixture was refluxed. The reaction was monitored by TLC.
After completion of the reaction, as indicated by TLC, solvent was
evaporated under reduced pressure. The residue was dissolved in
ethyl acetate and extracted with 0.1N HCl. Organic layer was
washed with brine, dried over Na2SO4, and concentrated again
under reduced pressure. The crude product was purified by
crystallization using hexane-ethyl acetate mixture to afford the
4.490 g of Tolbutamide in an isolated yield of 83%.
22 F. Bigi, R. Maggi and G. Sartori, Green Chem., 2000, 2, 140.
23 D. Carnaroglio, K. Martina, G. Palmisano, A. Penoni, C. Domini
and G. Cravotto, Beilstein J. Org. Chem., 2013, 9, 2378.
24 O. Kreye, H. Mutlu and M. A. R. Meier, Green Chem., 2013, 15,
1431.
25 N. Ma, Z. J. Fan, B. L. Wang, Y. H. Li and Z. M. Li, Chin. Chem.
Lett., 2008, 19, 1268.
26 H. Zhou, F. Shi, X. Tian, Q. Zhang and Y. Deng, J. Mol. Catal. A:
Chem., 2007, 271, 89.
27 M. Litwinowicz and J. Kijeński, Sustainable Chem. Processes,
2015, 3: 1. DOI: 10.1186/s40508-015-0027-4.
28 K. Harada, R. Sugise, K. Kashiwagi and T. Matsuura, 1998, US
Patent. 6,143,917.
29 T. Sima, S. Guo, F. Shi and Y. Deng, Tetrahedron Lett., 2002, 43,
8145.
30 A. V. Bogolubsky, Y. S. Moroz, P. K. Mykhailiuk, Y. V. Dmytriv, S.
E. Pipko, L. N. Babichenko, A. I. Konovets and A. Tolmachev, RSC
Adv., 2015, 5, 1063.
31 R. Hron and B. S. Jursic, Tetrahedron Lett., 2014, 55, 1540.
32 S. Ilieva, D. Nalbantova, B. Hadjieva, and B Galabov, J. Org.
Chem., 2013, 78, 6440.
Acknowledgements
This study was supported by National Institute of
Pharmaceutical Education & Research, S.A.S. Nagar, Punjab
(INDIA). Dinesh Kumar Tanwar thanks University Grants
Commission (UGC), New Delhi (INDIA) for awarding scholarship
for doctoral studies.
Notes and references
1
2
3
4
C. C. Quianzon and I. E. Cheikh, J. Community Hosp. Intern. Med.
Perspect., 2012, 2: 19081. DOI: 10.3402/jchimp.v2i3.19081.
U. Panten, M. Schwanstecher and C. Schwanstecher, Exp. Clin.
Endocrinol. Diabetes, 1996, 104, 1.
S. Fukuen, M. Iwaki, A. Yasui, M. Makishima, M. Matsuda and I.
Shimomura, J Biol. Chem., 2005 ,280, 23653.
M. Scarsi, M. Podvinec, A. Roth, H. Hug, S. Kersten, H. Albrecht,
T. Schwede, U. A. Meyer and C. Rucker, Mol. Pharmacol., 2007,
71, 398.
5
U. M. Kabadi, J. Diabetes Mellitus, 2015, 5, 211.
8 | J. Name., 2012, 00, 1-3
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Page 9 of 9
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB00872D
A facile synthesis of Sulfonylureas via water assisted preparation of
Carbamates
Dinesh Kumar Tanwar,a Anjali Ratan,a Manjinder Singh Gill*,a
aDepartment of Pharmaceutical Technology (Process Chemistry), National Institute of
Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab-160062, India
*Corresponding author: E-mail address: msingh@niper.ac.in
Graphical abstract:
O
O
H2N
S
R2
O
O
S
O
Ph
Ph
O
R1
R1
Ph
O
O
N
N
R2
N
O
O
H
H
Sulfonamide
H
R1 NH2
Sulfonylureas
Carbamates
Highly efficient and green method
No use of phosgene, isocyanates and/or chloroformates
No use of catalysts
Simple and scalable
Water:THF
Water:THF
Water:THF as the reaction solvent for preparation of carbamates