A new strategy for the chemoselective sulfonamide N-alkylation of sulfonyl ureas under neutral and mild conditions

Article abstract of DOI:10.1016/j.tetlet.2010.06.054

An efficient and chemoselective sulfonamide N-alkylation of sulfonyl ureas is described. The sulfonyl urea derivatives, prepared in situ by the addition of an amine to an arylsulfonyl isocyanate, are selectively alkylated in excellent yields under neutral and mild conditions by treatment with trialkylphosphite- dimethyl acetylenedicarboxylate at ambient temperature.

Full text of DOI:10.1016/j.tetlet.2010.06.054

Tetrahedron Letters 51 (2010) 5646–5648
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Tetrahedron Letters
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A new strategy for the chemoselective sulfonamide N-alkylation
of sulfonyl ureas under neutral and mild conditions
Mehdi Adib a, , Ehsan Sheikhi a, Gita Sheikhi Moghaddam b, Hamid Reza Bijanzadeh c
⇑
a School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
b Department of Chemistry, Payame-Noor University of Abhar, Abhar, Iran
c Department of Chemistry, Tarbiat Modarres University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and chemoselective sulfonamide N-alkylation of sulfonyl ureas is described. The sulfonyl
urea derivatives, prepared in situ by the addition of an amine to an arylsulfonyl isocyanate, are selectively
alkylated in excellent yields under neutral and mild conditions by treatment with trialkylphosphite–
dimethyl acetylenedicarboxylate at ambient temperature.
Received 3 February 2010
Revised 28 May 2010
Accepted 11 June 2010
Available online 16 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Arylsulfonyl isocyanates
Dimethyl acetylenedicarboxylate
Trialkylphosphites
Sulfonyl ureas
Chemoselective sulfonamide N-alkylation
N-Alkylation is an important reaction in synthetic organic
chemistry. The N-alkylation reaction with alkyl halides is well
known,1 but the use of alkyl halides is undesirable from an envi-
ronmental point of view. Other alkylating reagents and conditions
for N-alkylation include: alcohols/metal catalysts,2 alcohols/Ph3P/
DDQ,3 highly active methylating reagents such as Me2SO4, Me3PO4,
and Me2CO3,4 and also reductive amination of carbonyl com-
pounds.5 However, most of these methods have disadvantages
such as high reaction temperatures, long reaction times, use of
strong reducing reagents or hydrogen gas, and in some cases, use
of very hazardous reagents.
The sulfonyl urea unit is an important structural motif found in
biologically active organic compounds. These compounds, first dis-
covered by Janbon et al.,6 have been shown to be highly active her-
bicides, antidiabetics, and antitumor agents.7–12
Chemoselectively alkylated sulfonyl ureas are important com-
pounds in medicinal studies. An important procedure for acquiring
these compounds was reported by Roth et al. in 1995 in which sul-
fonyl ureas were alkylated with alkyl halides in the presence of
DBU in acetonitrile (Scheme 1).13
mild conditions. Thus, a mixture of an amine 1 and an aryl sulfonyl
isocyanate 2 was converted into the corresponding sulfonyl urea in
dry CH2Cl2 at ambient temperature. The reactions reached comple-
tion within a few minutes, which was indicated by TLC monitoring.
After addition of a trialkyl phosphite 3, a solution of dimethyl acet-
ylenedicarboxylate (DMAD) (4) in dry CH2Cl2 was slowly added to
the reaction mixture and stirring was continued at ambient tem-
perature for further two hours to afford the alkylated sulfonyl ur-
eas 5a–q in 85–98% yields (Scheme 2). TLC and 1H NMR analysis
of the reaction mixture clearly indicated the formation of the cor-
responding alkylated sulfonyl ureas 5. Any product other than 5 or
6 could not be detected by NMR spectroscopy.
The structures of the isolated products 5 were deduced on the
basis of IR, 1H, and 13C NMR spectroscopy and mass spectrometry.
The mass spectrum of 5a displayed the molecular ion (M++1) at m/
z = 333, which was consistent with the ethylated 1:1 adduct of
benzylamine and p-toluenesulfonyl isocyanate. The IR spectrum
of 5a showed absorptions at 3394 (w), 1691 (s), 1342 (s), and
1152 (s) cmꢀ1 indicating the presence of NH, C@O, and S@O func-
tional groups, respectively. The 1H NMR spectrum of 5a exhibited a
In this context, and as part of our continuing effort on the design
of new routes for the preparation of biologically active organic
compounds, herein, we report a new reagent for the chemoselec-
tive sulfonamide N-alkylation of sulfonyl ureas under neutral and
O
O
O
O
O
O
R"X, DBU
CH3CN
S
S
CH3(CH2)n
CH3(CH2)n
N
NHAr
N
NHAr
H
R
R'
R
R"
R'
⇑
Corresponding author. Tel./fax: +98 21 66495291.
E-mail address: madib@khayam.ut.ac.ir (M. Adib).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.054

M. Adib et al. / Tetrahedron Letters 51 (2010) 5646–5648
5647
CO2Me
CO2Me
O
O
O
O
CH2Cl2
r.t., 2 h
S
R
P
ArSO2NCO
DMAD
RNH2
+
P(OR')3
+
+
+
O
N
N
H
Ar
O
H
R'
R'
R'
4
1
2
3
6
5
Product
R
Ar
R'
Et
Yield of 5 (%)a
CH2
5a
98
H3C
H3C
H3C
H3C
F
CH2
5b
5c
Et
Et
98
96
CH2
CH2
5d
Et
90
H3C
Cl
H3C
H3C
H3C
H3C
5e
5f
Et
95
94
97
96
98
96
95
91
92
85
86
94
92
Cl
Et
5g
5h
5i
Me
Me
Me
Me
Me
Et
CH2
CH2
H3C
CH2
H3C
Cl
5j
5k
5l
F
CH2
CH2
CH2
CH2
5m
n
H3C
Et
CH2
H3C
H3C
H3C
i-Pr
i-Pr
5o
5p
5q
H3C
n-Bu
n-Bu
H3C
a Isolated yield
Scheme 2.
sharp singlet at d 2.39 due to the aryl methyl group along with
characteristic resonances for the ethyl group (d 1.24, t and 3.74,
q; J = 7.0 Hz for both). Signals confirming the selective alkylation
were seen as a doublet and a triplet for the mutually coupled
methylene (at d 4.44, J = 5.6 Hz) and the adjacent NH (d 7.69,
J = 5.6 Hz) groups. Characteristic signals for the nine protons of
the two aryl substituents were observed with appropriate chemical
shifts and coupling constants. The 1H decoupled 13C NMR spectrum
of 5a showed characteristic signals at d 15.33 (CH2CH3), 21.55 (Ar-
CH3), and 41.72 and 44.94 (for the two CH2 groups) along with fur-
ther nine distinct resonances (5CH, 3C, and the urea carbonyl) in
agreement with the proposed structure.14
A plausiblemechanismfor the formationof the alkylatedsulfonyl
ureas 5 is provided in Scheme 3. It is reasonable to assume that the
zwitterionic intermediate 7, formed by nucleophilic addition of the
phosphite 3 to DMAD 4,15–20 is protonated by the in situ-prepared
sulfonyl urea 8 from the reaction of the amine 1 and the arylsulfonyl
isocyanate 2. Next, the alkyl group of the vinyltrialkoxyphosphoni-

5648
M. Adib et al. / Tetrahedron Letters 51 (2010) 5646–5648
CO2Me
CO2Me
C
C
CO2Me
+
P(OR')3
+
_
(R'O)3P
CO2Me
CO2Me
O
O
O
CO2Me
S
R
O
O
R'
+
+
4
3
7
N
_
N
R'
P
Ar
H
O
H
O
O
R'
O
9
10
S
R
RNH2
ArSO2NCO
+
N
N
Ar
H
H
8
1
2
CO2Me
CO2Me
O
O
O
O
S
R
+
N
N
Ar
P
H
O
R'
O
H
R'
R'
5
6
Scheme 3.
5. Byun, E.; Hong, B.; Kathlia, A.; De Castro, K. A.; Lim, M.; Rhee, H. J. Org. Chem.
2007, 72, 9815–9817.
6. Janbon, M.; Chaptal, J.; Vedel, A.; Schaap, J. Montpellier Med. 1942, 441, 21–22.
7. Saari, L. L.; Cotterman, J. C.; Primiani, M. M. Plant Physiol. 1990, 93, 55–61.
8. Faidallah, H. M.; Al-Saadi, M. S.; Rostom, S. A. F.; Fahmy, H. T. Y. Med. Chem. Res.
2007, 16, 300–318.
9. Lawrence, D. B.; Ragucci, K. R.; Long, L. B.; Helfer, L. A. J. Manag. Care Pharm.
2006, 12, 466–471.
10. Heron, L.; Virsolvy, A.; Peyrollier, K. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8387–
8391.
11. Thomas, P. M.; Cote, G. J.; Wohllk, N. Science 1995, 268, 426–429.
12. Rissanen, J.; Markkanen, A.; Kärkkäinen, P. Diabetes Care 2000, 23, 70–73.
13. Roth, B. D.; Roark, H.; Picard, J. A.; Stanfield, R. L.; Bousley, R. F.; Anderson, M.
K.; Hamelehle, K. L.; Homan, R.; Krouse, B. R. Bioorg. Med. Chem. Lett. 1995, 5,
2367–2370.
um ion 10 may be attacked by the conjugate base 9 of the NH-acid to
afford the corresponding selectively alkylated sulfonyl urea 5. Di-
methyl (E)-2-(diethoxyphosphoryl)-2-butenedioate (6, R0 = ethyl)
was isolated as a by-product and characterized. This further sup-
ports the possibility of the proposed mechanism.21
In conclusion, we have developed a simple and efficient strategy
for the direct one-pot synthesis and chemoselective sulfonamide
N-alkylation of sulfonyl ureas which are of potential synthetic
and pharmacological interest. Excellent yields of the products,
short reaction times, ambient temperature, and mild conditions
are the main advantages of this method. The reactions were per-
formed under neutral conditions, and the starting materials and re-
agents do not require any activation.
14. Typical procedure for the preparation of compounds 5a–q, exemplified with 5a: A
solution of benzylamine (0.107 g, 1 mmol) and p-toluenesulfonyl isocyanate
(0.197 g, 1 mmol) in dry CH2Cl2 (5 mL) was stirred at 25 °C for 5 min. Then
triethylphosphite (0.166 g, 1 mmol) was added. Next, a solution of dimethyl
acetylenedicarboxylate (0.142 g, 1 mmol) in dry CH2Cl2 (3 mL) was added
dropwise over 10 min, and the resulting mixture was stirred at 25 °C for 2 h.
The solvent was removed under reduced pressure, and the residue was purified
by column chromatography (Merck silica gel, 60 mesh) using n-hexane–EtOAc
(4:1) as eluent. {[(Benzylamino)carbonyl](ethyl)amino}(4-methylphenyl)dioxo-
k6-sulfane (5a): Yield: 0.32 g (98%); colorless crystals, mp 135–136 °C. IR (KBr)
Acknowledgment
This research was supported by the Research Council of the Uni-
versity of Tehran as research project 6102036/1/03.
(m
max/cmꢀ1): 3394 (NH), 1691 (C@O), 1597, 1520, 1342, 1242, 1152, 1087, 944,
812, 728, 699, 666. EI-MS, m/z (%): 333 (M++1, 51), 290 (4), 177 (75), 155 (12),
106 (100), 91 (84), 77 (4), 65 (22). 1H NMR (500.1 MHz, CDCl3): d 1.24 (t,
J = 7.0 Hz, 3H, CH2CH3), 2.39 (s, 3H, CH3), 3.74 (q, J = 7.0 Hz, 2H, CH2CH3), 4.44
(d, J = 5.6 Hz, 2H, NHCH2), 7.20–7.33 (m, 7H, 7CH), 7.62 (d, J = 8.3 Hz, 2H, 2CH),
7.69 (t, J = 5.6 Hz, 1H, NH). 13C NMR (125.8 MHz, CDCl3): d 15.33 (CH2CH3),
21.55 (CH3), 41.72 and 44.94 (2CH2), 126.87, 127.49, 127.65, 128.68 and 130.00
(9CH), 136.40, 138.23 and 144.68 (3C), 152.51 (C@O).
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