A highly efficient synthesis of sulphonamide derivatives in the presence of n-methyl-2-pyrrolidone

Article abstract of DOI:10.1080/00397910903470517

The sulphonamide derivatives are synthesized by two component condensation of alkyl bromide and sodium arylsulphonamide using N-methyl-2-pyrrolidone (NMP) as a reaction medium. This method results in high yields without the formation of unwanted side products, and expanding substrate scopes. Copyright

Full text of DOI:10.1080/00397910903470517

Synthetic Communications1, 40: 3648–3653, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903470517
A HIGHLY EFFICIENT SYNTHESIS OF
SULPHONAMIDE DERIVATIVES IN THE
PRESENCE OF N-METHYL-2-PYRROLIDONE
Yong Tan, Su Juan Wang, Yi Ting Wang, Bao Xiang Gao, and
Xin Wu Ba
College of Chemistry and Environment Science, Hebei University, Baoding,
P. R. China
The sulphonamide derivatives are synthesized by two component condensation of alkyl bro-
mide and sodium arylsulphonamide using N-methyl-2-pyrrolidone (NMP) as a reaction
medium. This method results in high yields without the formation of unwanted side products,
and expanding substrate scopes.
Keywords: Amides; NMP; nucleophiles; solvent effects; synthesis
INTRODUCTION
Multiamines and their derivatives are found to be among the most widely used
building block in hyperbranched, linear polymers and supramolecular chemistry.[1–3]
For example, in the group of Mcauley, an interesting Ni-N coordinate complex was
developed that possessed the pentaerythrityl tetraamine.[4] Moreover, these com-
pounds are intermediates, which could be widely used in drugs and food industries.
In addition, these multierythrityltetramines have been suggested as precipitant for
nitric acid and synthetic intermediates for many natural products.[5]
Due to the great importance, continuous efforts have been devoted and several
synthetic strategies have been reported.[6–8] The methods include the following:
(i) treating the readily available 1,3-dichloro-2,2-bis(chloromethyl)propane with
excess supercritical ammonia at high temperature; (ii) treatment of 1,3-dibromo-2,2-
bis(bromomethyl)propane (TBrMP) with sodium azide in organic solvent; (iii) treat-
ment of TBrMP with sodium p-toluenesulphonamide (SPTPA). However, most of
these approaches suffer from significant drawbacks and limitations. The first proto-
col involves the high temperature and pressure and the second includes the easily
explosive compound such as sodium azide. In addition, the target products have a
number of side unwanted compounds. It should be noted that these methods often
result in low to moderate yields. Among them, the third one will lead to more prac-
tical applications, which the key step is the synthesis of the sulphonamide-derivatives
Received May 19, 2009.
Address correspondence to Professor Xin Wu Ba, Chemistry, Hebei University, WuSi East Road
180, Baoding 071002, China. E-mail: baxw@mail.hbu.edu.cn
3648

SYNTHESIS OF SULPHONAMIDE DERIVATIVES
3649
Scheme 1. Synthesis of compound 3.
in the preparation of organic pentaerythrityltetramine. The low yields of
sulphonamide-derivative represent major drawbacks of this approach. Therefore,
the development of simple, efficient, and generally synthetic routes using available
reagents remains important.
Here we wish to report a novel and highly efficient procedure for the synthesis
of sulphonamide derivatives in the presence of NMP solution (Scheme 1).
RESULTS AND DISCUSSION
During the careful investigations, this type of reaction is very sensitive to
temperature, the ratio of reactants, reaction time, and solvent. We firstly investigated
the temperature effect on the yield of compound 3. The corresponding
tetrasulphonamido-derivative 3a could not be afforded at 190 ꢀC in NMP solution
after 8 h, whereas 3a was produced in 92% yield at 204 ꢀC in the same time.
Moreover, the ratio of reactants plays a very important role in synthesis of the target
compounds. Figure 1a shows the yield curves for TBrMP with SPTPA in different
ratio. The molar of TBrMP was kept constant and the yield of compound 3a was
followed as a function of increasing molar of SPTPA. When the molar of sodium salt
was increased from 50% to 67%, the obtained yields were 30% and 92%, respectively.
Figure 1. (a) The yield curves for TBrMP with SPTPA in different ratio. (b) Time dependent yield
measurement for TBrMP with SPTPA.

3650
Y. TAN ET AL.
Table 1. Synthesis of compound 3
Entry Compound 1 (R¼)
Compound 2
Solvent
Temp. (ꢀC) T.M. Yielda (%)
1
2
4-CH3-
4-CH3-
4-CH3-
4-CH3-
4-CH3-
4-CH3-
4-CH3-
4-CH3-
4-CH3-
4-CH3-
TBrMP
TBrMP
TBrMP
NMP
DMF
204
152
165
189
210
210
140
20
3a
92
trace
trace
0
3
DMAc
DMSO
DEG
4
TBrMP
TBrMP
TBrMP
5
0
6
NMP=DEG
NMP
NMP
0
85
7
1-bromodecane
1,3-dibromopropane
1,4-dibromomethyl benzene
1-bromo-2,2-dibromo
Methyl-butane
TBrMP
3b
3c
3d
3e
8
95
95
9
10
NMP
NMP
20
204
85
11
12
13
4-H-
4-CH3O-
4-Cl-
NMP
NMP
NMP
204
204
204
3f
3g
3h
67
93
0
TBrMP
TBrMP
aYields refer to pure isolated products.
With further addition of sodium salt to the reaction mixture, the yield (90%)
was slightly decreased. The observation might result from the carbonized sodium
p-toluenesulphonamide and the interaction of solvent and SPTPA as a strong
base at high temperature. These results also indicated the optimal ratio was 1:2
([TBrMP]:[SPTPA]). The time dependence of yields was investigated as shown in
Figure 1b. The yield increased gradually with increasing reaction time and reached
a constant value at 8 h. Shorter or longer reaction time gave the lower yields of 3a.
Various solvents were tested for the reaction of TBrMP and sodium salt at high
temperature, and selected examples were summarized in Table 1 (entries 1–6). The
reaction in the presence of NMP solution afforded the desired product 3a in high
yield (entry 1). However, when performing in N,N-dimethylformamide (DMF) or
N,N-dimethylacetamide (DMAc) solution at refluxed temperature, the trace yields
were observed as determined by TLC analysis (entries 2 and 3). The above results
suggested that the low activity energy deactivated the reaction in DMF or DMAc
solution. As a comparison, compound 3a could not be obtained in diethylene glycol
(DEG) or NMP=DEG solution, which might result from the nucleophilic compe-
tition of hydroxy and amino groups. Among the conditions tested, the reaction in
NMP solution gave the best yield and this was selected as the optimal condition
in the following experiments.
In NMP solution, the desired products (3b, 3c, 3d, 3e, 3f, 3g) were afforded in
excellent yields and high purities (entries 7, 8, 9, 10, 11, and 12). This reaction con-
dition was also applicable to other aromatic salts even in the presence of other func-
tionalities such as hydrogen, methoxyl groups (Table 1, entries 11 and 12). It should
be noted that condensation of the aromatic salt with electron-withdrawing units
(entry 13, -Cl) with TBrMP could not afford the target compound (3h). All the pro-
1
ducts were characterized by H NMR, 13C NMR, FT-IR, and elemental analysis,
which were shown to be in full agreement with the structures presented.
In summary, this article describes a facile synthesis of sulphonamide deriva-
tives in the presence of NMP. The method offers several advantages including very

SYNTHESIS OF SULPHONAMIDE DERIVATIVES
3651
high yields, cleaner reactions, inexpensive solvent, and ease of isolation of the
products which makes the process convenient.
EXPERIMENTAL
Melting points were taken on a TX-4 hot stage apparatus and are uncorrected.
1H NMR and 13C NMR spectra were obtained on Bruker 400 spectrometers using
CDCl3 as a solvent with tetramethylsilane (TMS) as the internal standard. Infrared
(IR) spectra were measured on a Nicolet 380 instrument. Elemental analyses were
carried out on a Carlo Erba 1106 elemental analyzer.
General Procedure for the Preparation of Compound 3
Compound 3a. A mixture of sodium p-toluenesulphonamide (35.82 g,
185.6 mmol) and 1,3-dibromo-2,2-bis(bromomethyl)propane (9.0 g, 23.2 mmol) in
NMP (30 mL) was stirred for 8 h at refluxed temperature. After cooling down to
room temperature, ice-water (1 L) was added and the precipitate was filtered off
and carefully dried. The crude solid was purified on silica gel column using pet-
roleum ether=ethyl acetate (3:2, v=v). The product was obtained as white solid
(92%). Mp: 255–256 ꢀC; FT-IR (KBr): 3309, 3062, 2922, 1597, 1451, 1329, 1281,
1159, 660, 552 cmꢁ1
;
1H NMR (400 MHz, CDCl3, 298 K, TMS): d ¼ 7.69 (d,
J ¼ 8.0 Hz, 8H), 7.31 (d, J ¼ 8.0 Hz, 8H), 5.79 (t, 4H), 2.70 (s, 8H), 2.43 (s, 12H);
13C NMR (100 MHz, CDCl3, 298 K): d ¼ 141.2, 136.7, 129.0, 127.2, 40.2, 32.9,
24.3; Anal. Calcd. for C33H40N4O8S4: C, 52.92; H, 5.38; N, 7.48; O, 17.09; S,
17.13. Found: C, 52.93; H, 5.39; N, 7.49; O, 17.05; S, 17.14. Compound 3a was pre-
pared in other solvents (DMF, DMAc, DMSO, DEG, NMP=DEG) according to
this typical method.
Compound 3b. A mixture of sodium p-toluenesulphonamide (1.73 g,
9.0 mmol) and 1-bromodecane (1.0 g, 4.5 mmol) in NMP (20 mL) was stirred for
8 h at 140 ꢀC. After cooling down to room temperature, ice-water (200 mL) was
added and the precipitate was filtered off and carefully dried. The crude solid was
purified on silica gel column using petroleum ether=ethyl acetate (2:1, v=v). The pro-
duct was obtained as white solid (85%). Mp: 120–121 ꢀC; FT-IR (KBr): 3486, 3284,
2922, 2852, 1458, 1323, 1158, 1094, 813, 663, 550 cmꢁ1; 1H NMR (400 MHz, CDCl3,
298 K, TMS): d ¼ 7.74 (d, J ¼ 8.0 Hz, 2H), 7.30 (d, J ¼ 8.0 Hz, 2H), 4.23 (s, 1H), 2.93
(q, 2H), 2.43 (s, 3H), 1.44 (m, 2H), 1.23 (m, 14H), 0.88 (t, 3H); 13C NMR (100 MHz,
CDCl3, 298 K): d ¼ 141.2, 136.7, 129.2, 127.2, 40.3, 32.0, 29.7, 29.5, 29.3, 26.9, 24.4,
23.2, 14.1; Anal. Calcd. for C17H29NO2S: C, 65.55; H, 9.38; N, 4.50; O, 10.27; S,
10.29. Found: C, 65.53; H, 9.38; N, 4.53; O, 10.27; S, 10.29.
Compound 3c. A mixture of sodium p-toluenesulphonamide (3.83 g,
19.8 mmol) and 1,3-dibromopropane (1.0 g, 4.95 mmol) in NMP (20 mL) was stirred
for 8 h at 20 ꢀC. After cooling down to room temperature, ice-water (200 mL) was
added and the precipitate was filtered off and carefully dried. The crude solid was
purified on silica gel column using petroleum ether=ethyl acetate (2:1, v=v). The pro-
duct was obtained as white solid (95%). Mp: 188–189 ꢀC; FT-IR (KBr): 3485, 2995,
1
2915, 2872, 1594, 1445, 1344, 1162, 1131, 953, 819, 669, 609, 548 cmꢁ1; H NMR

3652
Y. TAN ET AL.
(400 MHz, CDCl3, 298 K, TMS): d ¼ 7.73 (d, J ¼ 8.0 Hz, 4 H), 7.37 (d, J ¼ 8.0 Hz,
4H), 3.77 (t, 4H), 2.46 (s, 6H), 2.06 (m, 2H); 13C NMR (100 MHz, CDCl3, 298 K):
d ¼ 141.1, 136.7, 129.2, 127.2, 33.9, 26.9, 23.9; Anal. Calcd. for C17H22N2O4S2: C,
53.38; H, 5.80; N, 7.32; O, 16.73; S, 16.77. Found: C, 53.36; H, 5.81; N, 7.30; O,
16.75; S, 16.78.
Compound 3d. A mixture of sodium p-toluenesulphonamide (4.52 g,
23.4 mmol) and 1,4-dibromomethyl benzene (1.54 g, 5.8 mmol) in NMP (20 mL)
was stirred for 8 h at 20 ꢀC. Ice-water (200 mL) was added and the precipitate was
filtered off and carefully dried. The crude solid was purified on silica gel column
using petroleum ether=ethyl acetate (4:1, v=v). The product was obtained as white
solid (95%). Mp: 134–135 ꢀC; FT-IR (KBr): 3425, 3242, 2919, 2865, 1652, 1592,
1
1455, 1439, 1239, 1148, 1068, 970, 827, 649 cmꢁ1; H NMR (400 MHz, CDCl3,
298 K, TMS): d ¼ 7.70 (d, J ¼ 8.4 Hz, 4H), 7.32 (d, J ¼ 8.4 Hz, 4H), 7.06 (s, 4H),
5.79 (t, J ¼ 8.0 Hz, 2H), 4.44 (s, 4H), 2.42 (s, 6H);13C NMR (100 MHz, CDCl3,
298 K): d ¼ 141.1, 139.7, 136.8, 129.5, 128.1, 126.9, 46.2, 24.3; Anal. Calcd. for
C22H24N2O4S2: C, 59.44; H, 5.44; N, 6.30; O, 14.40; S, 14.43. Found: C, 59.46; H,
5.44; N, 6.28; O, 14.39; S, 14.43.
Compound 3e. A mixture of sodium p-toluenesulphonamide (3.60 g,
18.6 mmol) and 1-bromo-2,2-di(bromomethyl)-butane (1.0 g, 3.1 mmol) in NMP
(20 mL) was stirred for 8 h at refluxed temperature. After cooling down to room tem-
perature, ice-water (200 mL) was added and the precipitate was filtered off and care-
fully dried. The crude solid was purified on silica gel column using petroleum ether=
ethyl acetate (3:2, v=v). The product was obtained as white solid (85%). Mp:
250–252 ꢀC; FT-IR (KBr): 3524, 3354, 2928, 1654, 1620, 1415, 1239, 1148, 970,
1
927, 847, 805, 664 cmꢁ1; H NMR (400 MHz, CDCl3, 298 K, TMS): d ¼ 7.75 (d,
J ¼ 8.0 Hz, 6H), 7.31 (d, J ¼ 8.0 Hz, 6H), 5.79 (t, J ¼ 7.2 Hz, 3H), 2.70, (s, 6H),
2.43 (s, 9H), 1.25 (q, 2H), 0.88 (t, J ¼ 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3,
298 K): d ¼ 141.1, 136.7, 129.2, 127.2, 42.3, 32.8, 24.3, 23.5, 8.8; Anal. Calcd. for
C27H35N3O6S3: C, 54.61; H, 5.94; N, 7.08; O, 16.17; S, 16.20. Found: C, 54.61; H,
5.95; N, 7.09; O, 16.16; S, 16.29.
Compound 3f. A mixture of sodium phenylsulphonamide (4.3 g, 24.0 mmol)
and TBrMP (1.15 g, 2.96 mmol) in NMP (30 mL) was stirred for 8 h at refluxed tem-
perature. After cooling down to room temperature, ice-water (200 mL) was added
and the precipitate was filtered off and carefully dried. The crude solid was purified
on silica gel column using petroleum ether=ethyl acetate (4:1, v=v). The product was
obtained as white solid (67%). Mp: 237–238 ꢀC; FT-IR (KBr): 3442, 2955, 2932,
1
2853, 1641, 1558, 1457, 1399, 1377, 1334, 1156, 1091, 812, 655 cmꢁ1; H NMR
(400 MHz, CDCl3, 298 K, TMS): d ¼ 7.83 (d, J ¼ 7.2 Hz, 8H), 7.54–7.63 (m, 12H),
5.88 (t, J ¼ 7.2 Hz, 4H), 2.72 (s, 8H); 13C NMR (100 MHz, CDCl3, 298 K):
d ¼ 139.7, 132.1, 129.1, 127.3, 40.2, 32.8; Anal. Calcd. for C29H32N4O8S4: C,
50.27; H, 4.66; N, 8.09; O, 18.47; S, 18.51. Found: C, 50.26; H, 4.64; N, 8.09; O,
19.49; S, 18.51.
Compound 3g. A mixture of sodium (4-methoxyphenylsulfonyl)amide
(5.05 g, 24.2 mmol) and TBrMP (1.16 g, 3.0 mmol) in NMP (30 mL) was stirred for
6 h at refluxed temperature. After cooling down to room temperature, ice-water

SYNTHESIS OF SULPHONAMIDE DERIVATIVES
3653
(200 mL) was added and the precipitate was filtered off and carefully dried. The
crude solid was purified on silica gel column using petroleum ether=ethyl acetate
(5:1, v=v). The product was obtained as white solid (93%). Mp: 235–238 ꢀC; FT-IR
(KBr): 3441, 3262, 2919, 1853, 1652, 1455, 1401, 1321, 1154, 1086, 811, 659, 549 cmꢁ1
;
1H NMR (400 MHz, CDCl3, 298 K, TMS): d ¼ 7.83 (d, J ¼ 7.2 Hz, 8 H), 7.59 (d,
J ¼ 7.2 Hz, 8H), 5.80 (t, J ¼ 7.6 Hz, 4H), 3.74 (s, 12H), 2.70 (s, 8H); 13C NMR
(100 MHz, CDCl3, 298 K): d ¼ 161.9, 132.0, 128.1, 114.4, 55.9, 40.5, 33.1; Anal.
Calcd. for C33H40N4O12S4: C, 48.75; H, 4.96; N, 6.89; O, 23.62; S, 15.78. Found:
C, 48.75; H, 4.96; N, 6.89; O, 23.63; S, 15.78.
ACKNOWLEDGMENT
This work was supported by National Natural Science Foundation (20574016).
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