Ultrasound-promoted solvent-free aza-Michael addition of p-toluenesulfonamide to fumaric esters by potassium carbonate: Synthesis of p-toluenesulfonamide derivatives

Article abstract of DOI:10.1016/j.ultsonch.2012.09.003

An efficient, mild, inexpensive and eco-friendly protocol for the synthesis of p-toluenesulfonamide derivatives by aza-Michael addition reaction of p-toluenesulfonamide to fumaric esters using potassium carbonate under ultrasound irradiation was developed

Full text of DOI:10.1016/j.ultsonch.2012.09.003

Ultrasonics Sonochemistry 20 (2013) 722–728
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Ultrasound-promoted solvent-free aza-Michael addition of p-toluenesulfonamide
to fumaric esters by potassium carbonate: Synthesis of p-toluenesulfonamide
derivatives
⇑
Gholamhassan Imanzadeh , Fatemeh Kazemi, Mohammadreza Zamanloo, Yagoub Mansoori
Department of Chemistry, College of Science, University of Mohaghegh Ardabili, 56199-11367 Ardabil, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2011
Received in revised form 31 July 2011
Accepted 1 August 2012
Available online 26 September 2012
An efficient, mild, inexpensive and eco-friendly protocol for the synthesis of p-toluenesulfonamide deriv-
atives by aza-Michael addition reaction of p-toluenesulfonamide to fumaric esters using potassium car-
bonate under ultrasound irradiation was developed. This method is simple, convenient and the desired
compounds are produced in good to excellent yield. The bulkiness of alkoxy group (–OR) of fumaric esters
did not affect significantly on the yields and reaction times. This reaction worked well on linear and non-
linear alkyl fumarates. The reaction, surprisingly, was not successful on methyl fumarate. In this case
methyl fumarate has been hydrolyzed to fumaric acid under reaction conditions.
Keywords:
Ultrasound
Solvent-free
Ó 2012 Elsevier B.V. All rights reserved.
Aza-Michael addition
p-Toluenesulfonamide
Fumaric esters
Potassium carbonate
1. Introduction
tion of sulfonamides to acrylates in the presence of potassium
carbonate and tetrabutylamonium bromide (TBAB) under micro-
Sulfonamides exhibit a wide spectrum of biological activities
[1–4]. They are used as antibacterial, anticonvulsant, anticancer,
anti-inflammatory, and antiviral agents [5–7]. These compounds
are also used as herbicides [8] and plaguicides [9]. It has been re-
ported that the some of sulfonamide derivatives are antihyperten-
sive agent bosentan [9], HIV protease inhibitors [10], and the
phosphodiesterase-5 inhibitor sildenafi [11]. Sulfonamides have
been also applied in the prevention of diabetes mellitus, oedema,
hypertension and gout [12]. It has been well established that
sulfonamides have antiproliferative [13] and antimalarial [14]
properties. Besides clinical uses, sulfonamides have been em-
ployed, to construct molecular recognition molecules [15], and
for organocatalysts for Michael and aldol reactions [16]. These
compounds and their derivatives are prepared by various synthetic
methods [17–22]. Among these methods the most classically
method involves the nucleophilic attack of ammonia, primary
amines, and secondary amines to sulfonyl chlorides, but the most
untraditionally method, which is scarce in literature [23], involves
wave irradiation [24]. Herein, we report another method for
preparing of a new series of these compounds by the aza-Michael
addition of p-toluenesulfonamide to fumaric esters by using potas-
sium carbonate, a cheap and green base under ultrasound irradia-
tion conditions. Although potassium carbonate accompanied with
ionic liquid 1-butyl-3-methylimidazolium bromide has been used
previously for Michael addition of sulfonamides to acrylates, not
to fumarates [25], but in presence work we employed this base
in Michael addition of sulfonamides on fumarates in the absence
of ionic liquid media under ultrasound irradiation, which surpris-
ingly no other references available in the literature reported to
date (Scheme 1).
2. Experimental
2.1. General
the use of aza-Michael addition of sulfonamides to a,b-unsaturated
All alkyl fumarates were synthesized in our laboratory accord-
ing to the literature procedure [26] and their structures were con-
firmed by IR and 1H NMR spectroscopy. The progress of the
reactions was followed by TLC using silica gel SILIG/UV 254 plates.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a Bruker 300 MHz instrument. FT-IR spectra were recorded on a
Perkin-Elmer RX-1 instrument. Mass spectra were recorded on a
compounds. For these reasons and for mentioned advantages of
sulfonamide derivatives, recently, we reported a very efficient
method for synthesis of sulfonamide derivatives by addition reac-
⇑
Corresponding author. Tel.: +98 451 5514701; fax: +98 451 5514702.
E-mail address: imanzad2000@yahoo.com (G. Imanzadeh).
1350-4177/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ultsonch.2012.09.003

G. Imanzadeh et al. / Ultrasonics Sonochemistry 20 (2013) 722–728
723
CH3
O
S
O
O
S
NH
O
H3C
NH2
O
R
O
+
K2CO3
O
R
R
O
O
O
R
O
U.S
1
Solvent Free
O
2a-2r
3a-3r
Scheme. 1. Synthetic pathway of sulfonamides 3a-3r.
Shimadzu GC–MS-QP 1000PX. Elemental analysis for C, H, and N
were performed using a Heraeus CHN–O-Rapid analyzer. The
melting points were determined in open capillaries with a Stuart
Melting Point Apparatus and are uncorrected.
Sonication was performed in a Parsonic 2600s ultrasonic bath,
with a frequency of 28 kHz and a power 500 W was used for ultra-
sonic irradiation.
J = 8.1 Hz, J = 5.1 Hz, J = 4.2 Hz, 1H), 5.63 (d, J = 8.1 Hz, 1H), 7.30
(d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 10.13, 10.28, 21.50, 21.64, 21.82, 37.96, 52.19,
66.75, 67.73, 127.23, 129.65, 136.86, 143.65, 169.98, 170.23. MS
(EI, 70 eV) m/z (%): 372 (M+ + 1, 1.81) 284 (100.00), 242 (13.51),
224 (11.38), 216 (13.02), 155 (46.88), 91 (58.65), 65 (11.25), 43
(24.11), 41 (11.37). Analysis calculated for C17H25NO6S: C, 54.97;
H, 6.78; N, 3.77. Found C, 54.88; H, 6.69; N, 3.71.
2.1.1. General procedure under conventional conditions (method A)
To a well ground mixture of p-toluenesulfonamide (3 mmol)
and K2CO3 (3 mmol) was added fumaric esters (3 mmol) and mixed
thoroughly with a glass rod. The resulting mixture was kept in an
oil bath at 53 °C for appropriate time (Table 2). The progress of
reaction was monitored by TLC. After completion of reaction the
mixture was suspended in chloroform (45 mL), filtered and the fil-
trate was washed with water (3 Â 20 ml) and dried with MgSO4.
The solvent was removed under reduced pressure and the resulting
crude material was purified on short silica-gel column with ethyl
acetate/n-hexane (1:9) as the eluent.
2.1.2.3. Dibutyl 2-(tosylamino)succinate (3d). White Solid, mp 81–
82 °C. FT-IR (KBr) 3278, 2962, 1733, 1599, 1345, 1281, 1187,
1168, 820, 562 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz), d ppm 0.88
.
(t, J = 7.5 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H), 1.20–1.57 (m, 8H), 2.42
(s, 3H), 2.83 (dd, J = 17.0 Hz, J = 5.1 Hz, 1H), 2.97 (dd, J = 17.0 Hz,
J = 4.5 Hz, 1H), 3.99–4.17 (m, 5H), 5.64 (d, J = 7.2 Hz, 1H), 7.40 (d,
J = 8.1 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 13.57, 13.64, 18.87, 19.03, 21.52, 30.25, 30.47,
37.97, 52.18, 65.05, 66.02, 127.23, 129.66, 136.84, 143.64, 169.98,
170.26. MS (EI, 70 eV) m/z (%): 400 (M+ + 1, 1.14), 298 (100.00),
284 (3.32), 242 (16.77), 224 (9.39), 155 (37.77), 91 (43.60), 70
(11.26), 41 (2.43). Analysis calculated for C19H29NO6S: C, 57.12;
H, 7.32; N, 3.51. Found C, 57.18; H, 7.25; N, 3.60.
2.1.2. General procedure under sonochemical conditions (method B)
To a well ground mixture of p-toluenesulfonamide (1.5 mmol)
and K2CO3 (1.5 mmol) was added fumaric esters (1.5 mmol) and
mixed thoroughly with a glass rod. The mixture was irradiated in
the water bath of an ultrasonic cleaner at 53 °C. In order to control
the temperature of the water bath, addition or removal water tech-
nique was used. After completion of reaction the mixture was sus-
pended in chloroform (30 mL), filtered and the filtrate was washed
with water (3 Â 15 ml) and dried with MgSO4. The solvent was re-
moved under reduced pressure and the resulting crude material
was purified on short silica-gel column with ethyl acetate/n-hexane
(1:9) as the eluent.
2.1.2.4. Dipentyl 2-(tosylamino)succinate (3e). White Solid, mp 51–
53 °C. FT-IR (KBr) 3286, 2957, 1739, 1600, 1346, 1188, 1167,
1119, 1049, 815, 568 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz), d
.
ppm 0.89 (t, J = 6.9 Hz, 3H), 0.93 (t, J = 6.6 Hz, 3H), 1.16–1.33 (m,
8H), 1.50 (quintet, J = 6.9 Hz, 2H), 1.61 (quintet, J = 6.9 Hz, 2H),
2.43 (s, 3H), 2.84 (dd, J = 17.4 Hz, J = 4.8 Hz, 1H), 2.96 (dd,
J = 17.4 Hz, J = 4.5 Hz, 1H)
, 3.99 (t, J = 6.9 Hz, 2H), 4.05 (t,
J = 6.6 Hz, 2H), 4.13 (ddd , J = 8.1 Hz, J = 4.8 Hz, J = 4.5 Hz, 1H),
5.62 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz,
2H). 13C NMR (CDCl3, TMS, 75 MHz), d ppm 13.85, 13.90, 21.51,
22.17, 22.25, 27.76, 27.93, 28.14, 37.98, 52.19, 65.34, 66.31,
127.23, 129.65, 136.88, 143.62, 169.96, 170.24. MS (EI, 70 eV)
m/z (%): 428 (M+ + 1, 2.1), 382 (5.53), 312 (100.00), 272 (14.70),
242 (19.94), 224 (8.04), 155 (35.21), 91 (43.80), 70 (2.22), 43
(4.16), 41 (4.96). Analysis calculated for C21H33NO6S: C, 58.99; H,
7.78; N, 3.28. Found C, 58.92; H, 7.78; N, 3.38.
2.1.2.1. Diethyl 2-(tosylamino)succinate (3b). White Solid, mp 73–
75 °C. FT IR (KBr) 3282, 2984, 1733, 1599, 1344, 1280, 1193,
1167, 1091, 956, 815, 555 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz),
.
d ppm 1.13 (t, J = 7.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), 2.42 (s, 3H),
2.83 (dd, J = 17.1 Hz, J = 4.8 Hz, 1H), 2.96 (dd, J = 17.1 Hz,
J = 4.2 Hz, 1H), 4.10–4.30 (m, 5H), 5.64 (d, J = 7.8 Hz, 1H), 7.30 (d,
J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 13.82, 14.06, 21.51, 37.99, 52.20, 61.15, 62.17,
127.24, 129.65, 133.62, 136.85, 169.91, 170.15. MS (EI, 70 eV) m/
z (%): 344 (M+ + 1, 2.49), 270 (100.00), 224 (15.22), 188 (9.72),
155 (43.89), 91 (54.07), 70 (5.63), 65 (10.93). Analysis calculated
for C15H21NO6S: C, 52.46; H, 6.16; N, 4.08. Found C, 52.55; H,
6.24; N, 4.13.
2.1.2.5. Dihexyl 2-(tosylamino)succinate (3f). White Solid, mp 49–
52 °C. FT-IR (KBr) 3289, 2954, 1745, 1600, 1457, 1342, 1187,
1123, 1092, 815 , 567 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz), d
.
ppm 0.87–0.91 (m, 6H), 1.24–1.31 (m, 12H), 1.47–1.60 (m, 4H),
2.43 (s, 3H), 2.84 (dd, J = 16.8 Hz, J = 4.8 Hz, 1H), 2.97 (dd,
J = 16.8 Hz, J = 4.5 Hz, 1H), 3.99 (t, J = 6.9 Hz, 2H), 4.05 (t,
J = 7.2 Hz, 2H), 4.14 (ddd, J = 7.8 Hz, J = 4.8 Hz, J = 4.5 Hz, 1H), 5.62
(d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 HZ, 2H), 7.76 (d, J = 8.1 Hz, 2H).
13C NMR (CDCl3, TMS, 75 MHz), d ppm 13.95, 21.52, 22.45, 22.49,
25.31, 25.48, 28.20, 28.42, 31.29, 31.37, 37.98, 52.18, 65.37,
66.33, 127.24, 129.66, 136.86, 143.62, 169.97, 170.25. MS (EI,
70 eV) m/z (%): 456 (M+ + 1) (2.36), 326 (100.00), 300 (12.99),
242 (17.94), 224 (5.40), 155 (25.54), 91 (28.31), 70 (7.62), 43
2.1.2.2. Dipropyl 2-(tosylamino)succinate (3c). White Solid, mp 79–
81 °C. FT-IR (KBr) 3283, 2968, 1733, 1598, 1343, 1279, 1189,
1169, 1092, 812, 561 cmÀ1 1H NMR (CDCl3), d 0.84 (t, J = 7.5 Hz,
.
3H), 0.93 (t, J = 7.2 Hz, 3H), 1.50–1.65 (m, 4H), 2.42 (s, 3H), 2.84
(dd, J = 16.8 Hz, J = 5.1 Hz, 1H), 2.97 (dd, J = 16.8 Hz, J = 4.2 Hz,
1H), 3.94 (t, J = 7.5 Hz, 2H), 4.01 (t, J = 7.2 Hz, 2H), 4.15 (ddd,

724
G. Imanzadeh et al. / Ultrasonics Sonochemistry 20 (2013) 722–728
(15.66), 41 (5.93). Analysis calculated for C23H37NO6S: C, 60.63; H,
8.19; N, 3.07. Found C, 60.55; H, 8.13; N, 3.14.
1168, 1118, 1092, 816, 675, 567 cmÀ1 1H NMR (CDCl3, TMS,
.
300 MHz), d ppm 0.84 (d, J = 6 Hz, 6H), 0.89 (d, J = 6.6 Hz, 6H),
1.36 (q, J = = 7.2 Hz, 2H), 1.48 (q, J = 6.9 Hz, 2H), 1.51–1.66 (m,
2H), 2.40 (s, 3H), 2.80 (dd, J = 16.9 Hz, J = 5.1 Hz, 1H), 2.93 (dd,
J = 16.9 Hz, J = 4.5 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 4.07 (t,
J = 6.6 Hz, 2H), 4.13 (ddd, J = 8.1 Hz, J = 5.1 Hz, J = 4.5 Hz, 1H), 5.68
(d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H).
13C NMR (CDCl3, TMS ,75 MHz), d ppm 21.48, 22.25, 22.30, 24.82,
24.96, 36.87, 37.11, 37.96, 52.20, 63.84, 64.80, 127.21, 129.63,
136.92, 143.57, 169.95, 170.21. Ms. m/z (%): 428 (M+ + 1) (1.06),
312 (100.00), 272 (12.26), 242 (17.43), 224 (5.99), 155 (29.48),
91 (37.27), 71 (10.59), 43 (26.68). Analysis calculated for C21H33NO6S:
C, 58.99; H, 7.78; N, 3.28. Found C, 58.91; H, 7.69; N, 3.31.
2.1.2.6. Dioctyl 2-(tosylamino)succinate (3g). White Solid, mp 49–
50 °C. FT-IR (KBr) 3291, 2924, 1747, 1342, 1292, 1093, 815, 679,
542 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz),
. d ppm 0.89 (t,
J = 7.0 Hz, 6H), 1.26–1.60 (m, 24H), 2.43 (s, 3H), 2.84 (dd,
J = 16.8 Hz, J = 4.8 Hz, 1H), 2.97 (dd, J = 16.8 Hz, J = 4.2 Hz, 1H),
4.01 (t, J = 6.6 Hz, 2H) 4.05 (t, J = 6.9 Hz, 2H), 4.15 (ddd, J = 7.8 Hz,
J = 4.8 Hz, J = 4.2 Hz, 1H), 5.62 (d, J = 7.8 Hz, 1H), 7.30 (d,
J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 14.05, 21.52, 22.61, 25.65, 25.82, 28.25, 28.46,
29.10, 29.17, 31.75, 37.98, 52.19, 65.37, 66.33, 127.23, 129.65,
136.89, 143.60, 169.96, 170.24. Ms. m/z (%): 512 (M+ + 1) (1.16),
400 (1.73), 354 (100.00), 242 (16.99), 224 (4.39), 155 (20.24), 91
(21.94), 70 (4.39), 57 (8.67), 43 (11.4). Analysis calculated for
2.1.2.11. Bis(2-methylbutyl) 2-(tosylamino)succinate (3l). White So-
lid, mp 57–61 °C. FT-IR (KBr) 3288, 2965, 1600, 1343, 1194,
C27H45NO6S: C, 63.37; H, 8.86; N, 2.74. Found C, 63.42; H, 8.91;
1169, 819, 674, 566 cmÀ1 1H NMR (CDCl3, TMS, 300 M Hz), d
.
N, 2.78.
ppm 0.76–0.90 (m, 12H), 1.05–1.42 (m, 4H), 1.53–1.68 (m, 2H),
2.39 (s, 3H), 2.82 (dd, J = 17.1 Hz, J = 5.1 Hz, 1H), 2.95 (dd,
J = 17.1 Hz, J = 4.5 Hz, 1H), 3.74–3.96 (m, 4H), 4.14 (ddd,
J = 8.1 Hz, J = 5.1 Hz, J = 4.5 Hz, 1H), 5.69 (d, J = 8.1 Hz, 1H), 7.27
(d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 11.01, 11.10, 16.10, 16.27, 21.46, 25.72, 25.89,
33.84, 33.95, 37.89, 52.17, 69.76, 70.69, 127.19, 129.64, 136.90,
143.58, 169.98, 170.25. Ms. m/z (%): 428 (M+ + 1. 2.41) 312
(100.00), 272 (16.47), 242 (52.72), 155 (41.59), 91 (48.93), 70
(23.28), 43 (57.43). Analysis calculated for C21H33NO6S: C, 58.99;
H, 7.78; N, 3.28. Found C, 58.84; H, 7.83; N, 3.19.
2.1.2.7. Didecyl 2-(tosylamino)succinate (3h). White Solid, mp 42–
43 °C. FT-IR (KBr) 3291, 2925, 1747, 1468, 1341, 1292, 1165,
1123, 1093, 815, 678, 542 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz),
.
d ppm 0.89 (t, J = 6.9 Hz, 6H), 1.28–1.60 (m, 32H), 2.43 (s, 3H),
2.83 (dd, J = 16.8 Hz, J = 4.8 Hz, 1H), 2.97 (dd, J = 16.8 Hz,
J = 4.5 Hz, 1H), 3.96 (t, J = 6.9 Hz, 2H), 4.03 (t, J = 6.6 Hz, 2H), 4.12
(ddd, J = 8.4 Hz, J = 4.8 Hz, J = 4.5 Hz, 1H), 5.63 (d, J = 8.4 Hz, 1H),
7.21 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3,
TMS, 75 MHz), d ppm 13.84, 21.51, 22.66, 25.66, 25.82, 28.26,
28.47, 29.15, 29.22, 29.28, 29.47, 29.50, 29.51, 31.87, 37.98,
52.19, 65.37, 66.33, 127.23, 129.66, 136.89, 143.60, 169.96,
170.24. Ms. m/z (%): 568 (M+ + 1) (3.27), 428 (2.68), 412 (18.92),
342 (100.00), 242 (14.12), 155 (18.83), 91 (20.66), 70 (8.67), 57
(10.60), 43 (14.81). Analysis calculated for C31H53NO6S: C, 65.57;
H, 9.41; N, 2.47. Found C, 65.49; H, 9.37; N, 2.54.
2.1.2.12. Bis(2-ethylhexyl) 2-(tosylamino)succinate (3m). Viscous
colorless oil. FT-IR (Neat) 3284, 2960, 1740, 1599, 1462, 1346,
1165, 1093, 814, 664, 562 cmÀ1 1H NMR (CDCl3, TMS, 300 M Hz),
.
d ppm 0.81 (t, J = 7.5 Hz, 6 Hz), 0.87 (t, J = 6.9 Hz, 6H), 1.16–1.37
(m, 16H), 1.40–1.55 (m, 2H), 2.40 (s, 3H), 2.83 (dd, J = 17.1 Hz,
J = 4.9 Hz, 1H), 2.95 (dd, J = 17.1 Hz, J = 4.2 Hz, 1H), 3.88–3.98 (m,
4H), 4.13 (ddd, J = 8.2 Hz, J = 4.9 Hz, J = 4.2 Hz, 1H), 5.67 (d,
J = 8.2 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H). 13C
NMR (CDCl3, TMS, 75 MHz), d ppm 10.79, 10.87, 13.96, 13.97,
21.47, 22.86, 22.90, 23.49, 23.64, 28.76, 28.85, 30.07, 30.10,
37.91, 38.52, 38.61, 52.15, 67.61, 68.47, 127.19, 129.64, 136.91,
143.56, 170.01, 170.29. Ms. m/z (%): 512 (M+ + 1, 3.67), 354
(100.00), 288 (4.26), 242 (65.33), 155 (32.04), 91 (37.24), 70
(21.18), 57 (42.68), 43 (25.17), 41 (16.43). Analysis calculated for
2.1.2.8. Didodecyl 2-(tosylamino)succinate (3i). White Solid, mp 57–
59 °C. FT-IR (KBr) 3292, 2956, 2851, 1749, 1600, 1468, 1340, 1292,
1165, 1123, 1093, 816, 679, 544 cmÀ1 1H NMR (CDCl3, TMS,
.
300 MHz), d ppm 0.89 (t, J = 6.9 Hz, 6H), 1.18–1.39 (m, 40H), 2.43
(s, 3H), 2.86 (dd, J = 16.9 Hz, J = 4.8 Hz), 2.94 (dd, J = 16.9 Hz,
J = 4.5 Hz), 3.96–4.13 (m, 5H), 5.63 (d, J = 7.8 Hz, 1H), 7.30 (d,
J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 14.07, 21.51, 22.66, 25.66, 25.73, 28.26, 28.47,
29.15, 29.23, 29.32, 29.42, 29.47, 29.50, 29.57, 29.61, 29.63,
31.90, 37.98, 52.19, 65.38, 66,33, 127.23, 129.64, 136.90, 143.59,
169.96, 170.23. Analysis calculated for C35H61NO6S: C, 67.38; H,
9.85; N, 2.24. Found C, 67.34; H, 9.78; N, 2.29.
C27H45NO6S: C, 63.37; H, 8.86; N, 2.74. Found C, 63.41; H, 8.92;
N, 2.65.
2.1.2.13. Diisopropyl 2-(tosylamino)succinate (3n). White Solid, mp
89–90 °C. FT-IR (KBr) 3287, 2984, 1743, 1600, 1333, 1043, 815,
2.1.2.9. Diisobutyl 2-(tosylamino)succinate (3j). White Solid, mp 67–
71 °C. FT-IR (KBr) 3291, 2962, 1740, 1598, 1473, 1344, 1284, 1122,
1091, 1048, 819, 672, 565 cmÀ1. 1H NMR (CDCl3, TMS, 300 MHz), d
ppm 0.82 (d, J = 6.6 Hz, 6H), 0.89 (d, J = 6.9 Hz, 6H), 1.74–1.92 (m,
2H), 2.40 (s, 3H), 2.84 (dd, J = 16.9 HZ, J = 4.8 Hz, 1H), 2.97 (dd,
J = 16.9 Hz, J = 4.5 Hz, 1H), 3.77 (d, J = 6 Hz, 2H), 3.83 (d,
J = 6.9 Hz, 2H), 4.15 (ddd, J = 8.1 Hz, J = 4.8 Hz, J = 4.5 Hz, 1H), 5.69
(d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H).
13C NMR (CDCl3, TMS ,75 MHz), d ppm 18.81, 18.98, 21.48, 27.47,
27.56, 37.89, 52.16, 71.22, 72.14, 127.21, 129.66, 136.84, 143.63,
169.94, 170.27. Ms. m/z (%): 400 (M+ + 1, 1.52), 298 (100.00), 270
(2.83), 242 (40.45), 224 (7.46), 173 (4.61), 155 (40.31), 132
(4.15), 91 (51.90), 70 (13.82), 57 (21.50), 41 (15.92). Analysis calcu-
lated for C19H29NO6S: C, 57.12; H, 7.32; N, 3.51. Found C, 57.18; H,
7.41; N, 3.48.
664, 563 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz) , d ppm 1.22 (d,
.
J = 6.3 Hz, 6H), 1.25 (d, J = 7.5 Hz, 6H), 2.42 (s, 3H), 2.77 (dd,
J = 16.8 Hz, J = 5.1 Hz, 1H), 2.91 (dd, J = 16.8 Hz, J = 4.5 Hz, 1H),
4.10 (ddd, J = 8.1 Hz, J = 5.1 Hz, J = 4.5 Hz , 1H), 4.89 (septed,
J = 6.3 Hz, 1H), 4.99 (septed, J = 7.5 Hz, 1H), 5.62 (d, J = 8.1 Hz,
1H), 7.29 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3,
TMS, 75 MHz), d ppm 21.31, 21.43, 21.6, 21.69, 38.26, 52.31, 68.80,
70.05, 127.24, 129.62, 136.94, 143.58, 169.40, 169.60. Ms. m/z (%):
372 (M+ + 1, 1.45) 284 (99.68), 242 (92.53), 216 (16.06), 155
(70.40), 91 (100.00), 70 (34.87), 65 (22.79), 43 (65.27), 41
(20.96). Analysis calculated for C17H25NO6S: C, 54.97; H, 6.78; N,
3.77. Found C, 54.88; H, 6.84; N, 3.65.
2.1.2.14. Di-sec-butyl 2-(tosylamino)succinate (3o). White Solid, mp
66–67 °C. FT-IR (KBr) 3290, 2977, 1743, 1600, 1344, 1197, 1168,
817, 677, 554 cmÀ1 1H NMR (CDCl3, TMS, 300 MHz), d ppm
.
2.1.2.10. Diisopentyl 2-(tosylamino)succinate (3k). White Solid, mp
68–72 °C. FT-IR (KBr) 3289, 2958, 1739, 1600, 1465, 1346, 1285,
0.78–0.86 (m, 6H), 1.04–1.21 (m, 6H), 1.42–1.63 (m, 4H), 2.42 (s,
3H), 2.80 (dd, J = 16.8 Hz, J = 4.5 Hz, 1H), 2.94 (dd, J = 16.8 Hz,

G. Imanzadeh et al. / Ultrasonics Sonochemistry 20 (2013) 722–728
725
J = 8.1 Hz, 2H).13C NMR (CDCl3, TMS, 75 MHz), d ppm 9.60, 18.93,
19.05, 19.26, 19.30, 21.48, 28.40, 28.65, 38.19, 52.27, 52.31,
73.38, 74.60, 74.71, 127.25, 129.64, 136.93, 143.59, 169.52,
169.78. Ms. m/z (%): 400 (M+ + 1, 2.30) (1.07), 298 (79.47), 284
(1.72), 270 (14.93), 242 (100.00), 224 (7.46), 173 (7.19), 155
(52.74), 149 (27.51), 91 (60.48), 70 (28.31), 57 (22.57), 43
(12.04), 41 (22.40). Analysis calculated for C19H29NO6S: C, 57.12;
H, 7.32; N, 3.51. Found C, 57.22; H, 7.28; N, 3.46.
Table 1
The addition of p-toluenesulfonamide to diethyl fumarate under various solvents.a
Entry
Solvent
Time (min)
U.S
Yield (%)b
U.S
D
D
1
2
3
4
5
6
7
8
DMF
30
30
30
30
30
30
30
30
30
30
30
30
30
100
100
120
100
100
120
120
100
120
120
100
100
120
38
57
32
25
27
40
36
30
21
43
–
17
30
–
–
–
–
–
–
–
DMSO
CH2Cl2
THF
CH3CN
CH3COCH3
CH3COOEt
MeOH
EtOH
2.1.2.15. Dipentan-2-yl 2-(tosylamino)succinate (3p). Viscous color-
less oil. FT-IR (Neat) 3283, 2961, 1734, 1599, 1457, 1343, 1165,
1093, 815, 664, 563 cmÀ1 1H NMR (CDCl3, TMS, 300 M Hz), d
.
9
10
11
12
13
Dioxane
Toluene
H2O
15
–
–
ppm 0.79–0.92 (m, 6H), 1.17–1.59 (m, 14), 2.40 (s, 3H), 2.72–
2.81 (m, 1H), 2.90 (dd, J = 17.1 Hz, J = 4.2 Hz, 1H), 4.09 (ddd,
J = 8.1 Hz, J = 4.5 Hz, J = 4.2 Hz, 1H), 4.79 (sextet, J = 6.3 Hz, 1H),
4.88 (sextet, J = 6 Hz, 1H), 5.66 (d, J = 8.1 Hz, 1H), 7.27 (d,
J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H). 13C NMR (CDCl3, TMS,
75 MHz), d ppm 18.37, 18.40, 18.55, 19.43, 19.53, 19.76, 19.80,
19.84, 21.47, 37.62, 37.66, 37.88, 38.13, 38.15, 38.19, 52.25,
52.30, 71.91, 71.97, 73.13, 73.26, 127.23, 129.61, 136.94, 143.53,
169.48, 169.52, 169.75, 169.78. Ms. m/z (%): 428 (M+ + 1, 3.21)
(4.56), 358 (4.64), 312 (84.14), 272 (13.34), 242 (100.00), 224
–
65
None
34
a
All reactions were run with 1 (1 mmol), 2b (1 mmol) and K2CO3 (1 mmol) in
5 mL solvent at 38 °C.
b
Isolated yields.
J = 4.2 Hz, 1H), 4.12 (ddd, J = 7.8 Hz, J = 4.5 Hz, J = 4.2 Hz, 1H), 4.71–
4.86 (m, 2H), 5.63 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.77 (d,
Table 2
Solvent-free Michael addition of p-toluenesulfonamide to fumaric esters in the presence of K2CO3 in a molar ratio of 1:1:1, respectively, under conventional thermal heating and
ultrasound irradiation at 53 °C.a
Entry
1
Ester
Product
Time
U.S
Yield (%)c
U.S
D
D
10b
20
–
–
2
40b
3
90
85
3
4
1
1
14
14
89
87
86
87
5
6
1
1
15
20
85
81
85
80
7
1
22
70
49
(continued on next page)

726
G. Imanzadeh et al. / Ultrasonics Sonochemistry 20 (2013) 722–728
Table 2 (continued)
Entry
Ester
Product
Time
Yield (%)c
U.S
U.S
D
D
8
1.5
22
67
14
9
2
22
20
60
80
60
82
10
1.5
11
12
1
19
20
87
86
85
84
1.5
13
14
2
1
25
19
80
85
78
85
15
1
24
83
80
16
17
1.5
1.5
42
29
78
74
75
74
a
Ar: 4-CH3Ph.
Time (min).
Isolated yields.
b
c
(5.86), 155 (37.34), 133 (10.09), 119 (10.92), 91 (35.21), 70 (21.01),
43 (18.65). Analysis calculated for C21H33NO6S: C, 58.99; H, 7.78; N,
3.28. Found C, 58.83; H, 7.65; N, 3.36.
1127, 814, 666, 559 cmÀ1 1H NMR (CDCl3, TMS, 300 M Hz), d
.
ppm 1.24–1.78 (m, 20H), 2.39 (s, 3H), 2.77 (dd, J = 16.8 Hz,
J = 5.1 Hz, 1H), 2.90 (dd, J = 16.8 Hz, J = 4.5 Hz, 1H), 4.10 (ddd,
J = 8.1 Hz, J = 5.1 Hz, J = 4.5 Hz, 1H), 4.63–4.74 (m, 2H), 5.65 (d,
J = 8.1 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H). 13C
NMR (CDCl3, TMS ,75 MHz), d ppm 21.46, 23.36, 23.38, 23.65,
2.1.2.16. Dicyclohexyl 2-(tosylamino)succinate (3r). White Solid, mp
99–102 °C. FT-IR (KBr) 3268, 2938, 1748, 1704, 1599, 1345, 1220,

G. Imanzadeh et al. / Ultrasonics Sonochemistry 20 (2013) 722–728
727
25.14, 25.24, 30.98, 31.09, 31.46, 38.31, 52.36, 73.72, 74.71, 127.22,
129.62, 136.98, 143.54, 169.32, 169.50. Ms. m/z (%): 452 (M+ + 1,
4.08), 324 (86.39), 296 (12.34), 242 (100.00), 155 (27.69), 91
(21.61), 70 (12.08), 55 (13.96), 41 (8.1). Analysis calculated for
of p-toluenesulfonamide to methyl fumarate was not successful
(Table 2, entry 1). The reaction gave fumaric acid and p-toluenesul-
fonamide 1 without the formation of any Michael adduct. We be-
lieve that methyl fumarate is more susceptible to hydrolysis
under the reaction conditions, due to its smaller alkoxy groups
(–OMe). Interestingly, in all these reactions only monosubstituted
products were obtained and no disubstituted products were ob-
served at all (Table 2). We repeated all of the reactions, even in
the presence of excess fumaric esters, and observed monosubsti-
tuted Michael adducts as the exclusive products of the reactions.
This can be related to the steric influence of the first substitute
on nitrogen atom of p-toluenesulfonamide that makes it poorer
nucleophile.
C23H33NO6S: C, 61.17; H, 7.37; N, 3.10. Found C, 61.22; H, 7.25;
N, 3.21.
3. Results and discussion
Initially, we investigated the reaction under conventional ther-
mal heating condition. In order to find the optimal reaction
conditions, the model reaction of diethyl fumarate 2b with
p-toluenesulfonamide was conducted in the presence of K2CO3 in
a molar ratio of 1:1:1, respectively, at 38 °C in divers solvents
which the results were listed in Table 1.
The influence of different organic and inorganic bases on this
reaction was also investigated under model reaction conditions
(Table 3). It appeared that the reasonable yield was given only un-
der the catalysis by K2CO3 (Table 3, entry 5).
Among all the solvents tested, only in a few of them the reaction
was successful (Table 1, entries 1, 2, 10,
D). The solvent DMSO as
well as none solvent media afforded better yield than some other
solvents tested under conventional thermal heating conditions
4. Conclusion
(Table 1, entries 2, 13,
D). However, the results did not satisfy
our interest of the reaction due to undesirable yields and long reac-
tion times.
In summary, we have developed a new methodology using ultra-
sound irradiation for the synthesis of p-toluenesulfonamide deriva-
tives by aza-Michael addition reaction of p-toluenesulfonamide to
fumaric esters under solvent-free condition. This technique is very
simple, efficient, and environmentally friendly. It was demonstrated
that, among the organic and inorganic bases, potassium carbonate,
as a cheap and green base, effectively catalysis this reaction.
In two last decades, ultrasonic irradiation technique has re-
ceived considerable attention [27,28]. In comparison with tradi-
tional heating methods, this technique has advantages such as
formation of purer products in high yields, shorter reaction times,
and easier manipulation and developed new reactions [29–31]. We
have, therefore, decided to apply this technique to the above men-
tioned model reaction. The effectiveness of ultrasound to promote
this conversion was tested in various solvents, at 38 °C (Table 1,
entries 1–12, U.S). Surprisingly, this conversion was successful in
almost of solvents tested (Table 1, entries 1–12, U.S) and the best
result were obtained in DMSO (Table 1, entry 2, U.S). Encouraged
by these results, we tried the reaction under solvent-free condition
at 38 °C. To our surprise, the result was satisfactory and even better
than in DMSO media (Table 1, entry 13, U.S). The new findings
promoted us to repeat this reaction with different fumarates to
explore the scope of reaction under solvent-free condition
(Table 2).
It is seen from results of Table 2 that in comparison with con-
ventional methods, the protocol using ultrasound irradiation in
all cases showed a significant decrease of reaction times (Table 2,
entries 2 and 16). It has been observed that the bulkiness of alkoxy
group (–OR) of fumaric esters did not affect significantly on the
yields and reaction times under both conventional thermal heating
and ultrasound irradiation conditions (Table 2). Michael addition
Acknowledgement
The authors thankful to, University of Mohaghegh Ardabili and
Tehran University Councils for the partial support to the work.
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