Reaction on water: A greener approach for the thia michael addition on N-Aryl maleimides

Article abstract of DOI:10.1080/00397910903576651

A greener, economical, and efficient methodology for the Michael addition of thiols to N-aryl maleimides has been developed.

Full text of DOI:10.1080/00397910903576651

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Reaction on Water: A Greener Approach
for the Thia Michael Addition on N-Aryl
Maleimides
Varun Kumar a , Rangan Mitra a , Sanjay Bhattarai a & Vipin A. Nair a
a Department of Medicinal Chemistry , National Institute of
Pharmaceutical Education and Research (NIPER) , Mohali, Punjab,
India
Published online: 13 Jan 2011.
To cite this article: Varun Kumar , Rangan Mitra , Sanjay Bhattarai & Vipin A. Nair (2011) Reaction
on Water: A Greener Approach for the Thia Michael Addition on N-Aryl Maleimides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:3, 392-404, DOI: 10.1080/00397910903576651
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Synthetic Communications1, 41: 392–404, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903576651
REACTION ON WATER: A GREENER APPROACH
FOR THE THIA MICHAEL ADDITION ON N-ARYL
MALEIMIDES
Varun Kumar, Rangan Mitra, Sanjay Bhattarai, and
Vipin A. Nair
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Mohali, Punjab, India
A greener, economical, and efficient methodology for the Michael addition of thiols to
N-aryl maleimides has been developed.
Keywords: N-Aryl maleimides; thia Michael addition; thiols; water
INTRODUCTION
Cyclic imides are an important class of molecules known for their diverse
array of bioactivities, which include a-1A adrenergic receptor antagonist, androgen
receptor antagonist, anxiolytic, antiviral, antibacterial, anti-inflammatory, and
antitumor properties.[1] Moreover, succinimide derivatives have exhibited potent
hypolipidaemic and fungicidal properties.[2] These biological activities and various
pharmacological uses of cyclic imides have been attributed to their unique structural
features, which encouraged us to look for their androgen receptor modulating
properties as a treatment for prostate cancer in our ongoing research activities
and further prompted us to look for newer and more advantageous methods for their
efficient synthesis.
Reported methods for the Michael addition on N-aryl maleimides (N-aryl-1H-
pyrrole-2,5-dione) employed either the use of pyridine as base in ethanol[3] or triethy-
lamine as base in dichloromethane.[4] These methods suffer from disadvantages such as
poor yields, long reaction time, use of hazardous chemicals, and halogenated solvent.
To nullify such predicaments, it is essential to develop reaction conditions that are
ecofriendly, highly efficient, better yielding, and that take place in a short time.
In recent years, reaction in water has attained significant importance because of
its advantages over other solvents. Water is one of the most environmentally benign
and inexpensive liquid used in organic synthesis, which justifies the current surge in
interest as a reaction medium. Moreover, the reaction in water is a greener and less
Received October 12, 2009.
Address correspondence to Vipin A. Nair, Department of Medicinal Chemistry, National Institute
of Pharmaceutical Education and Research (NIPER), Sector 67, Mohali, Punjab, India. E-mail: vnair@
niper.ac.in
392

THIA MICHAEL ADDITION ON N-ARYL MALEIMIDES
393
expensive approach to the synthesis of the molecule of interest. Organic reactions in
water have garnered a lot of interest in recent years because of advantages over haz-
ardous volatile organic liquids (VOLs) and high-boiling solvents. Many organic reac-
tions have been tried and tested in an aqueous medium with mixed results. Pericyclic
reactions, Michael additions, transition-metal catalysis, oxidations and reductions,
reactions of radicals and carbenes, and reactions of carbanion equivalents are being
explored in water for their simplistic approach and high efficiency.[5–8] The insolu-
bility of most organic reagents in water has created a need to improve
their compatibility in water with the use of phase-transfer catalysts or surfactants.
Nevertheless, there are inherent difficulties in handling such reactions.
RESULTS AND DISCUSSION
With an ever-interesting quest for greener solvents and exploration of new
reactions in water, we herein report the use of water for the Michael addition of
thiols to N-aryl maleimides to afford products in good yield, within short reaction
time, and in neutral conditions without the use of any catalyst. N-Aryl maleimides
were prepared by condensation of maleic anhydride with different anilines in ethyl
acetate medium using sodium acetate, followed by refluxing in acetic anhydride to
give the corresponding maleimide in excellent yield. As a model reaction, when
4-chlorothiophenol and N-(4-fluorophenyl)maleimide were taken in water and sha-
ken for 15 min at room temperature, the product precipitated out. To generalize
the reaction, conjugate addition with different aromatic thiols, aliphatic thiols,
and heteroaromatic thiols were tried as well (Scheme 1). The reaction proceeded well
in all the cases, and products were obtained within 10–15 min with 80–90% yields as
shown in Table 1. The reactions proceeded with complete selectivity, and no side
products were formed. When the reaction was tried with 2-mercaptoethanol, the
reaction afforded complete chemoselectivity, yielding only the thia Michael adduct
(entries 13–15).
Reaction in aqueous medium was carried out under shaking, which provided
adequate mechanical force for the two reactants to intermingle properly so as to
undergo the reaction in a complete manner. As both the reagents were insoluble
in water, the reaction was actually done ‘‘on water’’ by forming an aqueous suspen-
sion.[9] As reported by Sharpless, there is a substantial rate acceleration when
insoluble reactants are stirred in aqueous suspension, which he denoted as ‘‘on
water’’ conditions.[10]
The rate of acceleration and good yields in the reactions in water can be
explained by the ‘‘ambiphilic dual activation role’’ of water as first proposed by
Scheme 1. Michael addition of thiols to N-aryl maleimides.

394
V. KUMAR ET AL.
Table 1. Michael addition of different thiols to N-aryl maleimide
No. Michael acceptor
Thiol
Product
Reaction time (min) Yield (%)
1
15
15
85
80
2
3
15
90
4
5
15
15
94
89
6
7
8
15
15
15
96
91
90
(Continued )

THIA MICHAEL ADDITION ON N-ARYL MALEIMIDES
Table 1. Continued
395
No. Michael acceptor
Thiol
Product
Reaction time (min) Yield (%)
9
15
15
88
89
10
11
12
15
15
83
86
13
14
15
16
10
10
10
15
80
88
83
81
(Continued )

396
V. KUMAR ET AL.
Table 1. Continued
No. Michael acceptor
Thiol
Product
Reaction time (min) Yield (%)
17
18
15
15
80
91
Khatik et al.[7a] Hydrogen-bond formation between water and the carbonyl oxygen
of the maleimide causes electrophilic activation, making the b-position more suscep-
tible to nucleophilic attack. The oxygen atom of water in turn forms a hydrogen
bond with the thiol hydrogen and increases the electron density at the sulfur, result-
ing in activation of the nucleophile, which attacks the b-position of the maleimide.
This mechanism illustrated as in Scheme 2 can be assumed to take place through
the proposed transition state TS-I. Thus, because of hydrogen bonding between
the carbonyl oxygen and water, electrophilicity at the b-carbon increases, and simi-
larly the hydrogen bonding between the nucleophile and the water leads to nucleo-
philic activation. Here the dual activation role of water can be seen to be occurring
on both the nucleophile and the carbonyl oxygen.[7,11] Moreover, the hydrophobic
Scheme 2. Plausible mechanism for addition of thiols to N-aryl maleimides.

THIA MICHAEL ADDITION ON N-ARYL MALEIMIDES
397
character of both the reagents forced them to react to each other in the aqueous
environment of the reaction mixture, which had been conceptualized by Engberts
et al. as the ‘‘enforced’’ hydrophobic interactions, resulting in an additional
reduction of hydrophobic surface of the reaction accompanying the formation of
the activated complex.[11]
CONCLUSION
A simple and facile methodology for the conjugate addition of thiols on N-aryl
maleimides in water has been devised that not only overcomes the disadvantages
associated with previous methods but also endows a greener approach for the
synthesis of the desired products. The efficiency of the method lies in its operational
simplicity, and the products have been obtained with good yields in a cost-effective
manner over a very short span of time.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz,
respectively, on a Bruker Avance DPX 400 (400-MHz) spectrometer in CDCl3 or
CD3OD using tetramethylsilane (TMS) as an internal standard. The chemical shifts
(d) for 1H and 13C are given in parts per million (ppm) relative to residual signals of
the solvent. Coupling constants are given in hertz (Hz). The following abbreviations
are used to indicate the multiplicity: s, singlet; d, doublet; dd, double doublet; t,
triplet; q, quartet; and m, multiplet. The infrared (IR) spectra were recorded on a
Nicolet Impact 400 spectrometer as KBr pellets for solid samples. Mass spectra
(MS) were recorded on a Finnigan LCQ liquid chromatograph–mass spectrometer
(LCMS), and elemental analyses were done by Varion-EL elemental analyzer.
Reactions were monitored by thin-layer chromatography (TLC) performed with
0.2-mm Merck precoated silica-gel 60 F254 aluminium sheets.
General Procedure for the Preparation of 3-Arylsulfanyl-1-
arylpyrrolidine-2,5-dione Derivatives
In a typical experiment, 1-(4-fluorophenyl)-1H-pyrrole-2,5-dione (0.15 g,
0.812 mmol) was taken in a round-bottomed flask containing demineralized water
(2.5 mL), and 4-chlorothiophenol (0.10 g, 0.812 mmol) was added. The reaction
vessel was subjected to shaking for 15 min at room temperature, after which the reac-
tion mixture was washed with saturated sodium bicarbonate solution and extracted
with ethyl acetate. The solvent was evaporated under reduced pressure to obtain the
product 3-(4-chlorophenylthio)-1-(4-fluorophenyl)pyrrolidine-2,5-dione, which was
washed with hexane and dried under vacuum.
1-(4-Fluorophenyl)-3-phenylthiopyrrolidine-2,5-dione [2(a)(i)]
White solid; yield 85%; mp 141–143 ꢀC; FTIR (neat, KBr plates) nmax
1
2927, 1784, 1710, 1512, 1403, 1235, 1173, 1091, 834 cmꢁ1; H NMR (400 MHz,

398
V. KUMAR ET AL.
CDCl3): d 2.89–2.95 (dd, J ¼ 4.0, 19.0 Hz, 1H), 3.31–3.38 (dd, J ¼ 9.2, 19.0 Hz, 1H),
4.14–4.17 (dd, J ¼ 4.0, 9.4 Hz, 1H), 7.01–7.06 (m, 2H), 7.09–7.18 (m, 2H), 7.29–7.45
(m, 3H), 7.50–7.60 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.4, 44.0, 116.3,
127.3, 127.5, 128.2, 129.6, 135.1, 161.0, 163.5, 173.3, 174.4; MS (DI): m=z ¼ 300.34
[M ꢁ 1]þ. Anal. calcd. for C16H12FNO2S: C, 63.77; H, 4.01; N, 4.65; S, 10.64. Found:
C, 63.65; H, 4.11; N, 4.73; S, 10.77.
1-(4-Fluorophenyl)-3-(4-fluorophenylthio)pyrrolidine-2,5-dione [2(a)(ii)]
White solid; yield 77%; mp 152–154 ꢀC; FTIR (neat, KBr plates) nmax 2920,
1782, 1702, 1514, 1397, 1175, 1091, 834 cmꢁ1 1H NMR (400 MHz, CDCl3): d
;
2.86–2.91 (dd, J ¼ 4.0, 18.8 Hz, 1H), 3.31–3.38 (dd, J ¼ 9.2, 19.0 Hz, 1H),
4.08–4.11 (dd, J ¼ 4.0, 9.2 Hz, 1H), 7.05–7.16 (m, 6H), 7.56–7.61 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 36.1, 44.3, 116.6, 124.9, 127.3, 128.0, 137.6, 161.0,
162.6, 163.5, 165.1, 173.18, 174.2; MS (DI): m=z ¼ 318.29 [M ꢁ 1]þ. Anal. calcd.
for C16H11F2NO2S: C, 60.18; H, 3.47; N, 4.39; S, 10.04. Found: C, 60.27; H, 3.56;
N, 4.48; S, 10.15.
3-(4-Chlorophenylthio)-1-(4-fluorophenyl)pyrrolidine-2,5-dione [2(a)(iii)]
White solid; yield 90%; mp 124–126 ꢀC; FTIR (neat, KBr plates) nmax 2922,
1
1784, 1716, 1510, 1389, 1232, 1184, 1094, 834 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.84–2.89 (dd, J ¼ 4.0, 19.0 Hz, 1H), 3.31–3.38 (dd, J ¼ 9.2, 19.0 Hz, 1H),
4.12–4.15 (dd, J ¼ 4.0, 9.4 Hz, 1H), 7.06–7.16 (m, 4H), 7.31–7.38 (m, 2H),
7.49–7.56 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 44.1, 116.3, 127.3, 128.0,
129.3, 129.7, 130.6, 135.7, 136.2, 138.0, 173.0, 174.10; MS (DI): m=z ¼ 334.39
[M ꢁ 1]þ. Anal. calcd. for C16H11ClFNO2S: C, 57.23; H, 3.30; N, 4.17; S, 9.55.
Found: C, 57.17; H, 3.41; N, 4.09; S, 9.63.
3-(4-Bromophenylthio)-1-(4-fluorophenyl)pyrrolidine-2,5-dione [2(a)(iv)]
White solid; yield 94%; mp 137–140 ꢀC; FTIR (neat, KBr plates) nmax 1784,
1716, 1510, 1387, 1231, 1183, 1091, 835 cmꢁ1 1H NMR (400 MHz, CDCl3): d
;
2.84–2.90 (dd, J ¼ 4.0, 18.8 Hz, 1H), 3.32–3.39 (dd, J ¼ 9.2, 18.8 Hz, 1H),
4.13–4.17 (dd, J ¼ 4.0, 9.4 Hz, 1H), 7.06–7.17 (m, 4H), 7.42–7.47 (m, 2H),
7.49–7.52 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 44.0, 116.1, 124.3, 127.2,
128.0, 128.1, 129.2, 132.6, 136.2, 173.1, 174.1; MS (DI): m=z ¼ 379.29 [M ꢁ 1]þ.
Anal. calcd. for C16H11BrFNO2S: C, 50.54; H, 2.92; N, 3.68; S, 8.43. Found: C,
50.67; H, 2.84; N, 3.74; S, 8.59.
1-(4-Chlorophenyl)-3-phenylthiopyrrolidine-2,5-dione [2(b)(i)]
White solid; yield 89%; mp 165–167 ꢀC; FTIR (neat, KBr plates) nmax 2929,
1
1781, 1715, 1493, 1384, 1276, 1176, 1093, 826 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.87–2.93 (dd, J ¼ 3.6, 19.0 Hz, 1H), 3.28–3.36 (dd, J ¼ 9.2, 19.0 Hz, 1H),
4.12–4.15 (dd, J ¼ 3.6, 9.2 Hz, 1H), 6.99–7.03 (m, 2H), 7.33–7.43 (m, 4H),

THIA MICHAEL ADDITION ON N-ARYL MALEIMIDES
399
7.55–7.58 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.4, 44.1, 127.5, 129.3, 129.5,
129.6, 129.7, 129.9, 134.6, 135.1, 173.1, 174.2; MS (DI): m=z ¼ 316.32 [M ꢁ 1]þ.
Anal. calcd. for C16H12ClNO2S: C, 60.47; H, 3.81; N, 4.41; S, 10.09. Found: C,
60.54; H, 3.94; N, 4.47; S, 10.21.
1-(4-Chlorophenyl)-3-(4-fluorophenylthio)pyrrolidine-2,5-dione [2(b)(ii)]
White solid; yield 96%; mp 168–170 ꢀC; FTIR (neat, KBr plates) nmax 1782, 1715,
1492, 1384, 1275, 1178, 1091, 1016, 829 cmꢁ1; 1H NMR (400 MHz, CDCl3): d 2.85–2.91
(dd, J¼ 4.0, 19.0 Hz, 1H), 3.30–3.38 (dd, J¼ 9.2, 19.2 Hz, 1H), 4.04–4.11 (dd, J¼ 4.0,
9.4 Hz, 1H), 6.99–7.10 (m, 4H), 7.40–7.48 (m, 2H), 7.56–7.61 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 36.1, 44.3, 116.8, 124.9, 127.4, 129.4, 131.2, 134.6, 137.6, 137.7,
172.9, 174.1; MS (DI): m=z¼ 335.32 [M ꢁ 1]þ. Anal. calcd. for C16H11ClFNO2S: C,
57.23; H, 3.30; N, 4.17; S, 9.55. Found: C, 57.31; H, 3.43; N, 4.28; S, 9.64.
1-(4-Chlorophenyl)-3-(4-chlorophenylthio)pyrrolidine-2,5-dione [2(b)(iii)]
White solid; yield 91%; mp 149–151 ꢀC; FTIR (neat, KBr plates) nmax 2924,
1
1781, 1713, 1493, 1384, 1275, 1145, 1090, 828 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.84–2.90 (dd, J ¼ 4.0, 19.0 Hz, 1H), 3.32–3.39 (dd, J ¼ 9.2, 18.8 Hz, 1H),
4.12–4.15 (dd, J ¼ 4.0, 9.2 Hz, 1H), 7.05–7.08 (m, 2H), 7.33–7.36 (m, 2H),
7.40–7.44 (m, 2H), 7.50–7.7.53 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.2,
44.1, 127.4, 128.4, 129.4, 129.7, 129.8, 134.7, 136.1, 136.2, 172.9, 174.0; MS (DI):
m=z ¼ 350.37 [M ꢁ 1]þ. Anal. calcd. for C16H11Cl2NO2S: C, 54.56; H, 3.15; N,
3.98; S, 9.10. Found: C, 54.48; H, 3.28; N, 3.86; S, 9.19.
3-(4-Bromophenylthio)-1-(4-chlorophenyl)pyrrolidine-2,5-dione [2(b)(iv)]
Off-white solid; yield 90%; mp 128–131 ꢀC; FTIR (neat, KBr plates) nmax 2928,
1781, 1716, 1493, 1385, 1276, 1175, 1091, 823 cmꢁ1; 1H NMR (400 MHz, CDCl3): d
2.84–2.90 (dd, J ¼ 4.0, 19.0 MHz, 1H), 3.32–3.39 (dd, J ¼ 9.2, 19.2 MHz, 1H),
4.13–4.16 (dd, J ¼ 4.0, 9.2 MHz, 1H), 7.05–7.10 (m, 2H), 7.43–7.54 (m, 6H); 13C
NMR (100 MHz, CDCl3): d 36.2, 44.0, 127.4, 129.2, 129.4, 129.8, 132.7, 134.3,
134.7, 136.2, 172.8, 173.9; MS (DI): m=z ¼ 396.28 [M ꢁ 1]þ. Anal. calcd. for
C16H11BrClNO2S: C, 48.44; H, 2.79; N, 3.53; S, 8.08. Found: C, 48.54; H, 2.91;
N, 3.46; S, 8.16.
1-(4-Bromophenyl)-3-phenylthiopyrrolidine-2,5-dione ([2(c)(i)])
White solid; yield 88%; mp 150–153 ꢀC; FTIR (neat, KBr plates) nmax 1781,
1
1713, 1492, 1399, 1274, 1170, 1089, 1014, 826 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.89–2.95 (dd, J ¼ 3.6, 19.0 Hz, 1H), 3.31–3.38 (dd, J ¼ 9.2, 19.0 Hz, 1H),
4.13–4.17 (dd, J ¼ 3.6, 9.4 Hz, 1H), 6.94–6.98 (m, 2H), 7.35–7.45 (m, 2H),
7.54–7.61 (m, 4H); 13C NMR (100 MHz, CDCl3): d 36.4, 44.1, 122.6, 127.8, 129.5,
129.6, 129.8, 130.4, 132.3, 135.1, 173.1, 174.1; MS (DI): m=z ¼ 360.29 [M ꢁ 1]þ.
Anal. calcd. for C16H12BrNO2S: C, 53.05; H, 3.34; N, 3.87; S, 8.85. Found: C,
53.17; H, 3.43; N, 3.94; S, 8.92.

400
V. KUMAR ET AL.
1-(4-Bromophenyl)-3-(4-fluorophenylthio)pyrrolidine-2,5-dione [2(c)(ii)]
White solid; yield 89%; mp 157–159 ꢀC; FTIR (neat, KBr plates) nmax 1782,
1
1715, 1489, 1382, 1275, 1177, 1090, 1013, 834 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.85–2.90 (dd, J ¼ 4.0, 19.0 Hz, 1H), 3.30–3.38 (dd, J ¼ 9.6, 19.0 Hz, 1H),
4.07–4.10 (dd, J ¼ 4.0, 9.4 Hz, 1H), 6.97–7.01 (m, 2H), 7.05–7.10 (m, 2H), 7.55–7.61
(m, 4H); 13C NMR (100 MHz, CDCl3): d 36.1, 44.4, 116.6, 122.7, 124.9, 127.7,
130.3, 132.3, 137.6, 137.7, 172.9, 174.0; MS (DI): m=z ¼ 378.42 [M ꢁ 1]þ. Anal. calcd.
for C16H11BrFNO2S: C, 50.54; H, 2.92; N, 3.68; S, 8.43. Found: C, 50.63; H, 2.81; N,
3.76; S, 8.47.
1-(4-Bromophenyl)-3-(4-chlorophenylthio)pyrrolidine-2,5-dione [2(c)(iii)]
White solid; yield 83%; mp 135–137 ꢀC; FTIR (neat, KBr plates) nmax 1783,
1
1716, 1490, 1383, 1275, 1175, 1094, 1013, 823 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.84–2.90 (dd, J ¼ 4.0, 18.8 Hz, 1H), 3.32–3.39 (dd, J ¼ 9.6, 19.0 Hz, 1H),
4.12–4.15 (dd, J ¼ 4.0, 9.4 Hz, 1H), 6.99–7.04 (m, 2H), 7.29–7.36 (m, 2H),
7.50–7.54 (m, 2H), 7.56–7.61 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 44.1,
122.7, 127.7, 128.4, 129.7, 130.3, 132.3, 136.1, 136.2, 172.8, 173.9; MS (DI): m=
z ¼ 396.27 [M ꢁ 1]þ. Anal. calcd. for C16H11BrClNO2S: C, 48.44; H, 2.79; N, 3.53;
S, 8.08. Found: C, 48.56; H, 2.65; N, 3.59; S, 8.17.
1-(4-Bromophenyl)-3-(4-bromophenylthio)pyrrolidine-2,5-dione [2(c)(iv)]
White solid; yield 86%; mp 152–154 ꢀC; FTIR (neat, KBr plates) nmax 1781,
1
1716, 1489, 1384, 1275, 1168, 1092, 1010, 822 cmꢁ1; H NMR (400 MHz, CDCl3):
d 2.82–2.88 (dd, J ¼ 4.0, 19.2 Hz, 1H), 3.30–3.37 (dd, J ¼ 9.2, 19.0 Hz, 1H),
4.11–4.14 (dd, J ¼ 4.0, 9.2 Hz, 1H), 6.98–7.02 (m, 2H), 7.41–7.44 (m, 2H),
7.47–7.51 (m, 2H), 7.55–7.59 (m, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 44.0,
122.7, 124.4, 127.7, 129.2, 129.4, 130.3, 132.3, 136.1, 172.7, 173.8; MS (DI): m=
z ¼ 440.21 [M ꢁ 1]þ. Anal. calcd. for C16H11Br2NO2S: C, 43.56; H, 2.51; N, 3.18;
S, 7.27. Found: C, 43.48; H, 2.44; N, 3.09; S, 7.29.
1-(4-Fluorophenyl)-3-(2-hydroxyethylthio)pyrrolidine-2,5-dione [2(a)(v)]
Off-white solid; yield 73%; mp 82–84 ꢀC; FTIR (neat, KBr plates) nmax 3468, 3080,
1
2926, 1781, 1710, 1510, 1390, 1276, 1185, 1062, 1015, 946 cmꢁ1; H NMR (400 MHz,
CDCl3): d 2.68–2.74 (dd, J ¼ 4.0, 18.8 MHz, 1H), 2.88–2.98 (m, 2H), 3.13–3.19 (m,
1H), 3.29–3.36 (dd, J ¼ 9.2, 19.0 MHz, 1H), 3.84–3.95 (m, 2H), 4.00–4.04 (dd, J ¼ 9.6,
4.0 MHz, 1H), 7.13–7.19 (m, 2H), 7.25–7.34 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 35.5, 36.3, 39.5, 61.8, 116.4, 127.8, 128.3, 134.2, 161.0, 163.5, 173.5, 176.5; MS (APCI):
m=z ¼ 269.93 [M þ 1]þ. Anal. calcd. for C12H12FNO3S: C, 53.52; H, 4.49; N, 5.20; S,
11.91. Found: C, 53.47; H, 4.39; N, 5.16; S, 11.79.
1-(4-Chlorophenyl)-3-(2-hydroxyethylthio)pyrrolidine-2,5-dione [2(b)(v)]
White solid; yield 88%; mp 77–79 ꢀC; FTIR (neat, KBr plates) nmax 3469,
3099, 2929, 1780, 1712, 1493, 1387, 1277, 1180, 1064, 1017, 946 cmꢁ1 1H
;

THIA MICHAEL ADDITION ON N-ARYL MALEIMIDES
401
NMR (400 MHz, CDCl3): d 2.66 (s, 1H, OH), 2.70–2.76 (dd, J ¼ 4.0, 19.2 Hz,
1H), 2.88–2.97 (m, 1H), 3.17–3.23 (m, 1H), 3.31–3.38 (dd, J ¼ 9.2, 18.8 Hz, 1H),
3.91–3.97 (m, 2H), 4.02–4.05 (dd, J ¼ 4.0, 9.6 Hz, 1H), 7.25–7.29 (m, 2H),
7.44–7.48 (m, 2H); 13C NMR (100 MHz, CDCl3): d 35.6, 36.3, 39.5, 61.9, 127.6,
129.4, 129.9, 134.7, 173.1, 176.2; MS (APCI): m=z ¼ 285.93 [M þ 1]þ. Anal. calcd.
for C12H12ClNO3S: C, 50.44; H, 4.23; N, 4.90; S, 11.22. Found: C, 50.35; H, 4.41;
N, 4.79; S, 11.09.
1-(4-Bromophenyl)-3-(2-hydroxyethylthio)pyrrolidine-2,5-dione [2(c)(v)]
White solid; yield 83%; mp 78–80 ꢀC; FTIR (neat, KBr plates) nmax 3445, 3091,
2927, 1780, 1712, 1490, 1385, 1276, 1178, 1069, 1013, 946 cmꢁ1; 1H NMR (400 MHz,
CDCl3): d 2.67–2.73 (dd, J ¼ 4.0, 19.2 Hz, 1H), 2.87–2.93 (m, 2H), 3.12–3.18 (m, 1H),
3.28–3.35 (dd, J ¼ 9.2, 19.2 Hz, 1H), 3.88 (s, 2H), 3.99–4.02 (dd, J ¼ 4.0, 9.2 Hz, 1H),
7.17–7.29 (m, 2H), 7.53–7.60 (m, 2H); 13C NMR (100 MHz, CDCl3): d 35.4, 36.3,
39.5, 61.8, 127.9, 130.5, 132.4, 134.3, 173.2, 176.2; MS (APCI): m=z ¼ 331.87
[M þ 1]þ. Anal. calcd. for C12H12BrNO3S: C, 43.65; H, 3.66; N, 4.24; S, 9.71. Found:
C, 43.52; H, 3.53; N, 4.29; S, 9.60.
1-(4-Fluorophenyl)-3-(pyrimidin-2-ylthio)pyrrolidine-2,5-dione [2(a)(vi)]
Buff solid; yield 81%; mp 168–170 ꢀC; FTIR (neat, KBr plates) nmax 2928,
1
1783, 1714, 1509, 1380, 1179, 749 cmꢁ1; H NMR (400 MHz, CDCl3): d 3.11–3.17
(dd, J ¼ 5.6, 18.8 Hz, 1H), 3.41–3.48 (q, J ¼ 9.6, 18.6 Hz, 1H), 4.27–4.31 (dd,
J ¼ 5.6, 9.6 Hz, 1H), 7.05–7.07 (t, J ¼ 4.8 Hz, 1H), 7.14–7.21 (m, 2H), 7.28–7.35
(m, 2H), 8.50–8.51 (d, J ¼ 4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 41.3,
116.1, 116.3, 117.5, 128.2, 157.6, 161.0, 163.4, 169.8, 174.1, 174.3; MS (APCI): m=
z ¼ 304.00 [M þ 1]þ. Anal. calcd. for C14H10FN3O2S: C, 55.44; H, 3.32; N, 13.85;
S, 10.57. Found: C, 55.35; H, 3.39; N, 13.92; S, 10.38.
1-(4-Chlorophenyl)-3-(pyrimidin-2-ylthio)pyrrolidine-2,5-dione [2(b)(vi)]
White solid; yield 80%; mp 166–168 ꢀC; FTIR (neat, KBr plates) nmax 2924,
1
1779, 1716, 1493, 1382, 1179, 743 cmꢁ1; H NMR (400 MHz, CDCl3): d 3.11–3.17
(dd, J ¼ 5.6, 18.4 Hz, 1H), 3.42–3.49 (dd, J ¼ 9.6, 18.6 Hz, 1H), 4.27–4.31 (dd,
J ¼ 5.6, 9.8 Hz, 1H), 7.05–7.08 (t, J ¼ 4.8 Hz, 1H), 7.29–7.33 (m, 2H), 7.45–7.48
(m, 2H), 8.49–8.51 (d, J ¼ 4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 41.3,
117.5, 127.5, 129.4, 130.7, 134.5, 157.6, 169.8, 173.9, 174.1; MS (APCI): m=
z ¼ 320.07 [M þ 1]þ. Anal. calcd. for C14H10ClN3O2S: C, 52.59; H, 3.15; N, 13.14;
S, 10.03. Found: C, 52.45; H, 3.24; N, 13.02; S, 10.12.
1-(4-Bromophenyl)-3-(pyrimidin-2-ylthio)pyrrolidine-2,5-dione [2(c)(vi)]
Off-white solid; yield 91%; mp 182–184 ꢀC; FTIR (neat, KBr plates) nmax 2923,
1
1783, 1714, 1489, 1379, 1177, 745 cmꢁ1; H NMR (400 MHz, CDCl3): d 3.11–3.17
(dd, J ¼ 5.6, 18.4 Hz, 1H), 3.41–3.48 (dd, J ¼ 10.0, 18.6 Hz, 1H), 4.27–4.30

402
V. KUMAR ET AL.
(dd, J ¼ 5.6, 10.0 Hz, 1H), 7.05–7.07 (t, J ¼ 4.8 Hz, 1H), 7.23–7.28 (m, 2H), 7.59–7.64
(m, 2H), 8.48–8.52 (d, J ¼ 4.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 36.2, 41.3,
117.5, 127.8, 131.2, 132.4, 134.3, 157.6, 169.8, 173.8, 174.1; MS (APCI): m=
z ¼ 364.07 [M þ 1]þ. Anal. calcd. for C14H10BrN3O2S: C, 46.17; H, 2.77; N, 11.54;
S, 8.80. Found: C, 46.29; H, 2.63; N, 11.39; S, 8.87.
ACKNOWLEDGMENT
Funding for this research work from the Department of Science and
Technology (DST), Government of India, is gratefully acknowledged.
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