Microwave-assisted synthesis of some novel thiazolidinone and thiohydantoin derivatives of isatins

Article abstract of DOI:10.1080/10426500903567554

A simple, rapid, and efficient method for the synthesis of some new thiazolidinone and thiohydantoin derivatives of isatins along with some Mannich bases has been achieved in excellent yield from indole-2,3-dione-3- thiosemicarbazone employing microwave irradiation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903567554

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Microwave-Assisted Synthesis of Some
Novel Thiazolidinone and Thiohydantoin
Derivatives of Isatins
Dushyant Singh Raghuvanshi a & Krishna Nand Singh a
a Department of Chemistry, Faculty of Science , Banaras Hindu
University , Varanasi , India
Published online: 05 Nov 2010.
To cite this article: Dushyant Singh Raghuvanshi & Krishna Nand Singh (2010) Microwave-Assisted
Synthesis of Some Novel Thiazolidinone and Thiohydantoin Derivatives of Isatins, Phosphorus, Sulfur,
and Silicon and the Related Elements, 185:11, 2243-2248, DOI: 10.1080/10426500903567554
To link to this article: http://dx.doi.org/10.1080/10426500903567554
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Phosphorus, Sulfur, and Silicon, 185:2243–2248, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903567554
MICROWAVE-ASSISTED SYNTHESIS OF SOME NOVEL
THIAZOLIDINONE AND THIOHYDANTOIN DERIVATIVES
OF ISATINS
Dushyant Singh Raghuvanshi and Krishna Nand Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University,
Varanasi, India
A simple, rapid, and efficient method for the synthesis of some new thiazolidinone and thiohy-
dantoin derivatives of isatins along with some Mannich bases has been achieved in excellent
yield from indole-2,3-dione-3-thiosemicarbazone employing microwave irradiation.
Keywords Isatin; Mannich base; microwave; Schiff base; thiazolidinone; thiohydantoin
INTRODUCTION
Microwave-assisted organic synthesis has currently emerged as a fascinating and
clean methodology in synthetic organic chemistry.1 Isatin derivatives are endowed with a
variety of biological activities such as antibacterial, antifungal, antiplasmodial, and anti-
HIV activity.2–5 Schiff and Mannich bases of 1H-indole-2,3-dione have been found to
exhibit a broad spectrum of chemotherapeutic properties including antiviral, antitubercular,
antifungal, and antibacterial activity.6–9 An insight into the structure–activity relationships
of isatins reveals a profound increase in the biological activities of N-Mannich bases
and 3-thiosemicarbazones of 5-bromo-isatin.10–15 The hydantoin structure motifs display
a wide range of biological activities, such as antiarrhythmic, anticonvulsant, antiepilep-
tic, antineuralgic, trigeminal neuralgia, and skeletal muscle relaxant activity.16–18 Further,
4-thiazolidinones have been reported to be highly effective as antimicrobial, antiviral, an-
ticancer, and thrombolytic drugs.19,20 It may be anticipated that the combination of the
thiazolidinone and thiohydantoin moieties placed at suitable positions of the isatin frame-
work would remarkably enhance the biological activity. Taking this into consideration, an
efficient and safe synthesis of some new indole systems containing the thiazolidinone and
thiohydantoin moieties has been developed using microwave irradiation.
RESULTS AND DISCUSSION
A number of synthetic methods for the formation of Mannich and Schiff bases have
been described during the past two decades, but they usually suffer from drawbacks such as
Received in final form on 15 December 2009.
The authors are thankful to UGC, New Delhi, India, for financial assistance.
Address correspondence to Krishna Nand Singh, Department of Chemistry, Faculty of Science, Banaras
Hindu University, Varanasi 221005, India. E-mail: knsinghbhu@yahoo.co.in
2243

2244
D. S. RAGHUVANSHI AND K. N. SINGH
harsh reaction conditions, lack of versatility, use of corrosive reagents, long reaction times,
and tedious workup procedures. Therefore, the search for an easy and efficient method
for the preparation of N-Mannich bases, thiohydantoins, and thiazolidinones is always de-
sirable. With the current focus on green chemistry, carrying out organic synthesis under
microwave irradiation is an important goal in clean synthesis. As a result, we report in
this article a practical and efficient alternative for the synthesis of thiohydantoins, thiazo-
lidinones, and N-Mannich bases by the use of microwave irradiation. In the present study,
1H-indole-2,3-dione 1a and its 5-bromo derivative 1b were reacted with thiosemicarbazide
in ethanol containing a catalytic amount of glacial acetic acid in a household microwave
oven at 160 W to give the thiosemicarbazone derivatives 2a and 2b, respectively. Com-
pounds 2 were subsequently allowed to undergo a Mannich reaction using formaldehyde
solution and morpholine, piperidine, or diethyl amine in ethanol to furnish the Mannich
bases 3a–e in good yields. The 2-(isatin-3-azino)-4-thiazolidinones 4a,b were prepared by
the reaction of 2a,b with chloroacetic acid in ethanol containing anhydrous sodium acetate,
whereas the 3-(isatin-3-imino)-2-thiohydantoins 5a,b were obtained by the reaction of 2a,b
with chloroacetic acid in the presence of piperidine (Scheme 1). All products displayed IR
1
spectra as well as H and 13C NMR spectra consistent with the assigned structures. The
yields of the compounds 2–5 and their melting points are given in Table I.
EXPERIMENTAL
Melting points were measured in open capillaries and are uncorrected. IR spectra
were recorded on a Jasco FT/IR-5300 spectrophotometer. 1H NMR and 13C NMR spectra
were obtained with a JEOL AL 300 FTNMR spectrometer, and the chemical shifts are
given in ppm using TMS as internal reference. All commercially available chemicals were
purchased from Merck and Aldrich.
Table I Yields and physical data of compounds 2–5
Compound
R
R1
Formula
MWa Time (min)
Yieldb (%)
Mp (◦C)
2a
2b
3a
3b
H
Br
H
H
—
—
C9H8N4SO
4
4
4
5
75
80
87
85
240
255
130
180
C9H7N4SOBr
C14H19N5OS
C15H19N5OS
N(C2H5)2
3c
3d
3e
H
C14H17N5O2S
C15H18N5OSBr
C14H16N5O2SBr
C11H8N4O2S
5
4
5
90
84
82
210
215
230
Br
Br
4a
4b
5a
5b
H
Br
H
—
—
—
—
9
7
8
7
90
85
92
80
210
245
225
260
C
C
C
11H7N4O2SBr
11H8N4O2S
11H7N4O2SBr
Br
aIrradiation at 160 W.
bIsolated yield.

NOVEL THIAZOLIDINONE AND THIOHYDANTOIN DERIVATIVES
2245
S
NNHCNH2
S
O
R
R
NH2NHCNH2
MW, EtOH
O
O
N
H
N
H
1a
1b
R = H
R = Br
2a R = H
2b R = Br
S
NNHCNH2
R
Morpholine/piperidine/sec. amine
O
N
formalehyde (37 %), EtOH
MW
R1
R1, R: see Table I
3a-e
S
N
N
O
N
R
H
ClCH2COOH/NaOAc
O
2a,b
EtOH
MW,
N
H
4a R = H
4b R = Br
H
S
N
N
N
ClCH2COOH/piperidine
MW, EtOH
R
O
O
N
H
5a R = H
5b R = Br
Scheme 1
Synthesis of Compounds 2: General Procedure
Isatin/5-bromoisatin 1a/1b (0.01 mol) and thiosemicarbazide (0.011 mol) were in-
troduced into a 100 mL conical flask containing ethanol (15 mL) and a few drops of glacial
acetic acid. The reaction mixture was irradiated in an LG domestic microwave oven for 4
min at 160 W and was subsequently allowed to cool at room temperature. The mixture was
filtered and washed with water (10 mL), and the resulting precipitate was recrystallized
from ethanol (2 mL) to afford compounds 2.

2246
D. S. RAGHUVANSHI AND K. N. SINGH
Synthesis of Compounds 3: General Procedure
To a stirred suspension of isatin/5-bromo isatin 2a/2b (2 mmol) and formaldehyde
solution (37%, 0.5 mL) in absolute ethanol (10 mL) in a 100 mL conical flask, a mixture
of morpholine/piperidine/N,N-diethylamine (2 mmol) was added dropwise. The reaction
mixture was then introduced into the microwave oven and was irradiated for 4–5 min at 160
W. The course of the reaction was monitored by TLC. The resulting mixture was allowed
to stand overnight, and the resulting solid product was filtered and washed with petroleum
ether (10 mL) to furnish pure compounds 3a–e.
Synthesis of Compounds 4: General Procedure
A mixture of 2a/2b (0.01 mol), chloroacetic acid (0.015 mol), and anhydrous sodium
acetate (0.15 g) was placed in a 100 mL conical flask containing ethanol (10 mL) and was
irradiated in the microwave oven at 160 W for 7–9 min. After the reaction was complete
(TLC), the mixture was allowed to cool to room temperature. The resulting solid was
filtered, washed with water (10 mL), and recrystallized from ethanol (2 mL) to provide
compounds 4a,b.
Synthesis of Compounds 5: General Procedure
A mixture of 2a/2b (0.01 mol), chloroacetic acid (0.01 mol), and piperidine (1.5 mL)
in a 100 mL conical flask containing ethanol (10 mL) was introduced into the microwave
oven. The reaction mixture was initially irradiated for 30 sec at 160 W. After a break for 1
min and cooling to room temperature, it was again irradiated for 7–8 min. The solid product
obtained was filtered, washed with water (10 mL), and recrystallized from ethanol (2 mL)
to afford compounds 5a,b.
Data
1H-Indole-2,3-dione-3-thiosemicarbazone (2a). Mp: 240◦C (lit.21 247–
1
249◦C); IR (KBr): υ = 3425, 3238, 1682, 1611, 1130 cm−1; H NMR (DMSO-d6): δ =
12.45 (s, 1H), 11.18 (s, 1H), 9.02 (s, 1H), 8.67 (s, 1H), 7.65 (dd, J = 1.6 Hz, J = 7.9, 1H),
7.35 (t, J = 8.4 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 13C NMR
(DMSO-d6): δ = 108, 112.2, 116, 120, 129, 137, 155, 162 (C O/C S), 176 (C O/C S).
5-Bromo-1H-indole-2,3-dione-3-thiosemicarbazone (2b). Mp: 255◦C; IR
1
(KBr): υ = 3430, 3230, 1690, 1133 cm−1; H NMR (DMSO-d6): δ = 12.47 (s, 1H),
11.17 (s, 1H), 9.02 (s, 1H), 8.68 (s, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 8.5 Hz, 1H),
7.12 (m, 1H); 13C NMR (DMSO-d6): δ = 108.3, 112.5, 117.6, 121.9, 131.4, 140.0, 156.5,
164 (C O/C S), 175 (C O/C S).
N1-Diethylaminomethyl-indole-2,3-dione-3-thiosemicarbazone (3a). Mp:
130◦C (Lit.22 135◦C); IR (KBr): υ = 3436, 3240, 1670, 1140 cm−1; 1H NMR (DMSO-d6)
δ = 12.11 (s,1H), 9.06 (s, 1H), 8.68 (s, 1H), 7.73 (dd, J = 1.8 Hz, J = 7.5 Hz, 1H), 7.45 (m,
1H), 7.17 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.52 (s, 2H), 2.65 (q, J = 6.8 Hz, 4H), 1.08
(t, J = 6.9 Hz, 6H); 13C NMR (DMSO-d6): δ = 16.6 (CH3), 39.5 (CH2), 61.7 (N-CH2-N),
108, 112, 118.5, 121.8, 132, 140, 157, 163 (C O/C S), 175 (C O/C S).
N1-Piperidin-1-ylmethyl-indole-2,3-dione-3-thiosemicarbazone (3b). Mp:
180◦C (lit.22 177–178◦C); IR (KBr): υ = 3427, 2925, 1700, 1162 cm−1; 1H NMR (DMSO-
d6): δ = 12.36 (s, 1H), 9.06 (s, 1H), 8.68 (s, 1H), 7.71 (dd, J = 1.6 Hz, J = 7.8 Hz, 1H),
7.41 (m, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.17 (m, 1H), 4.47 (s, 2H), 2.54 (t, J = 4.8 Hz,

NOVEL THIAZOLIDINONE AND THIOHYDANTOIN DERIVATIVES
2247
4H), 1.46 (m, 4H), 1.33 (m, 2H), 13C NMR (DMSO-d6): δ = 24.2, 25.8, 39.6 (CH2), 62.5
(N-CH2-N), 107.8, 112.5, 117, 121, 130.5, 140, 155, 162 (C O/C S), 177 (C O/C S).
N1-Morpholin-4-ylmethyl-indole-2,3-dione-3-thiosemicarbazone (3c).
1
Mp: 210◦C (lit.22 215–216◦C); IR (KBr): υ = 3447, 3206, 2852, 1692, 1149 cm−1; H
NMR (DMSO-d6): δ = 12.38 (s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 7.73 (dd, J = 1.8 Hz, J =
7.8 Hz, 1H), 7.42 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.15 (m, 1H), 4.49 (s, 2H), 3.54 (br s,
4H), 2.58 (br s, 4H); 13C NMR (DMSO-d6): δ = 50.9 (CH2), 61.8 (N-CH2-N), 64.4 (CH2),
107.7, 112.8, 117.5, 121, 130.3, 140, 158.2, 162 (C O/C S), 177.5 (C O/C S).
5-Bromo-N1-piperidin-1-ylmethyl-indole-2,3-dione-3-thiosemicarbazone
1
(3d). Mp: 215◦C; IR (KBr): υ = 3447, 2933, 1695, 1112 cm−1; H NMR (DMSO-d6):
δ = 12.37 (s, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.45 (m, 1H), 7.28
(d, J = 8.2 Hz, 1H), 4.48 (s, 2H), 2.52 (t, J = 4.5 Hz, 4H), 1.46 (m, 4H), 1.34 (m, 2H), 13C
NMR (DMSO-d6): δ = 24.5, 25.6, 39.5 (CH2), 61.2 (N-CH2-N), 107.2, 112.5, 118, 121.2,
130.7, 140, 158.7, 163 (C O/C S), 177 (C O/C S).
5-Bromo-N1-morpholin-4-ylmethyl-indole-2,3-dione-3-thiosemicarba-
zone (3e). Mp: 230◦C; IR (KBr): υ = 3440, 2925, 1691, 1145 cm−1
;
1H NMR
(DMSO-d6): δ = 12.39 (s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.80 (d, J = 2.4, 1H), 7.47 (m,
1H), 7.30 (d, J = 8.2 Hz, 1H), 4.50 (s, 2H), 3.54 (br s, 4H), 2.56 (br s, 4H); 13C NMR
(DMSO-d6): δ = 49.5 (CH2), 61.6 (N-CH2-N), 64.3 (CH2), 107.6, 112.5, 117.9, 122,
130.7, 140, 159, 163 (C O/C S), 176.5 (C O/C S).
2-(Isatin-3-azino)-4-thiazolidinone (4a). Mp: 210◦C; IR (KBr): υ = 3260,
1
1675, 1467, 1129 cm−1; H NMR (DMSO-d6): δ = 12.46 (s, 1H), 11.18 (s, 1H), 7.66
(dd, J = 1.8 Hz, J = 8.2 Hz, 1H), 7.37 (m, 1H), 7.10 (m, 1H), 6.93 (d, J = 8.5 Hz, 1H),
3.30 (s, 2H); 13C NMR (DMSO-d6): δ = 41.5, 151 (thiazolidinone), 109, 111.3, 116, 122.8,
129, 142, 155, 165 (C O), 174 (C O).
5-Bromo-2-(isatin-3-azino)-4-thiazolidinone (4b). Mp: 245◦C; IR(KBr): υ =
3272, 1690, 1484, 1136 cm−1; 1H NMR (DMSO-d6): δ = 12.45 (s, 1H), 11.19 (s, 1H), 7.74
(d, J = 2.2 Hz, 1H), 7.41 (m, 1H), 7.13 (m, 1H), 3.29 (s, 2H); 13C NMR (DMSO-d6): δ =
41.5, 151 (thiazolidinone), 109, 110.8, 116, 122.8, 129.8, 142, 155.7, 165 (C O), 175.2
(C O).
3-(Isatin-3-imino)-2-thiohydantoin (5a). Mp: 225◦C; IR(KBr): υ = 3269,
1
1675, 1467, 1127 cm−1; H NMR (DMSO-d6): δ = 12.26 (s, 1H), 11.29 (s, 1H), 7.80
(dd, J = 1.6 Hz, J = 8.5 Hz, 1H), 7.47 (m, 1H), 6.86 (m, 1H), 6.77 (d, J = 8.7 Hz, 1H),
3.32 (s, 2H); 13C NMR (DMSO-d6): δ = 57.5 (thiohydantoin), 108, 112, 116.5, 122.7, 126,
143, 154, 163 (C O/C S), 171.5 (C O/C S), 179 (C O/C S).
5-Bromo-3-(isatin-3-imino)-2-thiohydantoin (5b). Mp: 260◦C; IR(KBr): υ =
3274, 1693, 1485, 1137; 1H NMR (DMSO-d6): δ = 12.27 (s, 1H), 11.28 (s, 1H), 7.87 (d,
J = 2.2 Hz, 1H), 7.51 (m, 1H), 6.89 (m, 1H), 3.34 (s, 2H); 13C NMR (DMSO-d6):
57.3 (thiohydantoin), 107.8, 112, 117, 122.5, 126.2, 143, 154.2, 162 (C O/C S), 172
(C O/C S), 180 (C O/C S).
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