An efficient method for the transformation of 5-ylidenerhodanines into 2,3,5-trisubstituted-4-thiazolidinones

Article abstract of DOI:10.1016/j.tetlet.2011.11.095

The use of 3-substituted-2-mercaptoacrylic acids, synthesized via hydrolysis of 5-ylidenerhodanines for the preparation of 2,3,5-trisubstituted-4- thiazolidinones via a new variant of the one-pot, three-component reaction has been studied.

Full text of DOI:10.1016/j.tetlet.2011.11.095

Tetrahedron Letters 53 (2012) 557–559
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Tetrahedron Letters
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An efficient method for the transformation of 5-ylidenerhodanines
into 2,3,5-trisubstituted-4-thiazolidinones
Danylo Kaminskyy a, Dmytro Khyluk a, Olexandr Vasylenko b, Roman Lesyk a,
⇑
a Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine
b Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Murmanska 1, Kyiv 02094, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of 3-substituted-2-mercaptoacrylic acids, synthesized via hydrolysis of 5-ylidenerhodanines for
the preparation of 2,3,5-trisubstituted-4-thiazolidinones via a new variant of the one-pot, three-
component reaction has been studied.
Received 2 September 2011
Revised 7 November 2011
Accepted 18 November 2011
Available online 25 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3-Substituted-2-mercaptoacrylic acids
5-Ylidenerhodanines
2,3,5-Trisubstituted-4-thiazolidinones
4-Thiazolidinones belong to privileged scaffolds in modern
medicinal chemistry and their derivatives possess a wide spectrum
of biological activity.1–3 2,3-Disubstituted-4-thiazolidinone deriva-
tives are the most investigated and they function as antiviral,4,5
anti-inflammatory,6 antimicrobial,7,8 antiasthmatic,9 and antipro-
liferative10,11 agents. The most convenient method for
2-substituted-4-thiazolidinone synthesis is the one-pot, three-
component reaction of a primary amine, an oxo-compound, and a
thiolic agent using various reaction conditions, such as extended
heating with a dehydrating agent, using an acylation agent, or
microwave-assisted organic synthesis.8,12–16 Taking into consider-
ation the critical influence of the presence and the nature of the
C5 fragment on the biological activity, introduction of the
aforementioned substituent is one of the most effective methods
for 4-thiazolidinone structural modification.1,17 This approach can
be realized using different mercapto-derivatives such as 2-mercap-
topropionic and 3-mercaptosuccinic acids and others in cyclo-
condensation reactions. However, the presence of an ylidene
moiety at the C5 position is desirable for biological activity,
especially anticancer activity.1,3,17 The synthesis of 5-ylidene-4-
thiazolidinones via Knoevenagel reaction, commonly using acetic
acid and sodium acetate as the catalysts is not effective due to
the low reactivity of the methylene group of 2-substituted-4-thia-
zolidinone in comparison with rhodanine (2-thioxo-4-thiazolidi-
none) or 2,4-thiazolidinedione derivatives.18
Hence, the aim of the present Letter was the synthesis of
5-ylidene-2,3-disubstituted-4-thiazolidinones via a novel one-pot,
three-component reaction.
The possibility of using 3-substituted-2-mercaptoacrylic acids
as thiolic agents in a one-pot, three-component reaction was
proposed based on the retrosynthetic approach for 5-ylidene-2,
3-disubstituted-4-thiazolidinones shown in Scheme 1.
For the synthesis of 3-substituted-2-mercaptoacrylic acids we
used alkaline hydrolysis of accessible 5-ylidenerhodanines 119
(Scheme 2), to obtain the appropriate thiolic agents 2.20 The
5-ylidene-2,3-disubstituted-4-thiazolidinones 3a–g were success-
fully obtained using a one-pot, three-component reaction based
on primary amines, aldehydes or cyclohexanone and thiolic agents
2 (Method a).21
The target compounds 3a–g were also synthesised using
Method b from 5-unsubstituted-2,3-substituted-4-thiazolidinones
4 via Knoevenagel reaction.21 The yields of target compounds 3a–g
using Method b were in the range 35–56%.22
The structures of the synthesized compounds were elucidated
from spectral data.22 The 1H NMR spectra of 2-arylsubstituted-4-
O
O
R
O
OH
SH
N
R
NH2
R1
+
+
R1
R2
S
R2
A
A
⇑
Corresponding author. Tel./fax: +38 032 275 7734.
E-mail address: dr_r_lesyk@org.lviv.net (R. Lesyk).
Scheme 1. General scheme for the synthesis of 2,3,5-trisubstituted-4-
thiazolidinones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.095

558
D. Kaminskyy et al. / Tetrahedron Letters 53 (2012) 557–559
Method a
O
O
H
OH
ii
i
R3
N
S
S
SH
1
2
1
2
3
3
a
R
R ; R or R +R
H; Ph
R
R
O
2a-e
1a-e
R
4-Cl-C6H4
Me
O
b
c
4-Cl-C6H4
H; 4-Me2N-C6H4 Cl
N
R1
R3
4-MeO-C6H4
4-MeO-C6H4
4-Me2N-C6H4
H; Ph
(CH2)5
H; Ph
Me
Cl
d
e
S
R2
Method b
Me
R
3a-g
f
Ph-CH=CH
2-HO-C6H4
H; Ph
Me
Cl
O
g
(CH2)5
OH
SH
N
R1
ii
iii
S
R2
4a-c
Scheme 2. Synthesis of 5-ylidene-2,3-disubstituted-4-thiazolidinones 3. Reagents, conditions and yields: (i) 1 (1.0 equiv), NaOH (5.0 equiv) 30% aq solution, reflux, 0.5 h;
conc. HCl (5.0 equiv) solution, 89–95%; (ii) 2 or thioglycolic acid (1.0 equiv), appropriate amine (0.5 equiv), appropriate aldehyde or cyclohexanone (0.5 equiv), benzene,
reflux, 24 h, 56–78% (compounds 3), 60–71% (compounds 4); (iii) 4 (1.0 equiv), appropriate aldehyde (1.1 equiv), KOt-Bu (1.5 equiv), i-PrOH, reflux, 3 h, 57–78%.
12. Shaker, R. M. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 149, 7–14.
13. Smith, R. L.; Lee, T.; Gould, N. P.; Cragoe, E. J. J. Med. Chem. 1977, 20, 1292–1299.
14. Dandia, A.; Singh, R.; Khaturia, S.; Mérienne, C.; Morgant, G.; Loupy, A. Bioorg.
thiazolidinones 3a–c,e,f showed a singlet at ꢀ4.70–6.85 ppm due
to a CH group. The chemical shift of the methylidene group of
the 5-arylidene derivatives was in the range 7.40–8.00 ppm. Sig-
nals at ꢀ6.0 ppm representative of E-isomers were not observed.
This indicated formation of Z-isomers, as in the case of rhodanine
or 2,4-thiazolidinone derivatives.1,23,24 The signals of the aromatic
protons and cyclohexyl fragment were at expected values.
Newly synthesized compounds 3a–c, 3e and 3g were selected
by the National Cancer Institute (NCI) Developmental Therapeutic
Program (http://www.dtp.nci.nih.gov) for in vitro cell line screen-
ing to investigate their anticancer activity. Anticancer assays were
performed according to the US NCI protocol.25–27 The tested com-
pounds (concentration 10À5 M) showed insignificant anticancer
activity—having weak average values (based on 60 cancer cell
lines) of anticancer activity, however, they possessed specific influ-
ence on some cancer cell lines.28 The leukemia panel was the most
sensitive to the tested compounds
Med. Chem. 2006, 14, 2409–2417.
15. Gududuru, V.; Nguyen, V.; Dalton, J. T.; Miller, D. D. Synlett 2004, 2357–2358.
16. Srivastava, T.; Haq, W.; Katti, S. B. Tetrahedron 2002, 58, 7619–7624.
17. Kaminskyy, D.; Zimenkovsky, B.; Lesyk, R. Eur. J. Med. Chem. 2009, 44, 3627–
3636.
18. Brown, F. C.; Jones, R. S.; Kent, M. Can. J. Chem. 1963, 41, 817–820.
19. Dobrina, V. A.; Ioffe, D. V. Pharm. Chem. J. 1978, 11, 817–818.
20. Preparation of 3-substituted-2-mercaptoacrylic acids 2. A 30% aq solution of
NaOH (50 mmol) was added to 5-ylidenerhodanine 1 (10 mmol). The reaction
mixture was refluxed for 30 min and cooled. An equimolar amount of conc. HCl
was added and the mixture was diluted with H2O (150 ml). The product was
filtered and recrystallized from EtOH or EtOH/H2O (1:1).
21. Preparation of 5-ylidene-2,3-disubstituted-4-thiazolidinones 3. Method a: A
mixture of appropriate amine (5 mmol), aldehyde or cyclohexanone (5 mmol)
and 3-substituted-2-mercaptoacrylic acid
2 (10 mmol) in benzene was
refluxed for 24 h using a Dean–Stark apparatus. The reaction mixture was
added to an aq solution of NaHCO3, after cooling. The crude precipitate was
filtered and recrystallized from AcOH. Method b: Preparation of 2,3-
substituted-4-thiazolidinones 4.
A mixture of the appropriate amine
(8 mmol), aldehyde or cyclohexanone (8 mmol) and thioglycolic acid
(16 mmol) in benzene was refluxed for 24 h using a Dean–Stark apparatus.
After cooling, the mixture was added to an aq solution of NaHCO3. The crude
precipitate was filtered and recrystallized from AcOH or EtOH. Preparation of
5-ylidene-2,3-disubstituted-4-thiazolidinones 3. A mixture of appropriate 2,3-
Acknowledgment
We thank Dr. V. L. Narayanan from the Drug Synthesis and
Chemistry Branch, National Cancer Institute, Bethesda, MD, USA,
for in vitro evaluation of anticancer activity.
disubstituted-4-thiazolidinone
4 (5 mmol), aromatic aldehyde (5.5 mmol),
KOt-Bu (7.5 mmol) and i-PrOH (15 ml) was refluxed for 3 h. AcOH (1 ml) was
added after cooling. The product was filtered and recrystallized from AcOH.
22. Spectral and analytical data for compounds 3. 5-(4-Chlorobenzylidene)-2-
phenyl-3-(4-methyphenyl)-4-thiazolidinone (3a). Yield 78% (Method a), 53%
(Method b), mp >230 °C (AcOH). 1H NMR (400 MHz, DMSO-d6): 2.24 (s, 3H,
CH3), 6.79 (s, 1H, 2-H), 7.10 (d, J = 8.2 Hz, 2H, Ar), 7.22–7.31 (m, 5H, Ar), 7.35 (d,
J = 7.35 Hz, 2H, Ar), 7.45 (d, J = 8.5 Hz, 2H, Ar), 7.49 (s, 1H, CH@), 7.55 (d,
J = 8.5 Hz, 2H, Ar). 13C NMR (100 MHz, DMSO-d6): 165.0, 138.9, 136.8, 135.2,
134.1, 133.3, 131.3, 129.8, 129.5, 129.4, 127.6, 127.5, 126.0, 123.6, 63.0, 21.0.
Anal. Calcd for C23H18ClNOS,% C, 70.49; H, 4.63; N, 3.57. Found,%: C, 70.60; H,
4.75; N, 3.90.
References and notes
1. Lesyk, R. B.; Zimenkovsky, B. S. Curr. Org. Chem. 2004, 8, 1547–1577.
2. Prabhakar, Y. S.; Solomon, V. R.; Gupta, M. K.; Katti, S. B. Top. Heterocycl. Chem.
2006, 4, 161–249.
3. Lesyk, R. B.; Zimenkovsky, B. S.; Kaminskyy, D. V.; Kryshchyshyn, A. P.;
Havryluk, D. Ya.; Atamanyuk, D. V.; Subtel’na, I. Yu.; Khyluk, D. V. Biopolym. Cell.
2011, 27, 107–117.
4. Barreca, M. L.; Chimirri, A.; De Luca, L.; Monforte, A. M.; Monforte, P.; Rao, A.;
Zappalà, M.; Balzarini, J.; De Clercq, E.; Pannecouque, C.; Witvrouw, M. Bioorg.
Med. Chem. Lett. 2001, 11, 1793–1796.
5. Barreca, M. L.; Balzarini, J.; Chimirri, A.; De Clercq, E.; De Luca, L.; Höltje, H. D.;
Höltje, M.; Monforte, A.-M.; Monforte, P.; Pannecouque, C.; Rao, A.; Zappalà, M.
J. Med. Chem. 2002, 45, 5410–5413.
5-(4-Chlorobenzylidene)-3-(4-chlorophenyl)-2-(4-dimethylaminophenyl)-4-
thiazolidinone (3b). Yield 56% (Method a), 35% (Method b), mp >230 °C (AcOH).
1H NMR (400 MHz, DMSO-d6): 2.88 (s, 6H, 2 Â CH3), 6.54 (d, J = 8.8 Hz, 2H, Ar),
6.72 (s, 1H, 2-H), 7.15 (d, J = 8.8 Hz, 2H, Ar), 7.31 (d, J = 8.8 Hz, 2H, Ar), 7.41–
7.45 (m, 4H, Ar), 7.47 (s, 1H, CH@), 7.54 (d, J = 8.8 Hz, 2H, Ar). 13C NMR
(100 MHz, DMSO-d6): 164.8, 139.3, 135.4, 133.7, 133.5, 133.3, 131.3, 130.1,
129.4, 129.2, 127.4, 128.5, 128.2, 125.8, 115.0, 62.8, 45.0. Anal. Calcd for
6. Look, G. R.; Schullek, J. R.; Holmes, C. P.; Chinn, J. P.; Gordon, E. M.; Gallop, M. A.
Bioorg. Med. Chem. Lett. 1996, 6, 707–712.
7. Babaoglu, K.; Page, M. A.; Jones, V. C.; McNeil, M. R.; Dong, C.; Naismith, J. H.;
Lee, R. E. Bioorg. Med. Chem. Lett. 2003, 13, 3227–3230.
8. Kavitha, C. V.; Basappa; Nanjunda Swamy, S.; Mantelingu, K.; Doreswamy, S.;
Sridhar, M. A.; Shashidhara Prasad, J.; Kanchugarakoppal Rangappa, S. Bioorg.
Med. Chem. 2006, 14, 2290–2299.
9. Allen, S.; Newhouse, B.; Anderson, A. S.; Fauber, B.; Allen, A.; Chantry, D.;
Eberhard, C.; Odingo, J.; Burges, L. E. Bioorg. Med. Chem. Lett. 2004, 14, 1619–
1624.
C
24H20Cl2N2OS. C, 63.30; H, 4.43; N, 6.15. Found,%: C, 63.50; H, 4.55; N, 6.40.
5-(4-Methoxybenzylidene)-2-phenyl-3-(4-methyphenyl)-4-thiazolidinone
(3c). Yield 71% (Method a), 47% (Method b), mp >230 °C (AcOH). 1H NMR
(400 MHz, DMSO-d6): 2.21 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 6.84 (s, 1H, 2-H),
7.04 (d, J = 8.3 Hz, 2H, Ar), 7.13 (d, J = 7.9 Hz, 2H, Ar), 7.22–7.37 (m, 7H, Ar),
7.51 (s, 1H, CH@), 7.52 (d, J = 8.8 Hz, 2H, Ar), 13C NMR (100 MHz, DMSO-d6):
165.5, 159.86, 139.3, 136.6, 135.4, 131.4, 129.8, 129.4, 129.3, 127.8, 127.4,
126.0, 125.0. 123.6, 115.0, 62.7, 55.8, 21.0. Anal. Calcd for C24H21NO2S. C, 74.39;
H, 5.46, N, 3.61. Found,%: C, 74.55; H, 5.65; N, 3.80.
4-(4-Chlorophenyl)-2-(4-methoxybenzylidene)-1-thia-4-aza-spiro[4.5]decan-
3-one (3d). Yield 71% (Method a), 48% (Method b), mp 194–197 °C (AcOH). 1
H
10. Gududuru, V.; Hurh, E.; Dalton, J. T.; Millera, D. D. Bioorg. Med. Chem. Lett. 2004,
14, 5289–5293.
11. Ottana, R.; Carotti, S.; Maccari, R.; Landini, I.; Chiricosta, G.; Caciagli, B.;
Vigorita, M. G.; Mini, E. Bioorg. Med. Chem. Lett. 2005, 15, 3930–3933.
NMR (400 MHz, DMSO-d6): 0.93–1.00 (m, 1H, cyclohex.), 1.49–1.60 (m, 3H,
cyclohex.), 1.68 (m, 2H, cyclohex.), 1.77 (m, 2H, cyclohex.), 2.00 (m, 2H,
cyclohex.), 3.80 (s, 3H, OCH3), 7.07 (d, J = 8.4 Hz, 2H, Ar), 7.34 (d, J = 8.2 Hz, 2H,

D. Kaminskyy et al. / Tetrahedron Letters 53 (2012) 557–559
559
Ar), 7.37 (s, 1H, CH@), 7.58 (d, J = 8.2 Hz, 4H, Ar). 13C NMR (100 MHz, DMSO-
d6): 166.2, 159.9, 135.8, 134.0, 133.1, 131.3, 129.8, 127.9, 124.6, 122.9, 114.9,
73.7, 55.8, 39.3, 24.1, 24.0. Anal. Calcd for C22H22ClNO2S. C, 66.07; H, 5.54; N,
3.50. Found,%: C, 66.20; H, 5.70; N, 3.60.
5-(4-Dimethylaminobenzylidene)-2-phenyl-3-(4-methyphenyl)-4-
thiazolidinone (3e). Yield 73% (Method a), 56% (Method b), mp >230 °C (AcOH).
1H NMR (400 MHz, DMSO-d6): 2.24 (s, 3H, CH3), 2.97 (s, 6H, N(CH3)2), 6.67 (s,
1H, 2-H), 6.77 (d, J = 7.6 Hz, 2H, Ar), 7.11 (d, J = 7.4 Hz, 2H, Ar), 7.22–7.42 (m,
9H, Ar), 7.45 (s, 1H, CH@). 13C NMR (100 MHz, DMSO-d6): 164.6, 139.4, 139.3,
136.3, 135.3, 131.3, 129.3, 129.1, 127.9, 127.7, 127.5, 124.5, 123.6, 122.2, 114.7,
62.6, 41.2, 20.9. Anal. Calcd for C25H24N2OS. C, 74.97; H, 6.04; N, 6.99. Found,%:
C, 75.10; H, 6.20; N, 7.15.
cyclohex.), 1.93–2.03 (m, 2H, cyclohex.), 6.89–6.96 (m, 2H, Ar), 7.14–7.23 (m,
1H, Ar), 7.32 (d, J = 8.6 Hz, 2H, Ar), 7.47–7.53 (m, 1H, Ar), 7.56 (d, J = 8.6 Hz, 2H,
Ar), 7.70 (s, 1H, CH@), 10.07 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6): 164.3,
151.2, 135.3, 134.1, 133.2, 130.1, 129.1, 127.5, 127.3, 124.1, 123.5, 118.2, 113.3,
75.1, 39.2, 23.9, 24.0. Anal. Calcd for C21H20ClNO2S. C, 65.36; H, 5.22; N, 3.63.
Found,%: C, 65.50; H, 5.30; N, 3.70.
23. Popov-Pergal, K.; Cekovic, Z.; Pergal, M. J. Gen. Chem. USSR 1991, 61, 1958–
1962.
24. Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm.
Bull. 1991, 39, 1440–1445.
25. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose,
C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A. J. Nat. Cancer Inst. 1991, 83, 757–766.
26. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91–109.
27. Monks, A.; Scudiero, D. A.; Johnson, G. S.; Paull, K. D.; Sausville, E. A. Anticancer
Drug Des. 1997, 12, 533–541.
28. Compounds 3a–c, 3e, and 3g were evaluated toward a panel of 60 human
tumor cell lines at a concentration of 10À5 M and showed the following mean
growth percent values: 3a—90.54%, 3b—109.56%, 3c—97.11%, 3e—98.75% and
3g—85.82%. However, growth percent values decreased for selected leukemia
cell lines under the action of compounds 3a, 3c and 3g: K562—27.25%, RPMI-
8226—39.76%, SR—62.30% (compound 3a); HL-60(TB)—61.22%, RPMI-8226—
64.84%, SR—60.47% (compound 3c); MOLT-4—65.22%, RPMI-8226—67.76%
(compound 3g).
2-Phenyl-5-(3-phenylallylidene)-3-(4-methyphenyl)-4-thiazolidinone
(3f).
Yield 75% (Method a), 42% (Method b), mp >230 °C (AcOH). 1H NMR
(400 MHz, DMSO-d6): 2.20 (s, 3H, CH3), 6.81 (s, 1H, 2-H), 6.84–6.91 (m, 1H,
Ar), 6.97–7.00 (m, 1H, Ar), 7.03–7.14 (m, 3H, Ar), 7.16–7.22 (m, 1H, Ar), 7.23–
7.42 (m, 9H, Ar), 7.55 (d, J = 7.9 Hz, 2H, Ar). 13C NMR (100 MHz, DMSO-d6):
173.8, 164.8, 139.4, 138.3, 136.8, 136.6, 135.4, 129.8, 129.4, 129.3, 129.1, 128.9,
127.5, 127.4, 125.8, 124.9, 124.6, 62.7, 21.0. Anal. Calcd for C25H21NOS. C,
78.30; H, 5.52; N, 3.65. Found,%: C, 78.50; H, 5.65; N, 3.80.
4-(4-Chlorophenyl)-2-(2-hydroxybenzylidene)-1-thia-4-aza-spiro[4.5]decan-
3-one (3g). Yield 75% (Method a), 42% (Method b), mp >230 °C (AcOH). 1H NMR
(400 MHz, DMSO-d6): 0.90–1.06 (m, 1H, cyclohex.), 1.49–1.73 (m, 7H,