Efficient solvent-free synthesis of thiazolidin-4-ones from phenylhydrazine and 2,4-dinitrophenylhydrazine

Article abstract of DOI:10.1016/j.tetlet.2010.04.026

An efficient solvent-free synthesis of thiazolidinones from reaction of mercaptoacetic acid, aldehydes (benzaldehyde and valeraldehyde) or ketones (cyclopentanone and cyclohexanone), and hydrazines (phenylhydrazine and 2,4-dinitrophenylhydrazine) is reported. The compounds were generally characterized by spectroscopic techniques and specifically for 2-cyclohexanyl-3-(N-phenyl)-1,3-thiazolidin-4-one by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2010.04.026

Tetrahedron Letters 51 (2010) 3106–3108
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient solvent-free synthesis of thiazolidin-4-ones from phenylhydrazine
and 2,4-dinitrophenylhydrazine
Patrícia D. Neuenfeldt a, Bruna B. Drawanz a, Geonir M. Siqueira a, Claudia R. B. Gomes b,
Solange M. S. V. Wardell b,c, Alex F. C. Flores d, Wilson Cunico a,b,
*
a Departamento de Química Orgânica, Universidade Federal de Pelotas (UFPel), Campus Universitário, s/n°, Caixa Postal 354, 96010-900 Pelotas, RS, Brazil
b Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos—Farmanguinhos, R. Sizenando Nabuco 100, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil
c CHEMSOL, 1 Harcourt Road, Aberdeen, AB155NY, Scotland, UK
d Departamento de Química, UFSM, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient solvent-free synthesis of thiazolidinones from reaction of mercaptoacetic acid, aldehydes
(benzaldehyde and valeraldehyde) or ketones (cyclopentanone and cyclohexanone), and hydrazines
(phenylhydrazine and 2,4-dinitrophenylhydrazine) is reported. The compounds were generally charac-
terized by spectroscopic techniques and specifically for 2-cyclohexanyl-3-(N-phenyl)-1,3-thiazolidin-
4-one by X-ray crystallography.
Received 14 October 2009
Revised 7 April 2010
Accepted 8 April 2010
Available online 13 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Solvent free
Thiazolidinones
Heterocycles
Hydrazones
In recent years, thiazolidinones and their derivatives have be-
come among the most extensively investigated compounds. They
constitute an important group of heterocyclic compounds, having
valuable biological activities in the areas of medicine and agricul-
ture. They have found uses, for example, as antimalarial,1 antimi-
crobial2,3 anti-inflammatory,4,5 and antiviral agents, specially as
anti-HIV agents.6,7 The biological activity of thiazolidinones is re-
ported to be associated with their ability to assume a ‘butterfly-
like’ conformation. This provides a binding mode similar to that
provided by others non-nucleosides reverse transcriptase inhibi-
tors (NNRTIs).8
The main synthetic routes to 1,3-thiazolidin-4-ones involve
three components (an aldehyde, an amine, and mercaptoacetic
acid), either in a one- or two-step process.9 The reactions proceed
by initial formation of an imine, which undergoes attack by the sul-
fur nucleophile, followed by intramolecular cyclization on elimina-
tion of water. The most common protocol to remove the water is
by azeotropic distillation. DCC, which is extensively used in pep-
tide synthesis dehydration, strongly promotes the dehydration
here too.10
fragment.11,12 Such reactions have also been carried out using
microwave irradiation with drastic reductions in reaction times.13
In continuation of our research program, we have studied the sol-
vent-free synthesis of five-membered heterocyclic thiazolidinones
from phenylhydrazine and 2,4-dinitrophenylhydrazine as the ami-
no cores.
The spirothiazolidinones 6a and 6b are know in the literature,
however, their synthesis require long reaction times (20 h) high
temperatures (110 °C) in either one- or two-step procedures.14
Recently, the N-phenylhydrazone 5d and the corresponding thia-
zolidinone 6d were obtained using microwave irradiation with
good yields in short reaction times.15 To our knowledge, the
2-butyl-3-anilino-1,3-thiazolidin-4-one 6c and thiazolidinones
8a–d have not been previously reported in the literature.
In our study, we initially isolated the hydrazones intermediates
5a–d and 7a–d16 in near quantitative yields (90–98%) on refluxing
the hydrazines (1,2) with carbonyl compounds 4a–d in toluene
with water removal using a Dean–Stark apparatus. The same yields
could also be obtained refluxing the precursors in methanol with
Dean–Stark system. Subsequently, the thiazolidinones 6a–d were
synthesized from cyclocondensation reactions of the phenylhyd-
razones intermediates 5a–d using a large excess of mercaptoacetic
acid 3, without any solvent at 60 °C (Scheme 1). To improve our
studies, we applied the same methodology to synthesize the het-
erocycles 8a–d from 2,4-dinitrophenylhydrazones 7a–d and the
mercaptoacetic acid as the solvent in good yields (Scheme 1).
Recently, we published some results on the formation of thiazo-
lidinones by cyclocondensation reaction of arenealdehydes,
mercaptoacetic acid and the aminoacid valine, as the amino
* Corresponding author. Tel.: +55 533275 7358.
E-mail address: wjcunico@yahoo.com.br (W. Cunico).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.026

P. D. Neuenfeldt et al. / Tetrahedron Letters 51 (2010) 3106–3108
3107
R
R
R
R2
H
N
O
O
NHNH2
R1
ii
N
i
1
R
R2
+
N
S
N
H
R
R
90-98%
R
R2 R1
1, 2
4a-d
5a-d, 7a-d
6a-d, 8a-d
R = H (1,5,6)
R = NO2 (2,7,8)
i: toluene or methanol, reflux, 3h
ii: HSCH2COOH 3, 60ºC, 1-3h
yields (%)a
89 (80)c
melting point (ºC)b
155-156 (157)c
product
6a
entry
R
H
R1
R2
1
2
3
4
5
6
7
8
-CH2CH2CH2CH2-
H
-CH2CH2CH2CH2CH2-
6b
81 (80)c
91
169-171 (171)c
oil
H
H
H
n-Bu
6c
H
Ph
6d
85 (76)d
84
166-168 (165)d
184-186
NO2
NO2
NO2
NO2
-CH2CH2CH2CH2-
8a
-CH2CH2CH2CH2CH2-
8b
86
199-200
H
H
n-Bu
8c
79
124-127
Ph
8d
81
191-192
Scheme 1.
The crude products were purified by column chromatography
using silica gel with hexane/ethyl acetate mixture (3:1) as the
eluent.
tion of thiazolidinones 8a–d even after long reaction time. In these
reactions, the precursors 7a–d were fully recovered.
The compounds 6a–d and 8a–d have been characterized gener-
ally by NMR and mass spectrometry. The structure of compound
6b was also confirmed by X-ray crystallography (Fig. 1). The atom
arrangements of spirothiazolidinone 2-cyclohexanyl-3-(N-phe-
nyl)-1,3-thiazolidin-4-one 6b with selected geometric parameters
are shown in Figure 1.17 According to Cremer and Pople puckering
analysis,18 the conformation of the thiazolidin-4-one ring is best
described as having a twisted conformation [on S1–C2] and the
cyclohexanyl ring has the expected chair conformation. The thiazo-
lidinone and phenyl rings are nearly orthogonal to each other, with
a best plane between the rings of 79.39 (0.05)°.
In conclusion, our methodology can be applied to the synthesis of
thiazolidinones from hydrazines, in particular to thiazolidinones de-
rived from 2,4-dinitrophenylhydrazine that cannot be synthesized
by literature methods. This new methodology is easy, requires low
temperatures, short reaction times, under solvent-free conditions
with the potential of preparing a wide range of thiazolidinones
We have investigated these reactions in more detail. The
one-pot reaction of 1 equiv of phenylhydrazine 1, 1 equiv of appro-
priated ketone (4a,b) or aldehyde (4c,d) with 3 equiv of mercapto-
acetic acid 3 in toluene using a Dean–Stark trap for 6 h, gave the
thiazolidinones 6a–d in good yields after purification by column
chromatography (Scheme 2). Unfortunately, the one-pot reaction
using 2,4-dinitrophenylhydrazine 2 as the amino precursor, car-
bonyl compounds 4a–d and mercaptoacetic acid 3 in toluene, did
not produce the expected thiazolidinones 8a–d, but rather the
2,4-dinitrophenylhydrazones intermediates 7a–d in excellent
yields (Scheme 2). The desired thiazolidinones 8a–d could not be
obtained even with very long reaction time (up to 96 h) or with
large excesses of mercaptoacetic acid in toluene. We also at-
tempted the synthesis of compounds 8a–d in a two-step process
from reaction of intermediates 7a–d and excess of mercaptoacetic
acid 3 in toluene reflux. However, we did not observe the forma-
O
R = H
N
S
N
H
74-85%
R2 R1
R
O
NHNH2
6a-d
i
+
HSCH2COOH
R1
4a-d
R2
+
R2
R
NO2
3
H
N
1, 2
R = NO2
88-97%
N
R1
i: toluene, Dean-Stark, 110ºC, 6 h
7a-d
O2N
Scheme 2.

3108
P. D. Neuenfeldt et al. / Tetrahedron Letters 51 (2010) 3106–3108
C2-S1
S1-C5
C5-C4
C4-N3
N3-C2
= 1.8411(16)
= 1.8102(18)
= 1.508(2)
= 1.355(2)
= 1.475(2)
N3-N11 = 1.4052(18)
N11-C12 = 1.412(2)
C2-C10
= 1.528(2)
C2-C6 = 1.532(2)
N3-N11-C12 = 116.64(13)
S1-C5-C4 = 107.20(12)
C5-C4-N3 = 111.63(14)
C4-N3-C2 = 119.45(13)
N3-C2-S1 = 102.62(10)
C2-S1-C5 = 92.91(8)
Figure 1. Molecular structure and selected geometric parameters, (Å, °), for compound 6b. Ellipsoids, for non-hydrogen atoms, are drawn at the 50% probability level: H
atoms are drawn as arbitrary spheres.
2. Kavitha, C. V.; Basappa, B.; Swamy, S. N.; Mantelingu, K.; Doreswamy, S.;
Sridhar, M. A.; Prasad, J. S.; Rangappa, K. S. Bioorg. Med. Chem. 2006, 14, 2290.
3. Shah, T. J.; Desai, V. A. Arkivoc 2007, Xiv, 218.
4. Kumar, A.; Sharma, S.; Archana, A.; Bajaj, K.; Sharma, S.; Panwar, H.; Singh, T.;
Srivastava, V. K. Bioorg. Med. Chem. 2003, 11, 5293.
5. Sharma, S.; Singh, T.; Mittal, R.; Saxena, K. K.; Srivastava, V. K.; Kumar, A. Arch.
Pharm. Chem. Life Sci. 2006, 339, 145.
6. Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.; De Clercq, E. Eur. J. Med.
Chem. 2008, 43, 2800.
7. Ravichandran, V.; Prashantha Kumar, B. R.; Sankar, S.; Agrawal, R. K. Eur. J. Med.
Chem. 2009, 44, 1180.
8. Barreca, M. L.; Carotti, A.; Carrieri, A.; Chimirri, A.; Monforte, A. M.; Pellegrini
Calace, M. L.; Rao, A. Bioorg. Med. Chem. 1997, 7, 2283.
9. Cunico, W.; Gomes, C. R. B.; Vellasco, W. T., Jr. Mini-Rev. Org. Chem. 2008, 5, 336.
10. Srivastava, T.; Haq, W.; Katti, S. B. Tetrahedron 2002, 58, 7619.
11. Cunico, W.; Capri, L. R.; Gomes, C. R. B.; Sizilio, R. H.; Wardell, S. M. S. V.
Synthesis 2006, 3405.
12. Cunico, W.; Gomes, C. R. B.; Ferreira, M. L. G.; Capri, L. R.; Soares, M.; Wardell, S.
M. S. V. Tetrahedron Lett. 2007, 48, 6217.
Unless otherwise indicated, all common reagents and sol-
vents were used as obtained from commercial suppliers without
further purification. 1H and 13C NMR spectra were recorded on a
Bruker DRX 400 spectrometer (1H at 400.14 MHz and 13C at
100.61 MHz) in CDCl3 containing TMS as an internal standard.
Mass spectra were registered in a SHIMADZU QP 2010 spectrome-
ter connected to a GC-SHIMADZU 2010. Melting points were deter-
mined using open capillaries on a Tecnopon PFM II apparatus and
are uncorrected.
General procedure for the synthesis of thiazolidinones 6a–d and
8a–d: A mixture of phenylhydrazone 5a–d or 7a–d (1 mmol) and
excess of mercaptoacetic acid 3 (1 ml) was heated at 60°C until reac-
tion was complete, as shown by TLC (about 3 h). Ethyl acetate (5 ml)
was added, the organic layer was washed with saturated NaHCO3
(3 Â 20 ml) and water (1 Â 10 ml), dried with MgSO4, and concen-
trated to give an oil. The oil was purified by column chromatography
on silica gel using hexane/ethyl acetate as eluent (3:1).
13. Cunico, W.; Vellasco, W. T., Jr.; Moreth, M.; Gomes, C. R. B. Lett. Org. Chem. 2008,
5, 349.
14. Reddy, R. R.; Iyengar, D. S.; Bhalerao, U. T. J. Heterocyclic Chem. 1985, 22, 321.
15. Suthakaran, R.; Kavimani, S.; Venkappayya, D.; Jayasree, P.; Deepthi, V.;
Tehseen, F.; Suganthi, K. Rasayan J. Chem. 2008, 1, 30.
16. Selected 1H NMR data for pentanal (2,4-dinitro)phenyl hydrazone 7c: 1H NMR
(400 MHz, CDCl3): 11.01 (s, 1H, NH); 9.11 (d, 1H, Ph, J = 2.4 Hz); 8.29 (dd, 1H,
Ph, J = 9.2 Hz, 2J = 2.4 Hz); 7.92 (d, 1H, Ph, J = 9.6 Hz); 7.54 (t, 1H, CH, J = 5.6 Hz);
2.43 (m, 2H, CH2); 1.60 (m, 2H, CH2); 1.43 (sext, 2H, CH2, J = 7.4 Hz); 0.97 (t, 3H,
CH3, J = 7.4 Hz).
Acknowledgments
The authors thank UFPel and Farmanguinhos for the financial
support of the research and thank the EPSRC X-ray Crystallo-
graphic Service, University of Southampton, England, for the data
collections.
17. X-ray crystal data for 6b: CCDC 749873; empirical formula C14H18N2OS;
formula weight 262.36; T = 120(2) K; k = 0.71073 Å; crystal system =
monocyclic; space group P21/n; unit cell dimensions a = 9.4203(4) Å,
a = 90°,
b = 6.8798(3) Å, b = 101.496(3)°, c = 20.8371(9) Å, d = 90°; V = 1323.36(10) Å3;
z-4; D = 1.317 mg/mÀ3
;
l
= 0.235 mmÀ1; F(0 0 0) = 560; crystal size = 0.28 Â
Supplementary data
0.14 Â 0.10 mm;
h range for data collection 3.12–27.56°; index ranges
À12 6 h 6 11; À8 6 k 6 8; À27 6 l 6 27; reflections collected 16,344;
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.026.
independent reflections 3026 [R(int) = 0.0550]; reflections observed = 2402;
data
completeness = 0.994;
absortion
correction = none;
refinement
method = full-matrix least-squares on FÀ2; goodness-of-fit on F2 = 1.059; final
R
indices R1 = 0.0424, wR2 = 0.0939 [I > 2r(I)]; R indices = R1 = 0.0580,
wR2 = 0.1018; largest difference peak and hole = 0.360 and À0.275 e AÀ3
.
References and notes
Structure solution and refinement were achieved using SHELX97 and SHELXL97
(Sheldrick, G.M.) SHELXS97 and SHELXL97, University of Göttingen, Germany, 1997.
18. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354.
1. Solomon, V. R.; Haq, W.; Srivastava, K.; Puri, S. K.; Katti, S. B. J. Med. Chem. 2007,
50, 394.