Microwave-assisted tandem reactions for the synthesis of 2-hydrazolyl-4-thiazolidinones

Article abstract of DOI:10.1016/j.tetlet.2008.12.020

A tandem method for the synthesis of 2-hydrazolyl-4-thiazolidinones (5) from commercially available materials in a 3-component reaction has been developed. The reaction connects aldehydes, thiosemicarbazides, and maleic anhydride, effectively assisted by

Full text of DOI:10.1016/j.tetlet.2008.12.020

Tetrahedron Letters 50 (2009) 901–904
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted tandem reactions for the synthesis of
2-hydrazolyl-4-thiazolidinones
Cecilia Saiz a, Chiara Pizzo a, Eduardo Manta a, Peter Wipf b, S. Graciela Mahler a,
*
a Laboratorio de Química Farmacéutica, DQO, Facultad de Química, Universidad de la República, Gral Flores 2124, CC 1157, Montevideo, Uruguay
b Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem method for the synthesis of 2-hydrazolyl-4-thiazolidinones (5) from commercially available
materials in a 3-component reaction has been developed. The reaction connects aldehydes, thiosemicar-
bazides, and maleic anhydride, effectively assisted by microwave irradiation. The synthesis of a new type
of compound, 2-hydrazolyl-5,5-diphenyl-4-thiazolidinone (7), obtained by treatment of thiosemicarba-
zone with benzil in basic media is also reported. HOMO/LUMO energies, orbital coefficients, and charge
distribution were used to explain the proposed reaction mechanism.
Received 9 September 2008
Revised 3 December 2008
Accepted 4 December 2008
Available online 10 December 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
2-Hydrazolyl-4-thiazolidinones
2-Hydrazolyl-5,5-diphenyl-4-
thiazolidinones
Microwave
Tandem reactions
4-Thiazolidinones are an important group of heterocycles found
in numerous natural products and pharmaceuticals.1 In particular,
2-hydrazolyl-4-thiazolidinones (5) are a class of compounds that
combine thiosemicarbazones with 4-thiazolidinones, two building
blocks with interesting biological activities. For example, Trypano-
soma cruzi,2 Plasmodium falciparum3, and antitumor4 activities have
been described for thiosemicarbazones, and COX-2 inhibition,5
anti-HIV,6 and antibacterial7 effects as well as human chondrocyte
antidegenerative8 properties have been found for 4-thiazolidinon-
es. In addition, the combination of these two pharmacophores has
been used to exhibit anti-Toxoplasma Gondii,9a antimicrobial,9b
antiviral,10 and antifungal properties.11
Among the reported methods for 2-hydrazolyl-4-thiazolidinone
synthesis is a 2 step sequence: (1) a reaction between aldehydes
(1) and thiosemicarbazides (2) to give thiosemicarbazones (3);
(2) a thia-Michael addition of thiosemicarbazones (3) to maleic
anhydride in dry PhMe and DMF at reflux to give the hydrazolyl-
4-thiazolidinone (5) (Scheme 1).9
are carried out independently and repeatedly to synthesize the tar-
get compounds. The former process allows a minimization of
waste, and, compared to stepwise reactions, the amount of solvent,
reagents, adsorbents, and energy is extensively decreased.13
The use of microwave ovens to perform organic synthesis has
received a great deal of attention over the last 10 years. Several
publications have shown that microwave irradiation can circum-
vent the need for prolonged heating,14 and it is generally accepted
that this source of energy minimizes side reactions and accelerates
the rate of chemical reactions.15
Herein, we wish to report an efficient tandem procedure for the
synthesis of 2-hydrazolyl-4-thiazolidinones under microwave con-
ditions. Different solvents and various reaction equivalents were
explored until we obtained good isolated yields of thiazolidinones
(Scheme 2, Table 1). Microwave heating for the synthesis of thiazo-
lidinone 5a resulted in a significantly better yield compared to
thermal conditions (75% vs 40%, entries 2 and 1, Table 1). Micro-
wave irradiation also allowed for a faster conversion .
As a part of our search for new biologically active heterocyclic
compounds, we focused on the possibility of optimizing this proce-
For tandem reactions, the best yields were obtained when a sol-
vent mixture of PhMe/DMF (1:1) was used. Thiazolidinone 5a was
prepared in 68% yield (54% considering both reactions) using a
stepwise sequence, and in 82% yield under tandem conditions
(entries 3 and 4, Table 1). We found that a tandem sequence was
more efficient than a stepwise conversion under microwave
irradiation.
The optimal conditions for the microwave-assisted tandem se-
quence were determined to be a mixture of PhMe/DMF (1:1) as a
solvent, with catalytic p-TsOH and an excess of maleic anhydride
(5 equiv) at 100–120 °C (Scheme 3).16
dure by developing
sequence.
a tandem microwave-assisted reaction
Multi-step or cascade reactions can be defined as the combina-
tion of two or more reactions in a specific order that occur in one
pot.12 They are very attractive due to their ease of setup. In tradi-
tional single-step processes, the reaction and product isolation
* Corresponding author. Tel.: +598 2 9290290; fax: +598 2 9241906.
E-mail address: gmahler@fq.edu.uy (S.G. Mahler).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.020

902
C. Saiz et al. / Tetrahedron Letters 50 (2009) 901–904
S
S
O
R
R
O
O
O
AcOH cat.
S
H2N
N
N
H
NHR1
4
N
H
NHR1
O
N
OH
R
EtOH/H2O
reflux
N
N
R1
O
2
PhMe/DMF
(25:1), reflux
1
3
5
Scheme 1. Stepwise 2-hydrazolyl-4-thiazolidinone synthesis under conventional conditions.
R
O
S
S
R
S
R
+
Δ or μW
Δ or μW
+
4
H2N
+
4
N
NHR1
N
H
NHR1
N
OH
N
H
O
1
N
N
R1
O
3
2
5
R = 1a p-(Me)2N-Ph
R1= H
Scheme 2. Tandem and stepwise reactions for the synthesis of 2-hydrazolyl-4-thiazolidinone.
Table 1
Comparison of stepwise and tandem reactions using regular thermal and microwave heating
Entry
Reagents
Conditions
, reflux, 12 h.
Solvent
Additive
Product, yielda (%)
1
2
3
4
3a (1 equiv), 4 (1.2 equiv)
3a (1 equiv), 4 (1.2 equiv)
3a (1 equiv), 4 (5 equiv)
D
PhMe
PhMe
PhMe/DMF
PhMe/DMF
p-TsOH (0.1 equiv)
p-TsOH (0.1 equiv)
p-TsOH (0.1 equiv)
p-TsOH (0.1 equiv)
5c (40)
5c (72)
5b (68)
5b (82)
lW, 120 °C, 6 min
lW, 120 °C, 6 min
lW, 120 °C, 6 min
1a (1 equiv), 2 (1.2 equiv), 4 (5 equiv)
a
Isolated yields after purification.
The reactivity of thiosemicarbazone 3g (R@P-MeOPh) with dif-
ferent Michael acceptors was also investigated. The reaction of 3g
with methyl acrylate17 or methyl cinnamate18 did not produce the
expected 6-membered 1,3-thiazin-4-one.
R
O
S
R
PhMe/DMF
S
H2N
4
+
+
N
H
NHR1
µW 100-120oC
p-TsOH (cat.)
N
OH
O
O
N
N
R1
1
2
5
Furthermore, we explored the reaction of thiosemicarbazones
3e (R@P-Cl-Ph) and 3g with benzil 6 as the electrophile. It is well
known that ureas and thioureas react with benzil 6 to give 4-imi-
dazolidinones through a benzilic acid rearrangement.19 Braibante
and co-workers reported recently the reaction of thiosemicarba-
zide (2, R1@H) with benzil to give 1,2,4-triazin-3-thione. The for-
mation of the 6-membered ring can be explained by the
nucleophilic attack of both N1 and N4 in compound 2 to the benzil
carbonyl groups.20 Our results indicate that the reaction of thio-
semicarbazone 3 with benzil 6 in KOH/DMSO under microwave
conditions led to 2-hydrazolyl-5,5-diphenyl-4-thiazolidinones 7e
and 7g in 45% and 22% yields, respectively (Scheme 4).21 This het-
Scheme 3. Optimized tandem reaction for 2-hydrazolyl-4-thiazolidinone synthesis
(R1@H).
Under optimized microwave conditions, a range of aromatic
and some aliphatic aldehydes were converted to the desired het-
erocycles (Table 2). Aromatic aldehydes provided good yields from
45% to 82%, at 120 °C after a 6–12 min reaction time, except for 2-
thiophene-carboxaldehyde where the yield dropped to 33%, prob-
ably due to the formation of polymeric materials derived from
the starting material (Table 2, entries 1–8). The reaction seems to
be independent of electron-withdrawing or electron-donating sub-
stitutions in the aldehydes (Table 2, entries 1 and 3).
For aliphatic aldehydes, we found that the optimum tempera-
ture was 100 °C; otherwise polymerization products were ob-
tained. Compounds 5i and 5j were thus isolated in 34% and 64%
yields, respectively (Table 2, entries 9 and 10).
KOH
DMSO
µW
Ph
S
O
O
Ph
O
S
R
N
R
N
+
N
N
NH2
120oC
Ph
Ph
N
H
3g
3e
H
6
7g 22%
7e 45%
Table 2
Scheme 4. Synthesis of 2-hydrazolyl-5,5-diphenyl-4-thiazolidinone (7).
Optimized tandem reaction for 2-hydrazolyl-4-thiazolidinone synthesis under micro-
wave irradiation conditions
Entry
Compound RCHO
Temperature
(°C), time (min)
Product
Mp (°C)
Table 3
(yield)a (%)
Electronic parameters for selected model compounds and intermediates
1
2
3
4
5
6
7
8
9
10
1a p-N(Me)2-Ph
1b p-OBut-Ph
1c p-NO2-Ph
1d o-F-Ph
1e p-Cl-Ph
1f Ph
1g p-MeOPh
1h 2-Thiophenyl
1i CH(Me)2
1j CH2CH2Ph
120, 6
120, 6
120, 12
120, 12
120, 12
120, 6
120, 9
120, 5
100, 12
100, 6
5a (82)
5b (63)
5c (61)
5d (57)
5e (70)
5f (45)
5g (61)
5h (33)
5i (34)
5j (64)
278–279 dec.
249–250
270–271 dec.
272–273
273–274
242–243
262–263
255–256
229–230
199–200
Entry
Compound
Energy (eV)
Coefficientsa(%)
Charge
HOMO
LUMO
HOMO
LUMO
1
2
3
3g
6
ꢀ8.77
ꢀ10.01
ꢀ8.69
ꢀ1.05
S 44.3
N 13.6
—
—
S ꢀ0.32
N 0.09
C1 0.29
C2 0.29
C2 0.09
C1 0.12
ꢀ0.61
ꢀ0.38
C1 25.5
C2 25.5
C2 17.0
C1 0.2
9
P
a
a
Coefficients were calculated as ð c2i Þ ꢁ 100.
Isolated yields after purification.

C. Saiz et al. / Tetrahedron Letters 50 (2009) 901–904
903
Ph
Ph
O
+
Ph
Ph
SH
NH2
OH
O
S
R
-C attack
R
-C attack
OH
Ph
S
N
S
S
1
2
R
1
N
1
N
N
N
N
N
2
2
O
8
NH2
N
Ph
OH
9
H
Ph
Ph
Ph
OH
Ph
migration
OH-
S
Ph
O-
R
N
R
N
a
N
N
H
O
N
N
9
H
7
-O
O
HO
pathways
S
OH-
Ph
Ph
Ph
S
R
S
R
R
N
Ph
Ph
N
N
N
Ph
migration
N
N
Ph
b
N
N
N
11
H
10
not observed
Scheme 5. Proposed mechanism for 2-hydrazolyl-5,5-diphenyl-4-thiazolidinone (7) formation.
erocycle was previously unknown and was now fully character-
ized. The HMBC experiment revealed a cross-peak between the
N–H proton and the carbonyl carbon at C4, thus confirming the reg-
iochemistry of the reaction.
With the goal to rationalize how this reaction proceeded, we
undertook a frontier orbital analysis using the semi-empirical
parametrization PM3.22 Table 3 shows HOMO/LUMO energies,
coefficients, and charge distributions calculated for model com-
pounds. The HOMO/LUMO energy gap is small and it would seem
that the reaction with thiosemicarbazone and benzil is kinetically
favored and frontier orbital control, and not charge control, should
govern the process.
calculations, and Dr. A. Rodríguez for HRMS ESI TOF-MS analyses
(Polo Tecnólogico-FQ; Proyecto Enlaces-UE URY-2003-5906).
References and notes
1. Verma, A.; Saraf, S. K. Eur. J. Med. Chem. 2008, 43, 897–905.
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McKerrow, J. H. U.S. Patent 6 897 240, 2004.
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Chem. 2003, 11, 999–1006.
The proposed mechanism for the formation of 2-hydrazolyl-5,5-
diphenyl-4-thiazolidinone 7 is depicted in Scheme 5. Based on
HOMO/LUMO energies and orbital coefficients, the first step should
be the nucleophilic attack of S3 to C1, one of the two carbonyl
groups present in benzil, to form the tetrahedral intermediate 8.
This intermediate proceeds by nucleophilic attack of N1 to C2 to
give intermediate 9, in similar fashion to imidazoline formation.23
According to our results, the diol 9 undergoes a phenyl group
migration, from C2 to C1, where the largest LUMO coefficient is lo-
cated (Table 3, entry 3), which is in agreement with the observed
regiochemistry, pathway a. Even though intermediate 10 was pro-
posed by Butler and co-workers as the most favorable for phenyl
group migration in the synthesis of imidazolines, in our case inter-
mediate 10 would lead to 5-thiazolidinone 11, which was never
isolated.
In summary, in this investigation we explored the microwave-
mediated tandem reactions of aldehydes, thiosemicarbazones,
and maleic anhydrides to produce 2-hydrazolyl-4-thiazolidinones,
with yields ranging from 33% to 82%. The advantages in the use of
this methodology are shorter reaction times, higher yields, and a
minimization of synthetic operations, solvent use, and waste gen-
eration. When we investigated the scope of the tandem synthesis
for hydrazolyl-4-thiazolidinones 5, we were able to demonstrate
that the process is general for aromatic and aliphatic aldehydes;
however, the use of different types of Michael acceptors has not
yet been accomplished. As an important part of this work, we also
present the synthesis of 2-hydrazoyl-5,5-diphenyl-4-thiazolidi-
none 7, a new class of 4-thiazolidinones. We propose a mechanism
for the heterocycle formation based on a benzilic acid rearrange-
ment promoted by thiosemicarbazone.
6. Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.; De Clerq, E. Bioorg. Med.
Chem. 2007, 15, 1725–1731.
7. Bonde, C. G.; Gaikwad, N. J. Bioorg. Med. Chem. 2004, 12, 2151–2161.
8. Ottanà, R.; Maccari, R.; Ciurleo, R.; Vigorita, M. G.; Panico, A. M.; Cardile, V.;
Garufi, F.; Ronsisvalle, S. Bioorg. Med. Chem. 2007, 15, 7618–7625.
9. (a) Tenorio, R.; Carvalho, C.; Pessanha, C.; de Lima, J.; de Faria, A.; Alves, A.; de
Melob, E. J.; Goes, A. Bioorg. Med. Chem. Lett. 2005, 15, 2575–2578;; (b) Aquino,
T.; Liesen, A.; Silva, R.; Lima, V.; Carvalho, C.; Faria, A.; de Araujo, J. M.; Lima, J.
G.; Alves, A. J.; de Melob, E. J. T.; Goesa, A. J. S. Bioorg. Med. Chem. 2008, 16, 446–
456.
10. Plut, M.; Pollak, A.; Tisler, M.; Likar, M.; Schauer, P. S. J. Med. Chem. 1966, 9,
430–431.
11. Krbavcic, A.; Badawy, M. A.; Abdel-Hady, S. A.; Kadry, A. M.; Ibrahim, Y. A.
Sulfur Lett. 1989, 9, 149–157.
12. Ho, T. Tandem Organic Reactions; Wiley-Interscience: New York, 1992.
13. (a) Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 32, 131–132; (b) Tietze, L. F.
Chem. Rev. 1996, 96, 115.
14. Wipf, P.; Fletcher, J. M.; Scarone, L. Tetrahedron Lett. 2005, 46, 5463–5466.
15. Hayes, B. L. Microwave Synthesis, Chemistry at the Speed of Light; CEM:
Matthews, North Carolina, 2002. Chapter 1, p 16.
16. Typical procedure for thiazolidinone preparation (5c): To a stirred solution of p-
N,N-dimethylamine benzaldehyde (300 mg, 2.0 mmol) in toluene (1 mL) and
DMF (1 mL) were added thiosemicarbazide (220 mg, 2.4 mmol), p-toluene
sulfonic acid (30 mg, 0.2 mmol,), and maleic anhydride (987 mg, 10.0 mmol).
The reaction mixture was heated in a stirred microwave vial for 9 min at 120 °C
(200 W), poured into water (30 mL), and extracted with ethyl acetate (3 x
30 mL). The combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was finally recrystallized from methanol to give
5 c (527 mg, 82% yield) as a yellow solid: mp 278–279 °C: 1H NMR (400 MHz,
D2O/K2CO3) d 2.42 (dd, J2 = 11.7, J3 = 16.2 Hz, 1H), 2.93 (s, 6H), 3.06 (dd, J2 = 4.1,
J3 = 16.2 Hz, 1H), 4.22 (dd, J1 = 4.1, J2 = 11.7 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 7.61
(d, J = 9.0 Hz, 2H), 8.20 (s, 1H); 13C NMR (100 MHz, D2O/K2CO3) d 40.02, 41.90
(Cendo), 41.99 (Cexo), 49.90, 113.44, 122.80, 129.22, 152.83, 155.88, 161.05,
178.95 (Cexo), 179.37 (Cendo), 190.77 (COOH); HRMS calcd for C14H16N4O3S
[M+ꢀH]: 319.0865, found: 319.0859.
17. Under the following reaction conditions: methyl acrylate acid, 3h, EtOH,
l
W,
K2CO3, 120 °C, 15 min or EtOH, KOH,
lW 120 °C, 15 min, no product was
observed.
18. Under the following reaction conditions: methyl cinnamate, 3h, PhMe,
120 °C, p-TosOH 19 min, no product was observed.
lW
Acknowledgments
19. Muccioli, G. G.; Poupaert, J. H.; Wouters, J.; Norberg, B.; Poppitz, W.; Scriba, G.;
Lambert, D. M. Tetrahedron 2003, 59, 1301–1307.
20. Braibante, M.; Braibante, H.; Uliana, M. P.; Costa, C. C.; Spenazzatto, M. J. Brazil
Chem. Soc. 2008, 19, 909–913.
21. To a stirred solution of 4-methoxybenzylidene thiosemicarbazone 3g (177 mg,
0.91 mmol) in DMSO (1.5 mL) were added benzil (150 mg, 0.60 mmol) and
This work was supported by the National Institutes of Health-
FIRCA (R03TW007772) and UdelaR (CSIC-No. 349). We would like
to thank Professor O. Ventura and Dr. P. Saenz in the Computa-
tional Chemistry and Biology Group for assistance in theoretical

904
C. Saiz et al. / Tetrahedron Letters 50 (2009) 901–904
KOH 1.2 M (0.3 mL, 0.36 mmol). The reaction mixture was heated in
a
microwave for 10 min at 120 °C (200 W) with stirring, poured into water
(30 mL), and extracted with ethyl acetate (3 ꢁ 30 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. The residue was finally
purified by chromatography on SiO2 (AcOEt/hexanes, 1:4) to give compound 7g
(80 mg, 22%) as a white solid: mp 192.5–193.1 °C; 1H NMR (400 MHz, CDCl3) d
3.85 (s, 3H), 6.94 (d, J = 8.8 Hz, 2H), 7.36–7.42 (m, 10H), 7.81 (d, J = 8.8 Hz, 2H),
9.08 (s, 1H), 9.10 (s, 1 HNH). 13C NMR (100 MHz, CDCl3) 55.41, 71.36, 114.25,
125.29, 127.01, 127.56, 128.69, 129.01, 130.64, 137.60, 162.91, 169.73, 180.14;
HRMS calcd for C14H16N4O3S [M+Na]+: 424.1081, found: 424.1090.
22. Available in the commercial computer program package Hyperchem Pro.
23. Butler, A. R.; Leitch, E. J. Chem. Soc., Perkin Trans. 1977, 14, 1972–1976.