Facile Synthesis of Some New Pyrazole-Based 2-Thioxo-4-thiazolidinone

Article abstract of DOI:10.1080/00397911.2015.1100312

5-Ethoxymethylene-2-thioxo-4-thiazolidinone (1) reacts with hydrazine hydrate at room temperature to afford 5-(hydrazinylmethylene)-2-thioxo-4-thiazolidinone (3). Compound 3 condensed with different aromatic aldehydes 6a-d in ethanol in the presence of a few drops of piperidine to give the corresponding Schiffs bases 7a-d. On the other hand, compound 3 reacts with o-hydroxybenzaldehyde derivatives 8a and 8b in refluxing ethanol catalyzed by a few drops of piperidine to yield 1H-inadzolyl-2-thioxo-4-thiazolidinones 9a and 9b. Reaction of compound 3 with α-ketoesters 10a and 10b or α-diketones 10c-e in refluxing glacial acetic acid furnished the pyrazolyl-2-thioxo-4-thiazolidinone derivatives 11a-e. Also, compound 3 reacts with some different enaminones 12a-f in refluxing glacial acetic acid to afford the new pyrazolyl-2-thioxo-4-thiazolidinone derivatives 13a-f. Pyrazoles 15a-d was obtained via reaction of compound 3 with chalcones 14a-d in dimethylformamide (DMF). The structures of all the newly synthesized products were confirmed on the basis of their elemental and spectral data, and a plausible mechanism has been postulated to account for their formation.

Full text of DOI:10.1080/00397911.2015.1100312

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile Synthesis of Some New Pyrazole-Based 2-
Thioxo-4-thiazolidinone
Nadia Hanafy Metwally & Ibrahim Adel El-Doseky
To cite this article: Nadia Hanafy Metwally & Ibrahim Adel El-Doseky (2015): Facile Synthesis
of Some New Pyrazole-Based 2-Thioxo-4-thiazolidinone, Synthetic Communications, DOI:
10.1080/00397911.2015.1100312
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Date: 03 December 2015, At: 21:29

Synthetic Communications1, 0: 1–8, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1100312
FACILE SYNTHESIS OF SOME NEW PYRAZOLE-BASED
2-THIOXO-4-THIAZOLIDINONE
Nadia Hanafy Metwally and Ibrahim Adel El-Doseky
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
GRAPHICAL ABSTRACT
Abstract 5-Ethoxymethylene-2-thioxo-4-thiazolidinone (1) reacts with hydrazine hydrate
at room temperature to afford 5-(hydrazinylmethylene)-2-thioxo-4-thiazolidinone (3).
Compound 3 condensed with different aromatic aldehydes 6a–d in ethanol in the
presence of a few drops of piperidine to give the corresponding Schiff’s bases 7a–d. On
the other hand, compound 3 reacts with o-hydroxybenzaldehyde derivatives 8a and 8b in
refluxing ethanol catalyzed by a few drops of piperidine to yield 1H-inadzolyl-2-thioxo-
4-thiazolidinones 9a and 9b. Reaction of compound 3 with a-ketoesters 10a and 10b or
a-diketones 10c–e in refluxing glacial acetic acid furnished the pyrazolyl-2-thioxo-4-
thiazolidinone derivatives 11a–e. Also, compound
3 reacts with some different
enaminones 12a–f in refluxing glacial acetic acid to afford the new pyrazolyl-2-thioxo-4-
thiazolidinone derivatives 13a–f. Pyrazoles 15a–d was obtained via reaction of compound
3 with chalcones 14a–d in dimethylformamide (DMF). The structures of all the newly
synthesized products were confirmed on the basis of their elemental and spectral data,
and a plausible mechanism has been postulated to account for their formation.
Received July 13, 2015.
Address correspondence to Nadia Hanafy Metwally, Department of Chemistry, Faculty of
Science, Cairo University, Giza, Egypt. E-mail: nhmmohamed@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1

2
N. H. METWALLY AND I. A. EL-DOSEKY
Keywords 5-Ethoxymethylene-2-thioxo-4-thiazolidinone; 5-hydrazinylmethylene-2-
thioxo-4-thiazolidinone; 5-pyrazolyl-2-thioxo-4-thiazolidinones
INTRODUCTION
2-Thioxo-4-thiazolidinone has a wide spectrum of biological activity as
antibacterial,[1–3] antiviral,[4] antidiabetic,[5] antitubercular,[6,7] anti-HIV,[8,9]
antiparasitic,[10] hypnotic,[11] and anathematic agents[12] and as intermediates in the
synthesis of dyes. 2-Thioxo-4-thiazolidinone-based molecules have been popular as
small molecule inhibitors of numerous targets such as HCV protease, aldo reductase,
and others.[13] Also, pyrazoles have diverse and interesting of biological activities
[17]
such as antiviral,[14] antibacterial,[15,16] antifungal,
anti-inflammatory,[18,19]
analgesic,[20] and other activities.[21,22] We have worked to synthesize heterocyclic
systems containing thiazolidine rings.[23–33] In view of all this, it is interesting to
construct new heterocyclic systems containing both thiazolidinone and pyrazole
rings, starting from 5-ethoxymethylene-2-thioxo-4-thiazolidinone (1) as key synthon
for our objective.
RESULTS AND DISCUSSION
5-Ethoxymethylene-2-thioxo-4-thiazolidinone (1) reacts with hydrazine hydrate
at room temperature to afford a colored product 3 (Scheme 1). The structure of
the isolated product 3 was confirmed by its elemental analysis and spectral data
(infrared [IR], 1H NMR, 13C NMR, and mass spectrometry [MS]). The IR spectrum
of the reaction product showed absorption bands at nmax 3424, 3215, 3050, and
1
1680 cmꢀ1 corresponding to NH2, NH, and CO groups, respectively. The H NMR
spectrum of product revealed the disappearance of the usual quartet and triplet sig-
nals of ethoxy protons and instead revealed three D2O exchangeable singlet signals
at d ¼ 5.01, 9.30, and 12.48 ppm attributable the NH2 and the two NH protons,
respectively, in addition to a singlet signal at d ¼ 7.36 ppm assigned to vinylic CH pro-
ton. Also, 13C NMR showed signals at d ¼ 110, 149, 165, 191 ppm corresponding to
vinylic (CH=C-), carbonyl (CO), and thiocarbonyl (C=S) carbons. Elemental analysis
with mass spectrum m=z 175 (Mþ) established the formula C4H5N3OS2, which indi-
cated that the reaction between compound 1 and hydrazine hydrate proceeded with
elimination of ethanol. Based on these data, structure 3 was assigned for the product
and the other structure 2 was ruled out. Similarly, the reaction of compound 1 with
ethyl hydrazinecarboxylate in ethanol at room temperature or refluxing in absolute
ethanol gave the corresponding ethyl 2-[(4-oxo-2-thioxothiazolidin-5-ylidene)
methyl]hydrazine-1-carboxylate (5). Spectral and analytical data are in complete
agreement with structure 5, which was assigned for this product (Scheme 1).
Condensation of compound 3 with different aromatic aldehydes 6a–d in
ethanol in the presence of a few drops of piperidine gave the corresponding Schiff’s
bases 7a–d (Scheme 2). The structure of the isolated products was inferred from
their analytical and spectral data. Thus, IR spectrum of compound 7a taken as typi-
cal example of the prepared series 7a–d showed absorption bands at nmax 3220,
1
3017, and 1680 cmꢀ1 corresponding to NH and CO groups, respectively. The H
NMR spectrum of product 7a revealed a singlet signal at d ¼ 7.58 ppm attributable

SYNTHESIS OF PYRAZOLE-BASED 4-THIAZOLIDINONE
3
Scheme 1. Synthetic route to 5-hydrazinyl-2-thioxo-4-thiazolidinone (3) and ethyl 2-[(4-oxo-2-
thioxothiazolidin-5-ylidene)methyl]hydrazine-1-carboxylate (5).
Scheme 2. Synthetic pathway to 4-thiazolidinones 7a–d and 5-[1H-indazol-1-yl)methylene]-4-
thiazolidinone derivatives 9a and b.

4
N. H. METWALLY AND I. A. EL-DOSEKY
to olefinic CH proton and two board singlet signals at d ¼ 11.87 and 12.92 ppm
assigned to the two NH protons. The 13C NMR of compound 7a revealed a signal
at d ¼ 145 ppm due to –CH=N carbon, beside to the other expected signals for aro-
matic and thiazolidine carbons. The mass spectrum together with the elemental
analysis are in consistent with the structure 7. On the other hand, compound 3
reacts with o-hydroxybenzldehyde derivatives 8a and b in refluxing ethanol cata-
lyzed by few drops of piperidine to yield colored solids 9a and b. The structure of
9 was confirmed by elemental analysis and spectral data (IR, 1H NMR, 13C
NMR, and MS). The IR spectrum of the isolated product 9a showed absorption
bands at nmax 3200 and 1676 cmꢀ1 corresponding to NH and CO groups. 1H
NMR spectrum of this isolated product revealed two singlet signals at d ¼ 7.55
and 8.52 ppm due to the olfinic and pyrazole protons, respectively. Besides the
expected protons for aromatic and NH protons. Also, 13C NMR showed signal
at d ¼ 141 ppm due to pyrazole carbon (C=N), in addition to the expected signals
assigned for aromatic and thiazolidine carbons. The mass spectrum with elemental
analysis are assigned the structures 9a and b.
Our study was extended to construct a pyrazole moiety on thiazole ring which
has wide applications in different biological and medicinal fields beside their appli-
cation in organic chemistry. Thus, the reaction of compound 3 with a-ketoester 10a
and b or a-diketones 10c–e in refluxing glacial acetic acid gave the 5-pyrazolyl-2-
thioxo-4-thiazolidinone derivatives 11a–e (Scheme 3). The structures were con-
firmed on their elemental analysis and spectral data (IR, 1H NMR, and MS).
The IR spectrum of the isolated product 11a showed absorption bands at nmax
3223–3110, 1687, and 1681 cmꢀ1 corresponding to NH and two CO groups.
1H NMR spectrum of this isolated product revealed two broad singlet signals at
d ¼ 12.76 and 13.13 ppm due to two NH protons, in addition to two singlet
signals at d ¼ 7.13 and 7.71 ppm corresponding to olefinic and pyrazole protons,
Scheme 3. Synthetic route to 5-pyrazoyl-2-thioxo-4-thiazolidinone derivatives 11a–e.

SYNTHESIS OF PYRAZOLE-BASED 4-THIAZOLIDINONE
5
Scheme 4. Synthetic pathway to 5-pyrazoyl-4-thiazolidinone derivatives 13a–f and 15a–d.
respectively. The mass spectrum with elemental analysis are in agreement with the
proposed structure 11.
Also, compound 3 reacts with some different enaminones 12a–f in refluxing in
glacial acetic acid to afford the new pyrazole derivatives 13a–f (Scheme 4). The struc-
1
tures were confirmed by elemental analysis and spectral data (IR, H NMR, and
MS). The IR spectrum of the isolated product 13a showed absorption bands at nmax
1
3121, 1684 cmꢀ1 corresponding to NH and CO groups. H NMR spectrum of this
isolated product revealed three singlet signals at d ¼ 7.20, 7.94, and 8.37 ppm due
to olefinic and pyrazole protons, respectively. In addition to a broad signal at d ¼
12.86 ppm corresponding to NH proton. The mass spectrum with elemental analysis
is in agreement with the proposed structure 13. The formation of 13 was assumed to
proceed via elimination of dimethylamine molecule, followed by dehydrative
cyclization to 5-pyrazolyl-4-thiazolidinone derivative 13. Cyclocondensation of
compound 3 with chalcones 14a–d in refluxing acetic acid afforded isolated products
15a–d (Scheme 4). The structure of compounds 15a–d was established by elemental
1
analysis and spectral data (IR, H NMR, and MS). The IR spectrum of product
15a showed absorption bands at nmax 3218, 1683, and cmꢀ1 corresponding to
1
NH and CO groups. Also, H NMR spectrum of product 15a revealed a broad
signal at d ¼ 12.85 ppm corresponding to NH. The formation of 15 was
assumed to proceed via Michael addition followed by dehydrative cyclization to
5-pyrazolyl-4-thiazolidinone derivative 15 (Scheme 4).
CONCLUSION
In conclusion, we have described an efficient synthesis of some new 5-[(2-
benzylidenehydrazinyl)methylene]-2-thioxothiazolidin-4-ones, 5-[1H-Indazol-1-yl)
methylene]-4-thiazolidinones, and 5-pyrazoyl-2-thioxo-4-thiazolidinones via the

6
N. H. METWALLY AND I. A. EL-DOSEKY
reaction of readily accessible starting material, 5-(hydrazinylmethylene)-2-thioxo-4-
thiazolidinone, with some chemical reagents.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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