Novel 2-(4-substitutedphenyl)-3-{3-[(S-ethoxyphthalimido)sulfanyl]-5-pyridin-4-yl-4H-1,2,4-triazol-4-yl}-1,3-thiazolidin-4-ones (6a-d) were synthesized via a multistep reaction sequence, using isoniazid (isonicotinic acid hydrazide) as starting material. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR and 1H NMR spectral data

Dangi, Rajaram

Joshi, Ajit

Sain, Devendra

Talesara, Ganapat

Thadhaney, Bhawana

Revistes Catalanes amb Accés Obert

AfinidAd LXVi, 543, Septiembre-Octubre 2009408
RESUMEN
Se sintetizan nuevas 2-(fenil 4-sustituido)-3-{3-[(N-
etoxiftalimido)sulfanil]-5-piridin-4-il-4H-1,2,4-triazol-4-
il}-1,3-tiazolidin-4-onas (6a-d) mediante una secuencia 
de reacciones usando isoniazida (hidrazida del ácido 
isonicotínico) como producto de partida. Las estructuras 
de los compuestos sintetizados se asignan a partir del 
análisis elemental y de los datos espectroscópicos de IR 
y 1H RMN.
Palabras clave: Isoniazida, Araldehidos, Tiazolidinona, 
Bromuro de ftalimidoxietilo
SUMMARY
Novel 2-(4-substitutedphenyl)-3-{3-[(S-ethoxyphthalimido) 
sulfanyl]-5-pyridin-4-yl-4H-1,2,4-triazol-4-yl}-1,3-
thiazolidin-4-ones (6a-d) were synthesized via a multistep 
reaction sequence, using isoniazid (isonicotinic acid 
hydrazide) as starting material. The structures of the 
synthesized compounds were assigned on the basis of 
elemental analysis, IR and 1H NMR spectral data.
Key Words:  Isoniazid, Araldehydes, Thiazolidinone, 
Phthalimidoxyethyl bromide 
RESUM
Es sintetitzen noves 2-(fenil 4-substituït)-3-{3-[(N-
etoxiftalimido)sulfanil]-5-piridin-4-il-4H-1,2,4-triazol-4-
il}-1,3-tiazolidin-4-ones (6a-d) mitjançant una seqüència 
de reaccions emprant isoniazida (hidrazida de l’àcid 
isonicotínic) com a producte de partida. Les estructures 
dels compostos sintetitzats s’assignen a partir de l’anàlisi 
Synthesis and characterization of some 
ethoxyphthalimide substituted  triazole 
derivatives assembled with pyridine 
and thiazolidinone heterocycles
Devendra Kr. Sain, Ajit Joshi, Bhawana Thadhaney, Rajaram Dangi and Ganapat L. Talesara*
Synthetic Organic Chemistry Laboratory, Department of Chemistry,  M. 
L. Sukhadia University, Udaipur (Raj.)- 313 001, índia, 
Síntesis y caracterización de derivados de triazol con un sustituyente etoxiftalimida unidos a 
heterociclos de piridina y tiazolidinona 
Síntesi i caracterització de derivats de triazole amb substituent etoxiftalimida units a heterocicles de 
piridina i tiazolidinona 
Recibido: 9 de abril de 2009; aceptado: 6 de julio de 2009
*Corresponding author: gtalesara@yahoo.com
elemental i de les dades espectroscòpiques de IR i 1H 
RMN.
Mots clau: Isoniazida, Araldehids, Tiazolidinona, Bromur 
de ftalimidoxietil
INTRODUCTION
The 1,2,4-triazole system has widespread uses, and it has 
been considered as an interesting component in terms of 
biological activities such as anticonvulsant1,2, antifungal3-5, 
anticancer6-8, antiinflammatory9-11 and antibacterial 
properties12-14. Many triazole compounds have good 
fungicidal and plant growth regulating activities15,16.
The chemistry of thiazolidin-4-one ring systems is of 
considerable interest as it is a core structure in various 
synthetic pharmaceuticals displaying a broad spectrum of 
biological activities such as antidiarrheal17, antimicrobial18, 
antidiabetic19, antihistaminic20, anticancer21, antiHIV22, 
cardioprotective23, anti-ischemic24 and tumor necrosis 
factor-α antagonist activities25.
Pyridine nucleus has been extensively explored for 
their versatile biological activities like anticancer and 
antitubercular etc26,27. Pyridine ring can be found in a 
broad variety of drugs, such as milirinone, which is useful 
for the treatment of the heart28, alzheimer disease29, anti-
tumor30 and anti amnesic agents31. A large number of 
imidoxy derivatives of various heterocycles reported to 
demonstrate a wide range of pharmacological activities like 
antimalarial32, anticonvulsant33, anticancer34 etc. Several 
derivatives of this framework have been synthesized35-38 
by our reserch group. 
AfinidAd LXVi, 543, Septiembre-Octubre 2009 409
The pharmacological properties of 1,2,4-triazoles 
encouraged us to synthesize several new compounds 
featuring the above mentioned heterocyclic rings, 
attached to triazole moieties. As a part of our aim to 
search for biologically active heterocycles containing 
sulfur and nitrogen, we have synthesised a series of 
2-(4-substitutedphenyl)-3-{3-[(S-ethoxyphthalimido)
sulfanyl]-5-pyridin-4-yl-4H-1,2,4-triazol-4-yl}-1,3-
thiazolidin-4-one (6a-d).
ExPERIMENTAL SECTION
General Procedure
Melting points were taken in open capillary tubes and 
are therefore uncorrected. Purity of the compounds was 
checked on silica gel G TLC plates of 2 mm thickness 
using n-hexane and ethylacetate as solvent system. The 
visualization of spot was carried out in an iodine chamber. 
The IR spectra of the compounds were recorded in the 
4000-450 cm-1 ranges using KBr discs on FTIR IR RX1 
Perkin Elmer spectrophotometers and 1H NMR were 
recorded on a Bruker DRX-300 MHz spectrometer (CDCl3) 
using TMS as an internal standard. The mass spectra 
were recorded on a Jeol SX-102 (FAB) mass spectrometer. 
Phthalimidoxyethyl bromide was prepared by reported 
methods39.  
Structure of all the synthesized compounds was assigned 
on basis of their analytical and spectral data.
Synthesis of 5-pyridin-4-yl-1,3,4-oxadiazole-2(3H)-
thione (1): 
A mixture of isoniazid (0.01mole) and KOH (0.015 mole) 
in ethanol was refluxed for 1 hr and dry carbondisulphide 
(0.015 mole) was slowly added to it. The reaction mixture 
was refluxed further for 8 hr on water bath. Excess of 
solvent was disttiled off and the residual mass poured into 
ice cold water. Then, the reaction content was acidified 
with conc. HCl. The precipitate was filtered off, washed 
with H2O and recrystallized from ethanol to get the desired 
compound.
Synthesis of 4-amino-5-pyridin-4-yl-2,4-dihydro-3H-
1,2,4-triazole-3-thione (2):
Hydrazine hydrate (0.04 mole) was added to a solution of 
(1, 0.01 mole) in ethanol and refluxed for 10 hr. Excess of 
ethanol and hydrazine hydrate were distilled under reduced 
pressure and the residual mass poured into ice cold water. 
The separated solid was washed with dilute acetic acid 
and recrystallized from ethanol.
Synthesis of 4-[(4-substitutedphenylmethylidine)
amino]-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-
thione (4a-d): 
An equimolar mixture of 4-amino-5-pyridin-4-yl-
2,4-dihydro-3H-1,2,4-triazole-3-thione (2) and 
4-substitutedaraldehydes (3a-d) in ethanol was refluxed 
for 10 h with catalytic amount of glacial acetic acid. The 
progress of reaction was monitered by TLC. After reaction 
completion, the reaction mass was cooled to room 
temperature, and poured onto ice-cold water with vigorous 
string. The separated solid was filtered, washed with 5% 
sodium bisulfite solution to remove excess of aldehyde 
and recrystallized from ethanol.
Synthesis of 2-(4-substitutedphenyl)-3-(3-pyridin-
4-yl-5-thioxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-1,3-
thiazolidin-4-one (5a-d) :
A solution of (4a-d, 0.01 mol) in DMF and mercaptoacetic 
acid (0.012 mol) was refluxed with a pinch of anhydrous 
ZnCl2 for 10-14 hr on a water bath. After completion of 
reaction, excess of DMF was distilled off and the resulting 
product was treated with 5% NaHCO3 solution to remove 
unreacted mercaptoacetic acid. The separated product 
was washed with water, dried and recrystallized from 
DMF.
Synthesis of 2-(4-substitutedphenyl)-3-{3-[(S-
ethoxyphthalimido)sulfanyl]-5-pyridin-4-yl-4H-1,2,4-
triazol-4-yl}-1,3-thiazolidin-4-one (6a-d):
Compound (5a-d, 0.01mole) and 
phthalimidoxyethylbromide (0.01 mole) were dissolved 
in ethanol and refluxed for 12-14 hr with pyridine (3mL). 
Excess of solvent was removed under reduced pressure. 
On cooling, separated solid was recrystallized from 
ethanol.
RESULTS AND DISCUSSION
In the present investigation, 5-pyridin-4-yl-1,3,4-
oxadiazole-2(3H)-thione (1) was obtained on reacting 
isonicotinic acid hydrazide with Br2 and ethanolic KOH. 
Formation of oxadiazole (1) was confirmed by the presence 
of  C=N and N-H streching at 1595, 3310 cm-1 in IR spectrum 
respectively. Compopund (1) undergo condensation with 
N2H4.H2O to form 4-amino-5-pyridin-4-yl-2,4-dihydro-3H-
1,2,4-triazole-3-thione (2). Structure of compound (2) was 
elucidated on the basis of absence of C-O streching band 
in IR spectrum. Reaction of compound (2) with various 
araldehydes (3a-d) in presence of glacial acetic acid yielded 
corresponding arylidine derivatives (4a-d). Presence of a 
singlet at δ 8.32 for Ar-CH confirms formation of 4b. On 
cyclocondensation with mercaptoacetic acid compound 
(4a-d) was converted to their thiazolidinone derivatives 
(5a-d). Formation of thiazolidinone ring was confirmed by 
the presence of a band at 1725 cm-1 for C=O streching and 
a singlet at δ 4.6 for CH2 protons in IR and NMR spectrum 
respectively. Subsequently, the SH proton was replaced 
by ethoxyphthlimide moiety to yield final compounds 
2-(4-substitutedphenyl)-3-{3-[(N-ethoxyphthalimido)
sulfanyl]-5-pyridin-4-yl-4H-1,2,4-triazol-4-yl}-1,3-
thiazolidin-4-one (6a-d). Structure of which, was confirmed 
by presence of C=O and N-O stretching bands at 1755, 
1723 and 1380  cm-1 respectively in IR spectrum and new 
signals in 1H NMR spectrum for side chain protons. The 
mass spectrum also supports the proposed structure by 
viewing molecular ion peaks of final compounds (6a-d). 
ACKNOWLEDGEMENTS
Authors are thankful to the Head, Department of Chemistry, 
M. L. Sukhadia University, Udaipur (Raj.) for providing 
laboratory facilities and to the Director, RSIC, CDRI, 
Lucknow, India for providing spectral and analytical data.
The physical and analytical data are given in Table 1 and 
spectral data are given in Table 2.
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AfinidAd LXVi, 543, Septiembre-Octubre 2009 411
Compd. 
No. 
Ar
Mol. Formula Mol. 
weight
m.p. 
(°C)
Yield 
(%)
Calculated / Found (%)
C H N S
1 – C7H5N3OS 179 204 88 46.92 
(46.85)
2.81 
(2.77)
23.45 
(23.34)
17.89 
(17.80)
2 – C7H7N5S 193 249 81 43.51 
(43.38)
3.65 
(3.62)
36.24 
(36.20)
16.59 
(16.46)
4a C6H5 C14H11N5S 281 184 85 59.77 
(59.70)
3.94 
(3.97)
24.89 
(24.87)
11.40 
(11.32)
4b 4-Cl-C6H4 C14H10N5SCl 315 198 78 53.25 
(53.19)
3.19 
(3.15)
22.18 
(22.10)
10.15 
(10.03)
4c 4-CH3O-C6H4 C15H13N5OS 311 188 80 57.86 
(57.78)
4.21 
(4.18)
22.49 
(22.36)
10.30 
(10.34)
4d 4-(CH3)2N-C6H4 C16H16N6S 324 210 62 59.24 
(59.21)
4.97 
(4.88)
25.91 
(25.79)
9.88 
(9.79)
5a C6H5 C16H13N5OS2 355 220 79 54.07 
(54.02)
3.69 
(3.54)
19.70 
(19.66)
18.04 
(18.00)
5b 4-Cl-C6H4 C16H12N5OS2Cl 389 224 66 49.29
(49.17)     
3.10
(2.95)
17.96
(17.99)
16.45
(16.33)
5c 4-CH3O-C6H4 C17H15N5O2S2 385 200 60 52.97
(52.81)
3.92
(3.90)
18.17
(18.00)
16.64
(16.50)
5d 4-(CH3)2N-C6H4 C18H18N6OS2 398 232 70 54.25
(54.21)
4.55
(4.48)
21.09
(21.07)
16.09
(15.97)
6a C6H5 C26H20N6O4S2 544 269 69 57.34
(57.38)
3.70
(3.59)
15.43
(15.26)
11.78
(11.61)
6b 4-Cl-C6H4 C26H19N6O4S2Cl 578 280 56 53.93
(53.90)
3.31
(3.18)
14.51
(14.43)
11.08
(10.94)
6c 4-CH3O-C6H4 C27H22N6O5S2 574 245 59 56.43
(56.41)
3.86
(3.84)
14.63
(14.71)
11.16
(11.00)
6d 4-(CH3)2N-C6H4 C28H25N7O4S2 587 180 52 57.23
(57.09)
4.29
(4.22)
16.68
(16.51)
10.91
(10.81)
Table 1 :  Characterization data of synthesized compounds
Compd. No. Spectral Data
1
IR (cm-1):
1H NMR (δ):
1595 (C=N str.), 3310 (N-H str.), 3037 (Ar-H str.)
7.61-8.26 (m, 4H, Ar-H), 8.1 (s, 1H, NH)
2
IR (cm-1):
1H NMR (δ):
3326, 3260, 3100 (N-H str.)
7.97 (s, 2H, NH2)
4a
IR (cm-1):
1H NMR (δ):
1610 (C=N str.), 3090 (N-H str.)
8.20 (s, 1H, Ar-CH=)
4b
IR (cm-1):
1H NMR (δ):
1663 (C=N str.), 3125 (N-H str.), 765 (C-Cl str.)
8.32 (s, 1H, Ar-CH=)
4c
IR (cm-1):
1H NMR (δ):
1600 (C=N str.), 3078 (N-H str.), 1122 (C-O str.)
3.78(s, 3H, OCH3), 8.18 (s, 1H, Ar-CH=)
4d
IR (cm-1):
1H NMR (δ):
1585 (C=N str.), 3070 (N-H str.)
3.29 (s, 6H, NMe2), 8.15 (s, 1H, Ar-CH=)
5a
IR (cm-1):
1H NMR (δ):
1770 (C=O str.), 710 (C-S-C str.)
4.2 (s, 2H, CH2), 3.3 (s, 1H, Ar-CH)
5b
IR (cm-1):
1H NMR (δ):
1725 (C=O str.), 760 (C-S-C str.), 750 (C-Cl str.)
4.6 (s, 2H, CH2), 3.5 (s, 1H, Ar-CH)
5c
IR (cm-1):
1H NMR (δ):
1680 (C=O str.), 683 (C-S-C str.)
4.0 (s, 2H, CH2), 3.1 (s, 1H, Ar-CH), 3.75 (s, 3H, OCH3)
5d
IR (cm-1):
1H NMR (δ):
1688 (C=O str.), 678 (C-S-C str.)
3.96 (s, 2H, CH2), 3.2 (s, 1H, Ar-CH), 2.98 (s, 6H, NMe2)
6a
IR (cm-1):
1H NMR (δ):
1389 (N-O str.), 1750, 1730 (C=O str.)
4.17 (t, 2H, O-CH2), 2.97 (t, 2H, S-CH2)
6b
IR (cm-1):
1H NMR (δ):
1429 (N-O str.), 1755, 1723 (C=O str.)
4.26 (t, 2H, O-CH2), 3.37 (t, 2H, S-CH2)
6c
IR (cm-1):
1H NMR (δ):
1372 (N-O str.), 1768, 1710 (C=O str.)
4.09 (t, 2H, O-CH2), 2.84 (t, 2H, S-CH2)
6d
IR (cm-1):
1H NMR (δ):
1360 (N-O str.), 1760, 1777 (C=O str.)
4.13 (t, 2H, O-CH2), 2.80 (t, 2H, S-CH2)
Table 2 :  Spectral data of synthesized compounds 1- 6(a-d)


Synthesis and characterization of some ethoxyphthalimide substituted triazole derivatives assembled with pyridine and thiazolidinone heterocycles

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