Synthesis of 4-substituted thiadiazolidinones Section A-Research paper

SYNTHESIS AND CHARACTERIZATION OF SOME 4-

SUBSTITUTED THIAZOLIDINONE DERIVATIVES

Assala Salam Jebur[a] and Mahmood Shakir Magtoof[a]*

Keywords: Thiazolidinones; imines; synthesis; NMR spectroscopy

This study is concerned with the synthesis and characterization of 4-thiazolidinone derivatives )3a-3h(. These compounds were prepared by
reacting mercaptoacetic acid with the appropriate Schiff bases (imines) by heating at 50-60 °C in chloroform with moderate yields (51-
75 %). The structures of these 4-thiazolidinone derivatives were established on the basis of the spectral studies using IR, 1H-NMR, 13C-
NMR, 13C-NMR DEPT and MS.

* Corresponding Authors General procedure for the preparation of imines (2a-2h)7-9

Tel: 009647813199256
E-Mail: [email protected] Preparation of mono-imines (2a-2d).
[a] Department of Chemistry, Science, College,Thiqar University,
Thiqar, Nasyria, Iraq In general, the mono-imines (2a-2d) were prepared by
the reaction of the mixture of 0.01 mol amine with 0.01 mol
aldehyde in 20 ml of methanol or ethanol and 4-6 drops of
Introduction glacial acetic acid. The reaction mixture was refluxed for
0.5-9 h, and the progress of the reaction was followed by
Thiazolidinones are ketone derivatives of the saturated TLC using hexane:ethyl acetate 6:4 as eluent. After
completion the reaction, the solvent was evaporated, and the
form of thiazole (called thiazolidine). 1,3-Thiazolidin-4-
residue was recrystallized from a suitable solvent.
ones are five-membered heterocycles with one sulfur and
one nitrogen atom (Figure 1(.
3-(4-Bromophenylimino)indolin-2-one (2a)
O
The compound was prepared by reacting 1.169 g (0.01
mol) of 4-bromoaniline and 1 g (0.01 mol) of indoline-2,3-
NH dione (isatin). Yield=75 %, M.p.=273-275 ºC, colour
S orange, IR (KBr disk) 1608 cm-1 (C=N).

Figure 1. Thiazolidinone ring 2-Chloro-N-(4-chlorobenzylidene)aniline (2b)

The compound was prepared by reacting 1.72 g (0.01

1,3-Thiazolidin-4-ones belong to the most intensively mol) of 2-chloroaniline and 1.4 g (0.01 mol) of 4-
investigated classes of five-membered heterocyclic chlorobenzaldehyde. Yield = 71.7 %, m.p. = 225-228 ºC,
compounds, the biological significance of this class of colour white, IR (KBr disk) 1614 cm-1 (C=N).
compounds attracted us to work on the synthesis of new
derivatives because numerous 4-Thiazolidinones known for
their versatile pharmacological activities1,2 such as 2-(3-Ethoxy-2-hydroxybenzylideneamino)benzoic acid (2c)
hypnotic,3 anti-cancer,4 cardiovascular5 and antioxidant6
effect.
The compound was prepared by reacting 0.825 g (0.01
mol) of 2-aminobenzoic acid and 1 g (0.01 mol) of 3-
ethoxy-2-hydroxybenzaldehyde. Yield = 87.5 %, m.p. =
Experimental part 208-209 ºC, colour orange, IR (KBr disk) 1625 cm-1 (C=N).

The 1H-NMR spectra were recorded using VARIAN

spectrophotometer (500 MHz), the 13C-NMR spectra were 4-Bromo-2-(4-bromophenyliminomethyl)phenol (2d)
recorded using VARIAN spectrophotometer (75 MHz).The
chemical shift values are expressed in δ(ppm), using The compound was prepared by reacting 0.85 g (0.01
tetramethylsilane (TMS) as internal standard and d 6-DMSO mol) of 4-bromoaniline and 1 g (0.01 mol) of 5-bromo-2-
as the solvent. The mass spectra were recorded at 70eV hydroxybenzaldehyde. Yield = 87.5 %, m.p. = 108-110 ºC,
using HPLC-LCQ Fleet/Thermo Scientific mass colour yellow, IR (KBr disk) 1618 cm-1 (C=N).
spectrophotometer

Eur. Chem. Bull., 2017, 6(5), 201-205 DOI: 10.17628/ecb.2017.6.201-205 201

Synthesis of 4-substituted thiadiazolidinones Section A-Research paper

Preparation of bis-imines (2e-2h) 3'-(4-Bromophenyl)spiro[indoline-3,2'-thiazolidine]-2,4'-dione

(3a)
In general, the bis-imines (2e-2h) were prepared by the
reaction of 0.01 mol diamine with 0.02 mol of aldehyde (20 The compound was prepared by reaction of 0.5 g (0.01
ml) of methanol or ethanol and 4-6 drops of glacial acetic mol) of 3-((4-bromophenyl)imino)indolin-2-one (2a) and
acid. The reaction mixture was refluxed for 1-9 h, with 0.153 g (0.115 ml, 0.01 mol) of thioglycolic acid.
monitoring the progress of the reaction by TLC using Yield=55 %, m.p.=180-182ºC, colour: yellow. IR (KBr)
hexane:ethyl acetate 6:4 as eluent. After completion the 1654 (C=O of thiazolidinone ring ); 3024cm-1 (Ar-H), 2909
reaction, the solvent was evaporated and the product was cm-1 (C-H aliphatic), 1393 cm-1 (C-N), 665 cm-1 (C-S). 1H-
recrystallized from a suitable solvent . NMR (500 MHz, DMSO-d6) δ=4.4 (s, 2H, C5H); 7.3-8.01
(m, 8H, ArH); 9.27(s, 1H, N-H). 13C NMR (75 MHz,
DMSO-d6) δ=36(s, -CH2-), 49(s, -C-), 107-139(m, Ar-C);
2,2'-{Benzene-1,4-diylbis[nitrilomethylylidene]}bis(6-ethoxy- 177(s, CH2-C=O); 179(s, N-H-C=O).
phenol) (2e)
3-(2-Chlorophenyl)-2-(4-chlorophenyl)thiazolidin-4-one (3b)
The compound was prepared by reacting 0.324 g (0.01
mol) of benzene-1,4-diamine with 1 g (0.02 mol) of 3- The compound was prepared by reaction of 0.8 g (0.01
ethoxy-2-hydroxybenzaldehyde. Yield = 85 %, m.p = 187- mol) of 2-chloro-N-(4-chlorobenzylidene)aniline (2b) and
190 ºC, colour orange, IR (KBr disk) 1624 cm-1 (C=N). 0.29 g (0.22 ml, 0.01 mol) of thioglycolic acid. Yield=61 %,
m.p.=248-251 ºC, colour: orange. IR (KBr) 1681 (C=O of
thiazolidinone ring), 3018 cm-1 (Ar-H), 2930 cm-1 (C-H
2,2'-{Naphthalene-1,5-diylbis[nitrilo(E)methylylidene]}bis(6- aliphatic), 1396 cm-1 (C-N), 667 cm-1 (C-S). 1H-NMR (500
MHz, DMSO-d6) δ=4.3(s, 2H,C5H), 7.2(s, 1H, C2H), 7.4-
ethoxyphenol) (2f)
8.01(m, 8H, ArH). 13C NMR (75 MHz, DMSO-d6) δ =36.9(s,
-CH2-), 43(s, -CH-), 111-142(m, Ar-C), 175(s, CH2-C=O).
The compound was prepared by reacting 0.452 g (0.01
mol) of naphthalene-1,5-diamine with 0.95g (0.02 mol) of
2-(2-(3-Ethoxy-2-hydroxyphenyl)-4-oxothiazolidin-3-yl)benzoic
3-ethoxy-2-hydroxybenzaldehyde. Yield = 96 %, m.p = 133-
136ºC, colour chartreuse, IR (KBr disk) 1618 cm-1 (C=N). acid (3c)

The compound was prepared by reaction of 2-((3-ethoxy-

2-hydroxybenzylidene)amino)benzoic acid (2c) (0.5 g, 0.01
2-Ethoxy-6-[({4-[(E)-(3-ethoxy-2-hydroxybenzylidene)amino]-
mol) and thioglycolic acid (0.16 g, 0.12 ml, 0.01 mol).
benzyl}imino)methyl]phenol (2g) Yield=70 %, m.p.=178-180 ºC, colour: orange. IR (KBr)
1691 cm-1 (C=O of thiazolidinone ring ); 3010 cm-1 (Ar-H),
The compound was prepared by reacting 0.595 g (0.01 2945 cm-1 (C-H aliphatic); 1399 cm-1 (C-N); 637 cm-1 (C-S).
mol) of 4-(4-aminobenzyl)benzenamine with 1 g (0.02 mol)
1
H-NMR (500 MHz, DMSO-d6) δ=1.9(s, 3H, -CH3); 4.2 (s,
of 3-ethoxy-2-hydroxybenzaldehyde. Yield = 87.6 %, m.p = 2H, C5H); 4.4(s, 2H, -CH2); 7.20(s, 1H, C2H); 7.22-8.7 (m,
157-158ºC, colour yellow, IR (KBr disk) 1615 cm-1 (C=N). 8H, ArH); 9.59(s, 1H, O=C-OH). 13C NMR (75 MHz,
DMSO-d6), δ=28(s, CH3); 35(s, -CH2-); 40(CH2O); 44(s, -
CH-); 116-153 (m, Ar-C); 172(s, CH2-C=O); 182(COOH).
4-bromo-2-[({4-[(E)-(5-bromo-2-hydroxybenzylidene)amino]-
benzyl}imino)methyl]phenol (2h) 2-(5-Bromo-2-hydroxyphenyl)-3-(4-bromophenyl)thiazolidin-4-
one (3d)
The compound was prepared by reacting 0.595 g (0.01
mol) of 4-(4-aminobenzyl)benzenamine with 1 g (0.02 mol) The compound was prepared by reaction of 0.7 g (0.01
of 5-bromo-2-hydroxybenzaldehyde. Yield = 84.2 %, m.p = mol) of 4-bromo-2-(((4-bromophenyl)imino)methyl)phenol
142-143 ºC, colour yellow, IR (KBr disk) 1623 cm-1 (C=N). (2d) and 0.18 g (0.137 ml, 0.01 mol) of thioglycolic acid.
Yield=78 %, m.p.=171-172 ºC, colour: yellow. IR (KBr)
1685 cm-1 (C=O of thiazolidinone ring ); 3052 cm-1 (Ar-H) ,
2913 cm-1 (C-H aliphatic) ; 1385 cm-1 (C-N) ; 681 cm-1 (C-
General procedures of mono and bis thiazolidinones (3a-3h)10
S). 1H-NMR (500 MHz, DMSO-d6) δ =4.48 (s, 2H,
Preparation of mono thiazolidinones (3a-3d) C5H);7.3(s, 1H, C2H); 7.5-8.01(m, 8H, ArH); 9.62 (s, 1H,
Ar-OH). 13C NMR (75 MHz, DMSO-d6) δ=37(s, -CH2-);
A mixture of appropriate Schiff bases (0.01 mol) (2a-2d) 45(s, -CH-); 120-157(Ar-C); 172(s, CH2-C=O).
and thioglycolic acid (0.01 mol, 0.20 ml) in a suitable
solvent (50) ml was refluxed for 10-30 h. Water formed
during the reaction was removed azeotropically by a Dean- Preparation of bis thiazolidinones (3e-3h)
Stark apparatus. The progress of the reaction was monitored
by TLC using hexane:ethyl acetate 6:4 as eluent. This A mixture of appropriate Schiff bases (0.02 mol) (2e-2h) and
mixture of reaction are treated with sodium bicarbonate thioglycolic acid (0.02 mole, 0.40 ml) in a suitable solvent
solution to remove unreacted acid. The obtained solids were (50 ml) was refluxed for 10-30 h, water formed during the
filtered, washed and purified by recrystallization from reaction was removed azeotropically by a Dean-Stark
dichloromethane to give color powders. apparatus.
Eur. Chem. Bull., 2017, 6(5), 201-205 DOI: 10.17628/ecb.2017.6.201-205 202
Synthesis of 4-substituted thiadiazolidinones Section A-Research paper

The progress of the reaction was checked by TLC using RESULTS AND DISCUSSION
hexane : ethyl acetate 6:4 as eluent . This mixture of
reaction was treated with sodium bicarbonate solution to Thiazolidinones 3a-3h have been prepared by reaction of
remove unreacted acid. The obtained solid was filtered, the appropriate Schiff bases (2a-2h) with thioglycolic acid
washed and purified by recrystallization from in a suitable solvent ( benzene or chloroform).
dichloromethane to give color powder.

3,3'-(1,4-Phenylene)bis(2-(3-ethoxy-2-hydroxyphenyl)thiazo-
lidin-4-one) (3e)

The compound was prepared by reaction of 0.4 g (0.01

mol) of 2e and 0.18 g (0.139 ml, 0.02 mol) of thioglycolic
acid. Yield=71 %, m.p.=155-157 ºC, colour: orange. IR
(KBr) 1654 cm-1 (C=O of thiazolidinone ring ); 3014 cm-1
(Ar-H), 2920 cm-1 (C-H aliphatic); 1380 cm-1 (C-N) ; 671
cm-1 (C-S). 1H-NMR (500 MHz, DMSO-d6) δ = 1.8(s, 6H,-
CH3); 4.0(s, 4H, -CH2); 4.6 (s, 4H, C5H); 7.2-8.04(m, 12H,
Ar-H); 9.5(s, 2H, Ar-OH). 13C NMR (75 MHz, DMSO-d6) δ
=29(d, -CH3); 38(d, -CH2); 42(d, CH2O); 53 (d, -CH-); 113-
153(m, Ar-C); 178(d, CH2-C=O).

3,3'-(Naphthalene-1,5-diyl)bis(2-(3-ethoxy-2-hydroxyphenyl)- Scheme 1. Mechanism of formation of mono thiazolidinone.

thiazolidin-4-one) (3f)

The compound was prepared by reaction of 0.5 g (0.01

mol) of 2f and 0.1 g (0.153 ml, 0.02 mol) of thioglycolic
acid. Yield=59 %, m.p.=154-157 ºC, colour: brown. IR
(KBr) 1650 cm-1 (C=O of thiazolidinone ring ); 3030 cm-1
(Ar-H), 2911 cm-1 (C-H aliphatic); 1387 cm-1 (C-N); 668
cm-1 (C-S). 1H NMR (500 MHz, DMSO-d6), δ=1.9(s, 6H, -
CH3); 4.11(s, 4H, -OCH2); 4.7 (s, 4H, C5H); 7.4(s, 2H, - Scheme 2. Synthesis of bis thiazolidinone.
C2H-); 7.58-8.1(m, 14H, Ar-H); 9.6 (s, 2H, Ar-OH).

2-(3-Ethoxy-2-hydroxyphenyl)-3-(4-(4-(2-(3-ethoxy-2-hydroxy-
phenyl)-4-oxothiazolidin-3-yl)benzyl)phenyl)thiazo-lidin-4-one
(3g)

The compound was prepared by reaction of 0.5 g (0.01

mol) of 2g and 0.093 g (0.141 ml, 0.02 mol) of thioglycolic
acid. Yield=76 %, m.p.=105-107 ºC, colour: orange. IR
(KBr) 1654 cm-1 (C=O of thiazolidinone ring ); 3027 cm-1
(Ar-H), 2915 cm-1 (C-H aliphatic); 1390 cm-1 (C-N); 672
cm-1 (C-S). 1H-NMR (500 MHz, DMSO-d6), δ=1.87(s, 6H, -
CH3); 2.9(s, 2H, -CH2-); 4.2(s, 4H, -OCH2); 4.4 (s, 4H,
C5H); 7.39(s, 2H, -C2H-); 7.59-8.16(m, 14H, Ar-H); 9.58 (s,
2H, Ar-OH).

2-(5-Bromo-2-hydroxyphenyl)-3-(4-(4-((R)-2-(5-bromo-2-hydr- Scheme 3. Probable mechanism of the formation of bis-

thiazolidinone
oxyphenyl)-4-oxothiazolidin-3-yl)benzyl)phenyl) thiazolidin-4-
one (3h)
Analysis of infrared spectra
The compound was prepared by reaction of 0.4 g (0.01
mol) of 2h and 0.18 g (0.139 ml, 0.02 mol) of thioglycolic The IR spectra of thiazolidinones 3a-3h in KBr disk show
acid. Yield=73 %, m.p.=246-247 ºC, colour orange. IR six band groups correspond to the stretching vibration of
(KBr) 1660 cm-1 (C=O of thiazolidinone ring ); 3032 cm-1. the aromatic C-H, aliphatic C-H, carbonyl amide group,
(Ar-H), 2918 cm-1 (C-H aliphatic); 1395 cm-1 (C-N); 677 aromatic C=C, the C-N and bending vibration of S-C bonds,
cm-1 (C-S). 1H-NMR (500 MHz, DMSO-d6), δ=2.8(s, 2H, - occur within the ranges 3107-2980, 2975-2887, 1691-1654,
CH2-); 4.2(s, 4H, C5H); 7.1(s, 2H, -C2H-); 7.59-8.16(m, 14H, 1399-1361, 738-654, and 925-617 cm-1 respectively.
Ar-H); 9.4 (s, 2H, Ar-OH).

Eur. Chem. Bull., 2017, 6(5), 201-205 DOI: 10.17628/ecb.2017.6.201-205 203

Synthesis of 4-substituted thiadiazolidinones Section A-Research paper

The absorption frequencies are affected by substitution of Analysis of 13C-NMR spectra

the phenyl ring, and the substitution by electron-donating
groups (methyl group decreases) while substitution by The 13C NMR spectrum of 3a showed thiazolidin-4-one
electron-withdrawing groups (bromo) increase the ring signals at δ 36 ppm for C5 carbon 5) at δ 49.94 ppm for
vibrational frequencies. C2 atom. A multiplet for aromatic carbons at δ 107-139
ppm, a singlet of carbonyl group at δ 177.06 ppm and a
signal for C4 carbon of the ring were observed at δ 179.78
ppm.

Analysis of mass spectra

The mass spectrum of 3a showed the molecular ion peak

corresponding to the particular compound at 375 m/z. The
fragmentation of 3a gave the peaks at 301, 283, 273, 205,
156, 117, 76 and 64 m/z which attributed to the fragments of
C14H9BrN2O+, C15H11N2O2S+, C13H9BrN2+, C10H7NO2S+,
C6H4Br+, C7H5N2+, C6H4+, and C5H4+, respectively.

The mass spectrum of 3b showed the molecular ion

peak corresponding to the particular compound at 359 m/z,
and the fragmentation of 3b gave the peaks at 342, 314,
238, 210, 181 and 154 m/z which attributed to the
fragments of C18H16NO4S+, C17H16NO3S+, C11H12NO3S+,
C10H12NO2S+, C8H7NO2S+, C7H8NOS+, respectively.

The mass spectrum of 3c showed the molecular ion

peak corresponding to the particular compound at 429 m/z,
and the fragmentation of 3c gave the peaks at 355, 183,
172, 156, 76, 64 m/z which attributed to the fragments of
C13H9Br2NO+, C7H5BrN+, C6H4BrO+, C6H4Br+, C6H4+,
C5H4+, respectively.

Analysis of 13C-NMR DEPT spectra

13
C-NMR DEPT spectra of 3a showed thiazolidin-4-one
ring signals at δ 36(negative) 49.94(positive) ppm for C5
carbon C2 carbons, respectively. Multiplet signals for
aromatic carbons were observed at δ 107-139 (positive) ppm,
while at δ 177.06(positive) and δ 179.78(positive) ppm the
carbonyl γ-lactam C4 signals could be observed,
respectively.
13
C-NMR DEPT spectrum of 3b showed the following
signals: δ 28.67 (positive) ppm for -CH3, δ 35.67(negative)
ppm for C5, δ 40.82(positive) ppm for -OCH2, and δ 44.94
ppm C2, multiplet signals for aromatic carbons at δ 106-
153 (positive) ppm, δ 172.90 (positive) ppm for C4 and δ
183.02(positive) ppm for carbonyl of carboxylic group.

Acknowledgements
Figure 2. Structures of the compounds 3a-3h.
This work is sponsored by the University of Thi-Qar as a
part of research development and higher studies projects.
1H-NMR spectral analysis

The 1H-NMR spectrum of 3a shows a singlet signal at δ

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Eur. Chem. Bull., 2017, 6(5), 201-205 DOI: 10.17628/ecb.2017.6.201-205 204

Synthesis of 4-substituted thiadiazolidinones Section A-Research paper
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Eur. Chem. Bull., 2017, 6(5), 201-205 DOI: 10.17628/ecb.2017.6.201-205 205