Synthesis of novel 2-iminothiazolidin-4-ones

Article abstract of DOI:10.1080/00397911.2011.582217

Thiazolidin-4-ones are known to exhibit diverse biological activities such as antimicrobial, anticancer, antidiarrheal, anticonvulsant, antidiabetic, antihistaminic, and antifungal activities. In the present investigation, a series of 2-haloacetamides was prepared by reacting chloroacetyl chloride with amines in dry benzene under reflux conditions. The formed 2-haloacetamides reacted with potassium thiocyanate in refluxing dry acetone to afford new 2-iminothiazolidin-4-ones. The 5-arylidene-2-imino-3 (napthalen-2yl)- thiazolidin-4-ones were prepared by condensing 2-iminothiazolidin-4-ones with substituted benzaldehydes. All the products were characterized by infrared, mass, and ¹H and ¹³C NMR techniques.

Full text of DOI:10.1080/00397911.2011.582217

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Synthesis of Novel 2-Iminothiazolidin-4-
ones
G. Saravanan a b , R. Selvaraju a & S. Nagarajan b
a Shasun Pharmaceuticals Ltd., Cuddalore, India
b Department of Chemistry, Annamalai University, Annamalainagar,
India
Accepted author version posted online: 11 Nov 2011.Published
online: 18 Jul 2012.
To cite this article: G. Saravanan , R. Selvaraju & S. Nagarajan (2012): Synthesis of Novel
2-Iminothiazolidin-4-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:22, 3361-3367
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Synthetic Communications1, 42: 3361–3367, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.582217
SYNTHESIS OF NOVEL 2-IMINOTHIAZOLIDIN-4-ONES
G. Saravanan,1,2 R. Selvaraju,1 and S. Nagarajan2
1Shasun Pharmaceuticals Ltd., Cuddalore, India
2Department of Chemistry, Annamalai University, Annamalainagar, India
GRAPHICAL ABSTRACT
Abstract Thiazolidin-4-ones are known to exhibit diverse biological activities such as
antimicrobial, anticancer, antidiarrheal, anticonvulsant, antidiabetic, antihistaminic, and
antifungal activities. In the present investigation, a series of 2-haloacetamides was prepared
by reacting chloroacetyl chloride with amines in dry benzene under reflux conditions. The
formed 2-haloacetamides reacted with potassium thiocyanate in refluxing dry acetone
to afford new 2-iminothiazolidin-4-ones. The 5-arylidene-2-imino-3 (napthalen-2yl)-
thiazolidin-4-ones were prepared by condensing 2-iminothiazolidin-4-ones with substituted
benzaldehydes. All the products were characterized by infrared, mass, and 1H and 13C
NMR techniques.
Keywords Arylidene; 2-iminothiazolidinone; thiazolidin-4-one
INTRODUCTION
Heterocycles bearing nitrogen and sulfur constitute the core structure of a
number of biologically interesting compounds. Thiazoles are one of the most
intensively investigated classes of aromatic five-membered heterocycles, which
display a broad spectrum of biological activities.[1–3] Thiazolidin-4-ones, a satu-
rated form of thiazoles with a carbonyl group on the fourth carbon, have been
considered a magic moiety (wonder nucleus), which possess almost all types of
biological activities such as antifungal, antimycobacterial, antiviral, in vitro
growth-inhibition against certain microbes, antibacterial, anti-inflammatory, anal-
gesic, antipyretic, anticonvulsant, anticancer, antiallergen, miticidal, nematocidal
or insecticidal, hypnotic, and in vitro antitoxoplasma gondii and herbicide activi-
ties.[4–11] Overviews of their synthesis, properties, reaction, and applications have
been published.[12,13] 5-Arylidene derivatives of thiazolidin-4-one are also known
to exhibit diverse bioactivities such as antidiarrheal,[14] anticonvulsant,[15]
Received January 21, 2011.
Address correspondence to S. Nagarajan, Department of Chemistry, Annamalai University,
Annamalainagar 608 002, India. E-mail: nagarajan.au@gmail.com
3361

3362
G. SARAVANAN, R. SELVARAJU, AND S. NAGARAJAN
antimicrobial,[16] antihistaminic,[17] anticancer,[18] anti-HIV,[19] and antiischemic
activities.[20] All these facts and our interest in the synthesis of new biologically
active heterocyclic compounds[21,22] prompted us to prepare new thiazolidin-4-ones.
In this article, we present the synthesis and characterization of a new series of
2-imino-thiazolidin-4-ones.
RESULTS AND DISCUSSION
We synthesized a series of new 2-iminothiazolidin-4-ones (4a–h) and
5-arylidene derivatives of 2-imino-3-(naphthalene-2yl)thiazolidin-4-ones (6a, b) as
per Scheme 1. The 2-iminothiazolidin-4-ones were synthesized via the key intermedi-
ate 2-chloroacetamides. The 2-chloroacetamides were formed by the reaction of
primary amines with chloroacetyl chloride. The N-acylation can be achieved either
by simply stirring the amine with the chloroacetyl chloride in a suitable solvent or
by adding base. 2-Chloroacetamide derivatives (3a–h) were obtained by refluxing
the primary amine (R-NH2) (1a–h) and chloroacetyl chloride in dry benzene (where,
R ¼ 2-naphthyl, 2-thiophene-2-ethyl, phenethyl, benzyl, 2-thiazolyl, cyclohexyl,
4-benzoic acid, and 5-methylthiophen-2yl-3-carbonitrile).
The compounds 3a–h on treatment with potassium thiocyanate in refluxing
acetone afforded the target compound 2-imino-3-N-substituted-thiazolidin-4-ones
(4a–h). During the course of the reaction, the 2-chloroacetamide reacts with the
triatomic fragment (-SCN) and leads to the cyclized product. Initially, the nucleo-
phile added to the CN bond generates intramolecularly cyclized 2-thiocyanato
acetamides and then 2-iminothiazolidin-4-ones. The interaction of 2-chloroaceta-
mide derivatives with thiocyanate ion is quite interesting and proceeds in two steps.
The first step is the nucleophilic substitution, followed by spontaneous ring closure
to form thiazolidinone. These 2-iminothiazolidin-4-ones are susceptible to hydro-
chloric acid; the latter hydrolyze the imino group to the carbonyl group. In the
present process, the product is isolated in neutral condition and the imino group
is retained. The reactive methylene group present at C-5 of 2-imino-3-(naphtha-
lene-2-yl)thiazolidin-4-one (4a) was condensed with 3-nitro and 2-bromobenzalde-
hydes to yield the related 5-arylidene-2-iminothiazolidin-4-ones (6a, b). The
condensation was carried out in acetic acid in the presence of anhydrous sodium
acetate as catalyst. The reaction gave 90% yield with 3-nitrobenzaldehyde and
60% yield with 2-bromobenzaldehyde.
The formed 2-chloroacetamides (3a–h) were confirmed on the basis of
infrared (IR) and mass spectral data. The IR spectrum exhibits a prominent
band at 1630 cmꢀ1 for the amide carbonyl group. The cyclized product 2-
iminothiazolidin-4-ones (4a–h) were characterized on the basis of IR, NMR,
and mass spectral data. It is established that thiocyanate in the present reaction
conditions cyclized intramoleculary and yielded only the 2-iminothiazolidinones
and not 2-thiocyanatoacetamide, as evident from the absence of an IR band
at 2150 cmꢀ1 for ꢀCN stretching. The IR spectra of compound 4a–h in KBr
showed a band at 2915–2991 cmꢀ1 for ꢀC-H stretching and at 1636–1713 cmꢀ1
for cyclic >C O group. The 1H NMR spectrum of compounds 4a–h in
=

NOVEL 2-IMINOTHIAZOLIDIN-4-ONES
3363
Scheme 1. Synthesis of 2-iminothiazolidin-4-one (4a–h) and 5-arylidene-2-imino-3-(naphthalene-2-yl)
thiazolidin-4-ones (6a, b).
CDCl3=dimethylsulfoxide (DMSO) showed a singlet at d 3.62ꢀ4.16 for two pro-
tons of the reactive methylene group and a broad signal at d 6.05–12.0 for the
imino group. In 13C NMR the signals were observed at d 34.8–41.1 for methyl-
ene carbons at the C-5 position and at d 111.4–116.8 for the imino carbon at the
C-2 position. The molecular ion peaks observed in the mass spectra of 4a–h
further proved the product formation. The IR spectra of compounds 6a and b
in KBr showed bands at 3421–3ꢀ4315 cmꢀ1 for –NH, 2923–3057 for ꢀCH,
=
=
1661–1720 for >C O, and 1626 cm for C C stretching. The methine proton
=
deshielded by the adjacent >C O group was detected at d 7.08–7.09, and a
broad signal observed at d8.02–11.95 for the imino group. Signals observed at
=
=
d 167.5–168.2 for >C O group, d 134.2–144.0 for CH, and d 116.0–116.4
for C NH carbons in 13C NMR. The mass spectra of compounds 6a and b gave
the corresponding molecular ion peaks, which further proved the product
=

3364
G. SARAVANAN, R. SELVARAJU, AND S. NAGARAJAN
Table 1. Physical constant and yield of the compounds 4a–h and 6a, b
Elemental analysisa
H
Mol.
formula
Subst.
group
Mp
(ꢁC)
Yield
(%)
Compound
C
N
4a
C
13H10N2OS
219–221 60.35 63.33 (64.44) 4.08 (4.16) 10.99 (11.56)
4b
—
C9H10N2OS2
C11H12N2OS
81.43 46.21 (47.76) 4.41 (4.45) 11.89 (12.38)
4c
4d
59–62
68–71
75.28 59.92 (59.97) 5.32 (5.49) 12.55 (12.72)
60.97 57.98 (58.23) 4.44 (4.89) 13.08 (13.58)
C
10H10N2OS
4e
C6H5N3OS2
C9H14N2OS
189–193 74.88 36.12 (36.17) 2.52 (2.53) 21.03 (21.09)
4f
86–88
80.96 54.38 (54.52) 6.98 (7.12) 13.99 (14.13)
4g
C
10H8N2O3S
292–294 60.44 48.94 (50.84) 3.32 (3.41) 11.37 (11.86)
4h
C9H7N3OS2
186–190 40.57 45.21 (45.55) 2.87 (2.97) 17.46 (17.71)
205–208 90.37 63.87 (63.99) 3.32 (3.49) 11.56 (11.19)
6a
6b
C20H13N3O3S
C20H13BrN2OS
2-NO2
2-Br
199–201 60.21 58.99 (58.69) 2.98 (3.20)
6.77 (6.84)
aValues within the parentheses are calculated.
formation. The physical constant and yield of the compounds 4a–h and 6a and b
are given in Table 1.
EXPERIMENTAL
Melting points were determined in open capillaries and are not corrected. The
1H NMR and 13C NMR spectra were recorded on a Bruker AMX-500 spectrometer
operating at 400 MHz using CDCl3=DMSO as solvents with Me4Si as an internal
reference. The Fourier transform (FT)–IR spectra were recorded on a Nicolet Ava-
tar 360 FT-IR instrument using KBr pellets. Mass spectra (MS) were recorded on a
Shimadzu GC-MS instrument. Elemental analysis were done on a Vario ELCHNOS
analyzer. All products are purified by recrystalization. Column chromatography is
performed on silica gel (60–120 mesh).
General Procedure for the Synthesis of Substituted
2-Haloacetamides (3)
A solution of appropriate (substituted heterocyclic, aryl or alkyl) primary
amine (0.02 mol) in dry benzene (60 ml) was cooled to 0–5 ꢁC. Chloroacetyl chloride
(0.04 mol) dissolved in dry benzene (20 ml) was slowly added to the solution with

NOVEL 2-IMINOTHIAZOLIDIN-4-ONES
3365
vigorous stirring. When the addition was complete, the reaction mixture was refluxed
for 3 h. Benzene was removed in vacuo. The residue was washed with 5% NaHCO3
followed by a water workup. The crude product was dried and crystallized from
ethanol to give corresponding 2-haloacetamides.
General Procedure for the Synthesis of 2-Imino-3(substituted)-
thiazolidin-4-ones (4a–h)
A mixture of appropriate 2-haloacetamide (0.03 mol) and potassium thiocyan-
ate (KSCN) (0.06 mol) in dry acetone (100 ml) was refluxed for 3 h. Excess acetone
was removed in vacuo and the residue was stirred with water (50 ml). The solid pro-
duct was filtered, washed with water, and dried. Crude product was purified by col-
umn chromatography (silica gel) using 5% ethylacetate=chloroform mixture as eluent.
General Procedure for the Synthesis of 5-Arylidine-2-imino-3-
(naphthalene-2-yl)-thiazolidin-4-ones (6a, b)
2-Imino-3-(naphthalene-2-yl)-thiazolidin-4-one (0.01 mol) and 3-nitro or
2-bromobenzaldehyde (0.02 mol) were added to a solution of anhydrous NaOAc
(0.02 mol) in acetic acid (30 ml). The mixture was refluxed for 5 h at 120 ꢁC and cooled
to room temperature. The solid product was filtered from the mixture, washed with
water, and dried. The crude product was purified by column chromatography (silica
gel) by using 25% ethylacetate=hexane mixture as eluent.
Data
Compound 4a. 1H NMR (CDCl3): d ¼ 7.10–7.85 (m, 7H, Ar-H), 3.8 (s, 2H,
13
=
S-CH2-), 7.9 (s, 1H, NH); C NMR (CDCl3): d ¼ 116.82 (C NH), 122.95–148.48
=
(Ar-C), 34.82 (CH2 ring), 160.34 (C O). IR: 3421, 3287, 1720, 1626, 1508, 1400,
1370, 1020, 775 cmꢀ1; MS: base peak m=z: 168, Mþ peak at m=z: 242.
Compound 4b. 1H NMR (CDCl3): d ¼ 6.85–7.19 (m, 3H Ar-H), 6.78 (s, 1H,
NH), 4.03 (s, 2H, S-CH2-), 3.05 (t, 2H, CH2), 3.54 (m, 2H, CH2); 13C NMR (CDCl3):
=
d ¼ 124.18–140.59 (Ar-C), 169.96 (C O), 41.10 (CH2 ring), 42.62 (CH2), 29.62(CH2);
IR: 3290, 2934, 1660, 1549, 1435, 1217, 847, 702 cmꢀ1; MS: base peak m=z: 110, Mþ
peak at m=z: 226.
Compound 4c. 1H NMR (CDCl3): d ¼ 7.18–7.34 (m, 5H, Ar-H), 6.33(s, 1H,
NH), 3.62 (s, 2H, S-CH2-), 3.53 (t, 2H, CH2), 2.83 (t, 2H, CH2); 13C NMR (CDCl3):
=
=
126.73–138.26 (Ar-C), 111.61 (C NH), 165.09 (C O), 36.80 (CH2), 41.44 (CH2),
35.30 (CH2); IR: 3272, 3102, 2870, 1644, 1573, 1410, 1315, 1150, 1025, 752,
695 cmꢀ1; MS: base peak m=z: 103, Mþ peak at m=z: 220.
Compound 4d. 1H NMR (CDCl3): d ¼ 7.26–7.36 (m, 5H, Ar-H), 6.78 (s, 1H,
NH), 4.42 (s, 2H, CH2), 3.64 (s, 2H, S-CH2-); 13C NMR (CDCl)3: d ¼ 127.87–136.96
=
=
(m, 5H, Ar-C), 111.47 (C NH), 164.96 (C O), 44.37 (CH2), 36.75 (CH2); IR: 3281,
3087, 1645, 1561, 1427, 1317, 1146, 1024, 742, 698 cmꢀ1; MS: base peak m=z: 43,
M þ peak at m=z: 206.

3366
G. SARAVANAN, R. SELVARAJU, AND S. NAGARAJAN
Compound 4e. 1H NMR (DMSO): d ¼ 7.38–7.59 (m, 2H, Ar-H), 12.0 (s, 1H,
NH), 4.00 (s, 2H, S-CH2-); 13C NMR (DMSO): d ¼ 139.80, 169.34, 173.98 (Ar-C),
=
=
116.43 (C NH), 162.34 (C O), 34.82 (CH2-ring); IR: 3082, 2964, 1712, 1599,
1491, 1398, 1325, 1138, 800 cmꢀ1; MS: base peak m=z: 125, Mþ peak at m=z: 199.
Compound 4f. 1H NMR (CDCl)3: d ¼ 1.16–1.97 (m, 10H, cyclohexyl-H),
3.73 (m, 1H,cyclohexyl-H), 6.05 (s, 1H, NH), 3.68 (s, 2H, S-CH2-); 13C NMR
=
=
(CDCl3): d ¼ 24.74–49.43 (cyclohexyl-C), 111.83 (C NH), 164.16 (C O), 37.08
(CH2-thiazole ring); IR: 3269, 3098, 2934, 1636, 1571, 1447, 1342, 1085, 698,
557 cmꢀ1; MS: base peak m=z: 117, Mþ peak at m=z: 199.
Compound 4g. 1H NMR (DMSO): d ¼ 7.40–7.96 (m, 4H, Ar-H), 10.7 (s, 1H,
NH), 4.16 (s, 2H, S-CH2-); 13C NMR (DMSO): d ¼ 118.59–142.29 (Ar-C), 112.75
=
=
(C NH), 164.82 (C O), 37.08 (CH2), 166.87 (COOH); IR: 3271, 2926, 1680,
1600, 1540, 1421, 1287, 1174, 858, 771, 710, 542 cmꢀ1; MS: base peak m=z: 69,
Mþ peak at m=z: 236.
Compound 4h. 1H NMR (DMSO): d ¼ 7.13 (s, 1H, Ar-H), 9.07 (s, 1H, NH),
3.88 (s, 2H S-CH2-), 2.47 (s, 3H, CH3); 13C NMR (DMSO): d ¼ 113.19, 138.86, 143.72
=
=
=
(Ar-C), 113.33 (C NH), 116.30 (C N), 164.55 (C O), 37.632 (CH2-ring), 90.05
(C-CN), 15.70 (CH3); IR: 3333, 3182, 1667, 1546, 1418, 1355, 1151, 763 cmꢀ1; MS:
base peak m=z: 165, Mþ peak at m=z: 237.
Compound 6a. 1H NMR (CDCl3): d ¼ 7.45–7.58 (m, 4H, naphthyl-H),
7.68–7.73 (m, 3H, naphthyl-H), 7.08 (d, 1H, benzylidene-H), 8.21 (s, 1H, NH), 7.86
(d, 1H, phenyl), 7.98 (d, 1H, phenyl), 8.12 (d, 1H, phenyl); 13C NMR (CDCl3):
=
d ¼ 151.39 (IPSO, naphthyl), 148.42 (IPSO, phenyl-C), 116.04 (C NH), 168.22
=
=
(C O), 144.08 (benzylidene CH), 123.29–135.49 (Ar-C); IR: 3432, 3052, 2958,
1719, 1651, 1526, 1431, 1348, 1195, 1015, 806, 735 cmꢀ1; MS: base peak 168, Mþ peak
at m=z: 375.
Compound 6b. 1H NMR (CDCl3): d ¼ 7.09 (d, 1H, benzylidene-H), 7.119–
7.34 (m, 3H, naphthyl-H), 7.41–7.53 (m, 3H, naphthyl-H), 7.59–7.92 (m, 4H,
phenyl-H), 8.02 (s, 1H, NH); 13C NMR (CDCl3): d ¼ 152.57 (IPSO, naphthyl-C),
=
=
143.25 (IPSO, phenyl-C), 134.28 (benzylidene CH), 167.55 (C O), 116.49
=
(C NH), 123.16–133.76 (Ar-C). IR: 3435, 2926, 1694, 1661, 1573, 1473, 1432,
1222, 1153, 1014, 808, 781, 757 cmꢀ1; MS: base peak 168, M þ peak at m=z: 410.
ACKNOWLEDGMENTS
We thank the Shasun Research Centre for NMR spectral measurements. One
of the authors (G.S.) is thankful to Shasun Pharmaceuticals Ltd. for support.
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