Synthesis of 5-substituted 2-ylidene-1,3-thiazolidin-4-one derivatives and evaluation of their anticancer and antioxidant activities

Article abstract of DOI:10.1007/s10593-019-02568-5

[Figure not available: see fulltext.] Novel 5-(aroyl)methyl- and 5-(aroyl)methylen-2-ylidene-1,3-thiazolidin-4-ones have been prepared in high yields using ketene N,S-acetal salts, obtained from phenyl isothiocyanate and propanedinitrile or ethyl cyanoacetate. Several of the newly synthesized 1,3-thiazolidin-4-one derivatives demonstrate high antioxidant and anticancer activities.

Full text of DOI:10.1007/s10593-019-02568-5

DOI 10.1007/s10593-019-02568-5
Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
Synthesis of 5-substituted 2-ylidene-1,3-thiazolidin-4-one derivatives
and evaluation of their anticancer and antioxidant activities
Khaled F. Saied1*, Kamal A. Kandeel2,
Salwa S. Abdelwahab3, Osama M. Ahmed4
1 Department of Basic Science, Faculty of Oral and Dental Medicine, Nahda University,
Beni-Suef 62511, Egypt; e-mail: fathykhaled905_7@yahoo.com
2 Department of Chemistry, Faculty of Science, Ain Shams University,
Abbassia, Cairo 11566, Egypt; e-mail: kamalkandeel@hotmail.com
3 Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt,
New Cairo 11835, Egypt; e-mail: salwa_elsayed@yamil.com
4 Department of Zoology, Faculty of Science, Beni-Suef University,
Beni-Suef 62511, Egypt; e-mail: osamamoha@yahoo.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(10), 993–1003
Submitted April 21, 2019
Accepted after revision June 26, 2019
Novel 5-(aroyl)methyl- and 5-(aroyl)methylen-2-ylidene-1,3-thiazolidin-4-ones have been prepared in high yields using ketene
N,S-acetal salts, obtained from phenyl isothiocyanate and propanedinitrile or ethyl cyanoacetate. Several of the newly synthesized
1,3-thiazolidin-4-one derivatives demonstrate high antioxidant and anticancer activities.
Keywords: ketene N,S-acetal, malononitrile, phenyl isothiocyanate, 1,3-thiazolidin-4-one, anticancer activity, antioxidant activity, cyclo-
condensation, transesterification.
Derivatives of 1,3-thiazolidin-4-one bearing thioxo, oxo,
or imino group at C-2 atom are important compounds that
exhibit antimicrobial,1 antischistosomal,2 and antitumor3
properties and act as inhibitors of HIV-1 integrase.4 In
addition, 2- or 5-ylidene-1,3-thiazolidin-4-ones have also
attracted increased interest due to their enhanced biological
activity.2,3,5 In this regard, ketene N,S-acetals, obtained by
reaction of alkyl or aryl isothiocyanates and active
methylene compounds, are valuable precursors of various
heterocyclic compounds, including 2-ylidene-1,3-thiazolidin-
4-ones.6 Herein, we report the synthesis of novel
5-substituted 2-ylidene-1,3-thiazolidin-4-ones from ketene
N,S-acetals. Anticancer and antioxidant activities of the
obtained 1,3-thiazolidin-4-one derivatives have been
demonstrated.
cyanoacetate (2b) in EtOH. As expected,1,6,7 nucleophilic
addition of the in situ formed ketene N,S-acetal salts 3a,b
to the α-carbon of 4-phenyl-, 4-(4-methylphenyl)-, and
4-(4-chlorophenyl)-4-oxobut-2-enoic acids 4a–c8 led to
formation of intermediates 5a–e. Further acid-catalyzed
cyclocondensation of adducts 5a–e afforded 5-substituted
2-ylidene-1,3-thiazolidin-4-ones 6a–e. In case of ketene
N,S-acetal salt 3a, obtained from propanedinitrile (2a),
reaction in refluxing concd HCl provided [5-(2-aryl-
2-oxoethyl)-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene]propane-
dinitriles 6a–c as white solids, whereas similar reaction of
ketene N,S-acetal salt 3b, derived from ethyl cyanoacetate
(2b), led to formation of ethyl (2E,2Z)-[5-(2-aryl-
2-oxoethyl)-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene](cyano)-
ethanoates 6d,e that were isolated by extraction with PhMe
as viscous oils. However, purification by refluxing products
(E,Z)-6d,e in MeOH afforded the respective methyl esters
(E,Z)-6f,g as white waxy solids. Most likely, suitable
The synthesis of 5-substituted 2-ylidene-1,3-thiazolidin-
4-ones commenced with KOH-promoted reaction of phenyl
isothiocyanate (1) and propanedinitrile (2a) or ethyl
0009-3122/19/55(10)-0993©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
Scheme 1
conditions for this transesterification9 were ensured by the
acid contamination of crude ethyl esters (E,Z)-6d,e
(Scheme 1).
C≡N group. Finally, mass spectra of 2-ylidene-1,3-thi-
azolidin-4-ones 6a–g, containing signals with m/z values of
the respective molecular ions, were in agreement with the
proposed structures of products.
IR spectra of compounds 6a–g revealed characteristic
absorption bands of C≡N group at 2210–2215 cm–1 and
two (compounds 6a–c) or three (compounds 6d–g) C=O
The synthesized novel 5-substituted 2-ylidene-1,3-thi-
azolidin-4-ones 6a–e,g were further treated with Br2 in
refluxing AcOH7,10 and converted into the respective
(E,Z)-2,5-diylidene-1,3-thiazolidin-4-ones 7a–e,g (Scheme 1).
Structures of compounds 7a–e,g were confirmed by IR and
1H and 13C NMR spectroscopy. Due to the conjugation
with the newly formed C=C bond, IR absorption bands of
1,3-thiazolidin-4-one and aroyl C=O groups of products 6a
–e,g were shifted to longer wavelengths, for example, from
1739 and 1671 (compound 6a) to 1731 and 1640 cm–1
1
groups at 1663–1747 cm–1. H NMR spectra of 5-sub-
stituted 2-ylidene-1,3-thiazolidin-4-ones 6a–g contained
the expected signals of protons of CHCH2C(O)Ar group
with AMX splitting pattern.1a,2 For products (E,Z)-6d,e,
signals of protons of OCH2CH3 group were observed as
triplets at 1.18 and 1.17 ppm and multiplets at 4.13–4.20
and 3.93–4.19 ppm, respectively. Similarly, formation of
methyl esters (E,Z)-6f,g was confirmed by a singlet at
3.70 ppm corresponding to the protons of CO2CH3 group.
In addition, 13C NMR spectrum of product 6g contained
two signals of C≡N group and two signals of OCH3 group.
This may be explained by the formation of a mixture of E-
and Z-isomers of compound 6e that was further converted
into the respective methyl ester (E,Z)-6g and deshielding of
the carbon atom of methyl group in compound (E)-6g by
the phenyl substituent at nitrogen atom. For the same
reason, 13C NMR chemical shift of the signal of one C≡N
group in propanedinitriles 6a–c was observed in lower field
than chemical shift corresponding to the signal of other
1
(compound 7a). According to H NMR spectra, olefinic
proton was observed as a singlet equivalent to one proton
and C=C bond at C-5 atom of products 7a–e,g, most likely,
possessed Z-configuration. Such assignment was proposed
by comparing chemical shift of this signal (8.20–8.46 ppm)
with the corresponding chemical shifts of E- and Z-isomers
(7.82–7.85 and 7.93–8.03 ppm, respectively) of 1,3-thi-
azolidin-4-ones.7
Furthermore, (4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene)-
propanedinitrile (8a) and ethyl (2E,2Z)-cyano(4-oxo-
3-phenyl-1,3-thiazolidin-2-ylidene)ethanoate (8b) were
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Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
Scheme 2
prepared by reaction of ketene N,S-acetal salts 3a,b and
potassium 2-chloroacetate11 (Scheme 1). Structures of
products 8a,b were substantiated by comparing their
melting points and Rf values with samples synthesized
according to previously reported procedure.6b In addition,
1
structure of compound 8a was also confirmed by H NMR
spectroscopy and mass spectrometry.
In continuation of this study, condensation of (oxo)-
phenylacetaldehyde and propanedinitrile 8a or ethyl acetate
(E,Z)-8b was carried out according to previously reported
procedure.12 Synthesis of compounds (E,Z)-7a,d allowed to
compare their structure to the same products, obtained via
addition of ketene N,S-acetal salts 3a,b to 4-oxo-4-phenyl-
but-2-enoic acid (4a). Moreover, structures of compounds
6a,d and (E,Z)-7a,d were thoroughly evidenced when (E,Z)-
2,5-diylidene-1,3-thiazolidin-4-ones 7a,d were converted
into the respective 5-substituted 2-ylidene-1,3-thiazolidin-
4-ones 6a,d by regioselective hydrogenation of C=C bond
at the C-5 atom using Zn in AcOH13 (Scheme 2). Such
chemical transformations allowed to rule out the possible
addition of ketene N,S-acetal salts 3a,b at β-carbon of
4-oxobut-2-enoic acids 4a–c and formation of 1,3-thiazinan-
2-ylidene derivatives 9 (Scheme 1). Compounds 6a,d and
(E,Z)-7a,d, synthesized from starting materials 8a,b, were
1
characterized by H NMR spectroscopic data that were in
agreement with the respective data for products 6a,d and
(E,Z)-7a,d, obtained from ketene N,S-acetal salts 3a,b and
4-phenyl-4-oxobut-2-enoic acid (4a). The structure of slightly
soluble in DMSO-d6 (E,Z)-2,5-diylidene-1,3-thiazolidin-
4-one 7a was also confirmed by 13C NMR spectroscopy.
Furthermore, bromination of propanedinitrile 8a and ethyl
acetate (E,Z)-8b in refluxing AcOH according to previously
reported method,10b afforded the respective 5-bromo-
1,3-thiazolidin-4-ones 10a,b. Refluxing of compounds
10a,b and KSCN in EtOH or AcOH promoted dimerization
of starting materials 10a,b leading to 5,5'-bithiazolylidenes
(E,Z)-11a,b. Products (E,Z)-11a,b were also obtained from
5-bromo-1,3-thiazolidin-4-ones 10a,b when KSCN was
replaced with NaOCN or NaOAc. However, 5-(benzyl-
amino)-1,3-thiazolidin-4-one 12 was successfully synthe-
sized by treatment of benzylamine solution in Et2O with a
solution of compound 10a in EtOAc (Scheme 2).
4.33 ppm. The magnetic inequivalence of these protons
was interpreted based on the chirality of the nitrogen
atom.15 Further splitting of the signals of NCH2 protons
was ensured by additional coupling with NH proton,
which, on the other hand, was observed as a triplet. This
rationalization was supported by the COSY spectrum of
5-(benzylamino)-1,3-thiazolidin-4-one 12 (Fig. 1).
In addition to (E,Z)-2,5-diylidene-1,3-thiazolidin-4-ones
7a–e,g, synthesis of compound (E,Z)-7h from (4-oxo-
3-phenyl-1,3-thiazolidin-2-ylidene)propanedinitrile (8a) was
also demonstrated. In this case, starting material 8a was
prepared by reaction of phenyl isothiocyanate (1), obtained
in situ by decomposition of ammonium phenylcarbamo-
dithioate (13), and propanedinitrile (2a). Subsequent
condensation of compound 8a and 4-methoxybenzaldehyde
afforded (E,Z)-2,5-diylidene-1,3-thiazolidin-4-one 7h in
90% yield (Scheme 3). The structure of product (E,Z)-7h
was established by comparing its melting point and
1H NMR spectroscopic data with previously reported
Structures of compounds 10a,b, (E,Z)-11a,b, and 12
1
were established by IR and H NMR spectroscopy and
mass spectrometry. In addition, structures of 1,3-thiazolidin-
4-ones (E,Z)-10b and 12 were also confirmed by 13C NMR
spectroscopy. The 13C NMR spectrum of compound
(E,Z)-10b revealed the expected number of carbon atoms
for each of E- and Z-isomer.
Scheme 3
Conversion of 5-bromo-1,3-thiazolidin-4-ones 10a,b
into the respective dimers (E,Z)-11a,b, most likely, occurs
in a similar way as the dimerization of 5-bromo-1,3-thi-
azolidin-4-ones under treatment with Et3N. The mechanism
of this transformation has been suggested to proceed via
formation of 1,3-thiazolidin-4-one-based carbanion or
carbene.14 However, there is still lack of evidence to
confirm the most plausible reaction pathway.
1
The H NMR spectrum of compound 12 showed ABq
splitting pattern of the signals of NCH2 protons at 4.23 and
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Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
Figure 1. COSY spectrum of 5-(benzylamino)-1,3-thiazolidin-4-one 12.
data.6b The 1H NMR spectrum of compound (E,Z)-7h
contained two singlets at 7.49 and 8.01 ppm in a ratio of
5:95 related to olefinic proton. Most likely, formation of
(Z)-2,5-diylidene-1,3-thiazolidin-4-one 7h is more pre-
ferred, since the olefinic proton is more deshielded by
4-oxo group than in the case of E-isomer.7
As described for propanedinitrile (2a), 3-phenyl-
2-thioxo-1,3-thiazolidin-4-one (14a)10b,16 and 3-phenyl-
1,3-thiazolidine-2,4-dione (14b)17 were also separately
used in reactions with phenyl isothiocyanate (1), followed
by treatment with potassium chloroacetate. Application of
starting material 14a provided (E,Z)-5-(4-oxo-3-phenyl-
1,3-thiazolidin-2-ylidene)-3-phenyl-2-thioxo-1,3-thiazolidin-
4-one (15), while similar reaction of compound 14b
produced 2-thioxo-1,3-thiazolidin-4-one 14a. Most likely,
KOH-promoted cleavage of dione 14b produced potassium
sulfanylacetate (16),14b which reacted with phenyl isothio-
cyanate (1) to form intermediate 17. Further cyclo-
condensation18 of intermediate 17 under acidic conditions
afforded 3-phenyl-2-thioxo-1,3-thiazolidin-4-one (14a)
(Scheme 4). The IR spectrum of compound (E,Z)-15
exhibited two absorption bands of C=O groups at 1671 and
1731 cm–1, and the respective 1H NMR spectrum contained
signals of aliphatic and aromatic protons in a ratio of 1:5.
Moreover, the mass spectrum of product (E,Z)-15 displayed a
molecular ion peak with m/z 384 and a base peak at m/z 80
corresponding to 3-isocyanatocycloprop-1-enyl cation.
Finally, condensation of 4-methoxybenzaldehyde and
compound (E,Z)-15 or 14a (obtained from starting material
14b) under previously reported conditions7,12 afforded
(E,Z)-2,5-diylidene-1,3-thiazolidin-4-one 18 and (E,Z)-5-(4-
methoxybenzylidene)-3-phenyl-2-thioxo-1,3-thiazolidin-4-one
(19),19 respectively (Scheme 4). In addition to the multiplet
1
representing ten protons of phenyl substituents, H NMR
spectrum of product (E,Z)-18 exhibited two doublets at
7.16 and 7.29 ppm relating to protons of 4-methoxyphenyl
substituent. Moreover, signal of protons of OCH3 group
was observed as a singlet at 3.85 ppm.
Products 6b–d,g, (E,Z)-7c,g, and (E,Z)-10b were
selected as test compounds for evaluation of antitumor and
antioxidant activities of the synthesized 5-substituted
2-ylidene-1,3-thiazolidin-4-ones following previously
reported procedures.20 Glutathione was applied as a
standard, and antioxidant activity was determined using
Scheme 4
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Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
Table 1. DPPH radical scavenging activity (%) of glutathione
solutions of the test compounds in EtOH with concentrations
0.25, 0.5, and 1.0 mg/ml (Table 1). The 2,2-diphenyl-
1-picrylhydrazyl (DPPH) radical scavenging activity
(RSA) was calculated according to equation:
and compounds 6b–d,g, (E,Z)-7c,g, and (E,Z)-10b
Concentration*, mg/ml
Compound
0.25
0.5
1.0
RSA = [(Acontrol – Asample)/Acontrol] × 100%,
83.7 0.1
88.73 0.04
71.3 0.2
67.4 0.2
41.5 0.5
26.0 0.2
35.1 0.3
67.4 0.9
88.2 0.1
86.7 0.2
74.4 0.1
72.0 1.0
38.8 0.1
22.9 0.2
44.8 1.0
85.6 0.7
90.76 0.07
82.6 0.2
80.4 0.1
74.7 0.6
41.9 0.1
40.3 0.3
58.2 0.1
88.1 0.7
6b
6c
where Acontrol – absorbance of DPPH radical in EtOH,
A
sample – absorbance of DPPH radical and test compound in
6d
EtOH.
All tested 1,3-thiazolidin-4-one derivatives exhibited
6g
(E,Z)-7c
(E,Z)-7g
(E,Z)-10b
Glutathione
antioxidant activity. 5-Substituted 2-ylidene-1,3-thiazolidin-
4-one 6b showed the highest antioxidant activity at concen-
tration 1.0 mg/ml, whereas compound 6c – at concen-
trations 0.25 and 0.5 mg/ml. At all applied concentrations,
{5-[2-(4-methylphenyl)-2-oxoethyl]-4-oxo-3-phenyl-1,3-thi-
azolidin-2-ylidene}propanedinitrile (6b) was more effective in
scavenging free radicals than glutathione. Compound 6c
demonstrated higher activity than glutathione at concen-
trations 0.25 and 0.5 mg/ml. Furthermore, 5-substituted
2-ylidene-1,3-thiazolidin-4-ones 6d,g also possessed high
RSA at all tested concentrations. Compound 6g exhibited
lower antioxidant activity than glutathione. However, RSA
of 1,3-thiazolidin-4-one derivative 6d at concentration
0.25 mg/ml was higher than the RSA of glutathione.
Compounds (E,Z)-7c,g and (E,Z)-10b demonstrated
moderate antioxidant activity, and the least active was
5-substituted 2-ylidene-1,3-thiazolidin-4-one (E,Z)-7g.
Antitumor activity of 5-substituted 2-ylidene-1,3-thi-
azolidin-4-ones 6b–d,g, (E,Z)-7c,g, and (E,Z)-10b was
compared with the activity of reference drug doxorubicin.
The test compounds demonstrated antiproliferative effect
on breast carcinoma cell line MDA-MB-231 and ensured
gradual decrease in the survival percentage of cells
MDA-MB-231, as the concentration of 1,3-thiazolidin-
4-one derivatives increased from 0 to 100 µg/ml. Anti-
tumor activity of all tested compounds increased according
to the following order: compounds 6c, (E,Z)-7c, 6b,
(E,Z)-7g, 6g, (E,Z)-10b, 6d, doxorubicin with the
respective half maximal inhibitory concentration (IC50)
values 90, 83, 74, 54.4, 53.7, 45, 44, and 10 µg/ml (Fig. 2).
* Solutions of glutathione and test compounds in EtOH.
Thus, the highest antitumor activity against cell line
MDA-MB-231 exhibited by 5-substituted 2-ylidene-1,3-
thiazolidin-4-ones 6d and (E,Z)-10b, whereas the lowest
activity by compound 6c.
In conclusion, synthesis of novel 5-(aroyl)methyl- and
5-(aroyl)methylen-2-ylidene-1,3-thiazolidin-4-ones has been
demonstrated. All tested compounds exhibited antioxidant
and anticancer activities. The highest antioxidant activity
was exhibited by {5-[2-(4-methylphenyl)-2-oxoethyl]-4-oxo-
3-phenyl-1,3-thiazolidin-2-ylidene}- and {5-[2-(4-chloro-
phenyl)-2-oxoethyl]-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene}-
propanedinitriles, the first one being more active than the
applied standard antioxidant glutathione. Among the
evaluated 1,3-thiazolidin-4-one derivatives, ethyl (2E,2Z)-
cyano[4-oxo-5-(2-oxo-2-phenylethyl)-3-phenyl-1,3-thiazo-
lidin-2-ylidene]ethanoate and ethyl (2E,2Z)-(5-bromo-
4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene)(cyano)ethanoate
have the most potent antitumor properties. However, their
antitumor activity is lower than that of doxorubicin. To
propose a possible mechanism of action, further in vitro
and in vivo studies of 5-substituted 1,3-thiazolidin-4-ones
with the highest antioxidant and antitumor activities will be
conducted.
Figure 2. Antiproliferative effect of 5-substituted 2-ylidene-1,3-thiazolidin-4-ones 6b–d,g, (E,Z)-7c,g, and (E,Z)-10b and reference drug
doxorubicin on breast carcinoma cell line MDA-MB-231.
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Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
Experimental
JAX = 8.4, JMX = 3.6, 5-CHX); 4.28 (1H, dd, JAM = 18.9,
JMX = 3.6, 1-CHM); 4.02 (1H, dd, JAM = 18.9, JAX = 8.4,
1-CHA). 13C NMR spectrum, δ, ppm: 40.8; 43.6; 53.6
(=C(CN)2); 109.8 (C≡N); 114.1 (C≡N); 128.2 (2C); 128.8;
128.9 (2C); 129.1; 129.6 (2C); 131.1; 133.4; 134.1; 135.1;
174.0; 174.6; 197.0 (C=O ketone). Mass spectrum, m/z
(Irel, %): 359 [M]+ (30), 254 [M−PhCO]+ (19), 226
[M−PhCO−CO]+ (29), 105 [PhC≡O]+ (100), 77 [Ph]+ (93).
Found, %: C 66.79; H 3.67; N 11.72. C20H13N3O2S.
Calculated, %: C 66.84; H 3.65; N 11.69.
IR spectra were recorded on a PerkinElmer 1600 FT-IR
1
spectrometer using KBr pellets. H and 13C NMR spectra
were acquired on Varian Mercury 300 (300 MHz (com-
pounds 6b–g, (E,Z)-7b–e,g,h, 8a, 10a,b, (E,Z)-11a,b, 12,
14a, (E,Z)-15, (E,Z)-18, (E,Z)-19) and 75 MHz (compounds
6a,g), respectively) and Bruker Avance FT-NMR 400
(400 MHz (compounds 6a, (E,Z)-7a) and 100 MHz
(compounds 6b–e, (E,Z)-7a, (E,Z)-10b, 12, 15), respec-
tively) spectrometers in DMSO-d6 or CDCl3 (1H NMR
spectra of compounds 10a,b) using TMS as internal
standard. COSY spectrum of compound 12 was recorded
on a Bruker Avance FT-NMR 400 (400 MHz) spectro-
meter. 13C NMR spectra of compounds (E,Z)-7c, (E,Z)-11a,b,
and (E,Z)-18 were not obtained due to their negligible
solubility in DMSO-d6. Mass spectra were recorded on a
Shimadzu GCMS-QP2010 Plus spectrometer (EI, 70 eV).
Elemental analyses were performed on a Vario EL III
elemental analyzer. Melting points were determined on a
GallenKamp melting point apparatus and are uncorrected.
4-Aryl-4-oxobut-2-enoic acids 4a–c,8 3-phenyl-2-thioxo-
1,3-thiazolidin-4-one (14a),10b,16 and 3-phenyl-1,3-thi-
azolidine-2,4-dione (14b)17 were synthesized according to
previously reported procedures. Antioxidant and antitumor
activity assays were carried out according to previously
reported methods.20
Synthesis of [5-(2-aryl-2-oxoethyl)-4-oxo-3-phenyl-1,3-
thiazolidin-2-ylidene]propanedinitriles and -ethanoates
6a–g (General method). Propanedinitrile (2a) (0.66 g,
10 mmol) or ethyl cyanoacetate (2b) (1.1 ml, 10 mmol)
was added to a solution of KOH (0.57 g, 10 mmol) and
phenyl isothiocyanate (1) (1.2 ml, 10 mmol) in 95% EtOH
(40 ml). The reaction mixture was stirred at room
temperature for 30 min. 4-Aryl-4-oxobut-2-enoic acid 4a–c
(10 mmol) was then added, and stirring at room temperature
was continued for 1 h. The mixture was poured into concd
HCl (30 ml) and refluxed for 5 min. Solid products 6a–c
were filtered off, washed with H2O (3×20 ml), air-dried,
and crystallized from 1,4-dioxane–PhMe, 2:3. Purification
method I. Oily residue, containing product 6d,e, was
extracted with PhMe (2×50 ml). The combined organic
layers were dried over anhydrous CaCl2, concentrated
under reduced pressure to 15 ml, triturated with petroleum
ether (5 ml), and kept at room temperature for 12 h. The
obtained crystals were filtered off, air-dried, and
crystallized from PhMe – petroleum ether, 3:2.
{5-[2-(4-Methylphenyl)-2-oxoethyl]-4-oxo-3-phenyl-
1,3-thiazolidin-2-ylidene}propanedinitrile (6b). Yield
3.20 g (85%), white crystals, mp 255–257°C. IR spectrum,
ν, cm–1: 3061 (=C–H), 2922 (C–H), 2215 (C≡N), 1737
(C=O), 1669 (C=O), 813 (C–H Ar), 743 and 691 (C–H Ph).
1H NMR spectrum, δ, ppm (J, Hz): 7.92 (2H, d, J= 8.1,
H-2,6); 7.60–7.46 (5H, m, H Ph); 7.38 (2H, d, J = 8.1,
H-3,5); 4.95 (1H, dd, JAX = 8.4, JMX = 3.6, 5-CHX); 4.23
(1H, dd, JAM = 18.9, JMX = 3.6, 1-CHM); 3.97 (1H, dd,
J
AM = 18.9, JAX = 8.4, 1-CHA); 2.41 (3H, s, CH3). 13C NMR
spectrum, δ, ppm: 21.7 (CH3); 41.2; 44.2; 54.1 (=C(CN)2);
110.4 (C≡N); 114.6 (C≡N); 128.8 (2C); 129.3; 129.6;
130.0 (3C); 130.1; 131.7; 133.2; 133.9; 145.3; 174.7;
175.2; 197.0 (C=O ketone). Mass spectrum, m/z (Irel, %):
373 [M]+ (13), 119 [4-MeC6H4C≡O]+ (100), 91
[4-MeC6H4]+ (40), 77 [Ph]+ (13). Found, %: C 67.50;
H 4.10; N 11.23. C21H15N3O2S. Calculated, %: C 67.54;
H 4.05; N 11.25.
{5-[2-(4-Chlorophenyl)-2-oxoethyl]-4-oxo-3-phenyl-
1,3-thiazolidin-2-ylidene}propanedinitrile (6c). Yield
3.35 g (85%), white crystals, mp 245–247°C. IR spectrum,
ν, cm–1: 3066 (=C–H), 2919 (C–H), 2213 (C≡N), 1736
(C=O), 1673 (C=O), 821 (C–H Ar), 733 and 690 (C–H Ph).
1H NMR spectrum, δ, ppm (J, Hz): 8.03 (2H, dd, J = 8.4,
J = 1.5, H-2,6); 7.67–7.49 (7H, m, H Ph, H-3,5); 4.96 (1H,
dd, JAX = 8.4, JMX = 3.0, 5-CHX); 4.27 (1H, dd, JAM = 18.9,
JMX = 3.0, 1-CHM); 3.99 (1H, dd, JAM = 18.9, JAX = 8.4,
1-CHA). 13C NMR spectrum, δ, ppm: 41.3; 44.1; 54.2
(=C(CN)2); 110.4 (C≡N); 114.6 (C≡N); 129.3; 129.6 (3C);
130.1; 130.2; 130.6 (2C); 131.7; 133.9; 134.3; 139.6;
174.6; 175.1; 196.7 (C=O ketone). Mass spectrum, m/z
(Irel, %): 393 [M]+ (44), 254 [M−4-ClC6H4CO]+ (50), 139
[4-ClC6H4C≡O]+ (100), 111 [4-ClC6H4]+ (79), 77 [Ph]+
(75), 64 [cycloC3H2CN]+ (16). Found, %: C 61.02; H 3.19;
N 10.87. C20H12ClN3O2S. Calculated, %: C 60.99; H 3.07;
N 10.67.
Ethyl (2E,2Z)-cyano[4-oxo-5-(2-oxo-2-phenylethyl)-
3-phenyl-1,3-thiazolidin-2-ylidene]ethanoate (6d). Yield
3.05 g (75%), white waxy flakes, mp 176–178°C.
IR spectrum, ν, cm–1: 3063 (=C–H), 2981 (C–H), 2210
(C≡N), 1747 (br, C=O), 1684 (br, C=O), 754 and 688
Purification method II. Oily residue, containing product
6d,e, was decanted, dissolved in MeOH (20 ml), and
refluxed for 3 min. The obtained solid product 6f,g was
filtered off, washed with H2O (3×20 ml), air-dried, and
crystallized from PhMe – petroleum ether, 3:2.
1
(C–H Ph). H NMR spectrum, δ, ppm (J, Hz): 8.01 (2H d,
[4-Oxo-5-(2-oxo-2-phenylethyl)-3-phenyl-1,3-thiazolidin-
2-ylidene]propanedinitrile (6a). Yield 2.90 g (80%),
white crystals, mp 226–238°C. IR spectrum, ν, cm–1: 3064
(=C–H), 2930 (C–H), 2215 (C≡N), 1739 (C=O), 1671
J = 8.1, H-2,6); 7.72 (1H, t, J = 7.2, H-4); 7.59–7.44 (7H,
m, H Ph, H-3,5); 4.62 (1H, dd, JAX = 8.4, JMX = 3.0,
5-CHX); 4.20–4.13 (3H, m, OCH2CH3, 1-CHM); 3.92 (1H,
dd, JAM = 18.9, JAX = 8.4, 1-CHA); E-isomer (50%): 1.178
(3H, t, J = 6.9, OCH2CH3); Z-isomer (50%): 1.175 (3H, t,
J = 6.9, OCH2CH3). 13C NMR spectrum, δ, ppm: 14.2
(OCH2CH3); 40.2; 41.5; 61.6 (OCH2CH3); 75.7 (=CCN);
1
(C=O), 727 and 689 (C–H Ph). H NMR spectrum, δ, ppm
(J, Hz): 8.03 (2H, d, J = 7.2, H-2,6); 7.72 (1H, t, J = 8.0,
H-4); 7.61–7.51 (7H, m, NPh, H-3,5); 4.97 (1H, dd,
998

Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
112.6 (C≡N); 128.6 (2C); 129.4 (2C); 129.5; 129.8 (2C);
172.0; 175.6; 196.4 (C=O ketone). Mass spectrum, m/z
(Irel, %): 406 [M]+ (7), 404 [M−H2]+ (14), 119
[4-MeC6H4C≡O]+ (100), 91 [4-MeC6H4]+ (42), 80
[cycloC3H2NCO]+ (68), 64 [cycloC3H2CN]+ (37). Found, %:
C 65.29; H 4.76; N 6.73. C22H18N2O4S. Calculated, %:
C 65.01; H 4.46; N 6.89.
Synthesis of [5-(2-aryl-2-oxoethylidene)-4-oxo-3-phenyl-
1,3-thiazolidin-2-ylidene]propanedinitriles and -ethanoates
(E,Z)-7a–e,g (General method).7,10 A solution of Br2
(0.3 ml, 6 mmol) in glacial AcOH (5 ml) was added
portionwise to a stirred hot (100°C) solution of compound
6a–e,g (5 mmol) in glacial AcOH (30 ml). The reaction
mixture was refluxed for 10 min, then cooled to room
temperature. The obtained solid was filtered off, washed
with H2O (3 × 30 ml), air-dried, and crystallized from
1,4-dioxane.
[(5E,5Z)-4-Oxo-5-(2-oxo-2-phenylethylidene)-3-phenyl-
1,3-thiazolidin-2-ylidene]propanedinitrile (7a). Yield
1.60 g (90%), yellow crystals, mp 261–263°C. IR spectrum,
ν, cm–1: 3065 (=C–H), 2214 (C≡N), 1731 (C=O), 1640
(C=O), 733 and 693 (C–H Ph). Mass spectrum, m/z (Irel, %):
357 [M]+ (21), 190 [M−PhNC=C(CN)2]+ (23), 105
[PhC≡O]+ (84), 80 [cycloC3H2NCO]+ (94), 77 [Ph]+ (100),
64 [cycloC3H2CN]+ (34). Found, %: C 66.99; H 3.24;
N 12.26. C20H11N3O2S. Calculated, %: C 67.22; H 3.10;
N 11.76.
{(5E,5Z)-5-[2-(4-Methylphenyl)-2-oxo-ethylidene]-4-
oxo-3-phenyl-1,3-thiazolidin-2-ylidene}propanedinitrile
(7b). Yield 1.73 g (93%), yellow crystals, mp 252–254°C.
IR spectrum, ν, cm–1: 3064 (=C–H), 2215 (C≡N), 1730
(C=O), 1639 (C=O), 818 (C–H Ar), 740 and 688 (C–H Ph).
1H NMR spectrum, δ, ppm, (J, Hz): 8.43 (1H, s, =CH);
8.19 (2H, d, J = 8.1, H-2,6); 7.59 (5H, br. s, H Ph); 7.44
(2H, d, J = 8.1, H-3,5); 2.43 (3H, s, CH3). Mass spectrum, m/z
(Irel, %): 371 [M]+ (25), 204 [M−PhNC=C(CN)2]+ (17), 119
[4-MeC6H4C≡O]+ (100), 91 [4-MeC6H4]+ (57), 80
[cycloC3H2NCO]+ (59), 77 [Ph]+ (32). Found, %: C 68.11;
H 3.47; N 11.45. C21H13N3O2S. Calculated, %: C 67.91;
H 3.53; N 11.31.
129.9; 131.0; 134.5; 135.5; 135.9; 165.4 (C=O ester);
172.3; 175.2; 197.5 (C=O ketone). Mass spectrum, m/z
(Irel, %): 406 [M]+ (75), 273 [M−PhCO−CO]+ (36), 255
[M−PhCO−EtOH]+ (79), 105 [PhC≡O]+ (66), 77 [Ph]+
(100). Found, %: C 65.41; H 4.66; N 6.83. C22H18N2O4S.
Calculated, %: C 65.01; H 4.46; N 6.89.
Ethyl (2E,2Z)-cyano{5-[2-(4-methylphenyl)-2-oxoethyl]-
4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene}ethanoate (6e).
Yield 3.15 g (75%), white waxy flakes, mp 198–200°C.
IR spectrum, ν, cm–1: 3065 (=C–H), 2983 (C–H), 2930
(C–H), 2210 (C≡N), 1742 (C=O), 1689 (C=O), 1665
1
(C=O), 815 (C–H Ar), 760 and 701 (C–H Ph). H NMR
spectrum, δ, ppm (J, Hz): 7.90 (2H, d, J = 8.1, H-2,6); 7.55–
7.43 (5H, m, H Ph); 7.37 (2H, d, J = 8.1, H-3,5); 4.59 (1H,
dd, JAX = 8.1, JMX = 3.6, 5-CHX); 4.19–3.93 (3H, m,
OCH2CH3, 1-CHM); 3.90 (1H, dd, JAM = 18.9, JAX = 8.4,
1-CHA); 2.39 (3H, s, CH3); E-isomer (50%): 1.174 (3H, t,
J = 6.9, OCH2CH3); Z-isomer (50%): 1.171 (3H, t, J = 6.9,
OCH2CH3). 13C NMR spectrum, δ, ppm: 14.6 (OCH2CH3);
21.7 (CH3); 41.3; 41.5; 61.6 (OCH2CH3); 76.6 (=CCN);
112.6 (C≡N); 128.8 (3C); 129.5; 129.8; 129.9 (3C); 131.0;
133.4; 135.5; 145.0; 165.5 (C=O ester); 172.3; 176.2; 197.0
(C=O ketone). Mass spectrum, m/z (Irel, %): 420 [M]+ (37),
301 [M−4-MeC6H4CO]+ (67), 273 [M−4-MeC6H4CO−CO]+
(69), 254 [M−4-MeC6H4CO−S−CH3]+ (100), 119
[4-MeC6H4C≡O]+ (34), 91 [4-MeC6H4]+ (97). Found, %:
C 65.64; H 4.67; N 6.29. C23H20N2O4S. Calculated, %:
C 65.70; H 4.79; N 6.66.
Methyl (2E,2Z)-cyano[4-oxo-5-(2-oxo-2-phenylethyl)-
3-phenyl-1,3-thiazolidin-2-ylidene]ethanoate (6f). Yield
3.15 g (80%), white waxy flakes, mp 222–224°C.
IR spectrum, ν, cm–1: 3065 (=C–H), 2948 (C–H), 2214
(C≡N), 1741 (C=O), 1693 (C=O), 1672 (C=O), 755 and
1
688 (C–H Ar). H NMR spectrum, δ, ppm (J, Hz): 8.01
(2H, d, J = 8.1, H-2,6); 7.72–7.45 (8H, m, H Ph, H-3,4,5);
4.63 (1H, dd, JAX = 8.1, JMX = 3.3, 5-CHX); 4.18 (1H, dd,
JAM = 19.2, JMX = 3.3, 1-CHM); 3.92 (1H, dd, JAM = 19.2,
JAX = 8.1, 1-CHA); 3.70 (3H, s, CO2CH3). Mass spectrum,
m/z (Irel, %): 392 [M]+ (30), 287 [M−PhCO]+ (23), 255
[M−PhCO−S]+ (55), 105 [PhC≡O]+ (70), 80
[cycloC3H2NCO]+ (94), 77 [Ph]+ (100), 64 [cycloC3H2CN]+
(53). Found, %: C 63.77; H 4.00; N 6.98. C21H16N2O4S.
Calculated, %: C 64.27; H 4.11; N 7.14.
{(5E,5Z)-5-[2-(4-Chlorophenyl)-2-oxoethylidene]-4-
oxo-3-phenyl-1,3-thiazolidin-2-ylidene}propanedinitrile
(7c). Yield 1.86 g (95%), yellow crystals, mp 266–268°C.
IR spectrum, ν, cm–1: 3064 (=C–H), 2219 (C≡N), 1731
(C=O), 1639 (C=O), 833 (C–H Ar), 746 and 693 (C–H Ph).
1H NMR spectrum, δ, ppm (J, Hz): 8.42 (1H, s, =CH); 8.29
(2H, d, J = 8.1, H-2,6); 8.13 (2H, d, J = 8.1, H-3,5); 7.60
(5H, br. s, H Ph). Mass spectrum, m/z (Irel, %): 391 [M]+
(12), 139 [4-ClC6H4C≡O]+ (83), 111 [4-ClC6H4]+ (74), 80
[cycloC3H2NCO]+ (14), 77 [Ph]+ (100), 64 [cycloC3H2CN]+
(23). Found, %: C 61.33; H 2.59; N 10.82. C20H10ClN3O2S.
Calculated, %: C 61.31; H 2.57; N 10.72.
Methyl (2E,2Z)-cyano{5-[2-(4-methylphenyl)-2-oxo-
ethyl]-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene}ethanoate
(6g). Yield 3.25 g (80%), white waxy flakes, mp 202–204°C.
IR spectrum, ν, cm–1: 3069 (=C–H), 2986 (C–H), 2926
(C–H), 2211 (C≡N), 1742 (C=O), 1693 (C=O), 1663
1
(C=O), 815 (C–H Ar), 767 and 703 (C–H Ph). H NMR
spectrum, δ, ppm (J, Hz): 7.89 (2H, d, J = 7.5, H-2,6); 7.55–
7.36 (7H, m, H Ph, H-3,5); 4.60 (1H, dd, JAX = 8.1, JMX = 3.0,
5-CHX); 4.12 (1H, dd, JAM = 19.2, JMX = 3.0, 1-CHM); 3.88
(1H, dd, JAM = 19.2, JAX = 8.1, 1-CHA); 3.70 (3H, s,
CO2CH3); 2.39 (3H, s, CH3). 13C NMR spectrum, δ, ppm:
21.1 (CH3); 40.1; 40.4; 52.3 (CO2CH3 Z-isomer); 61.1
(CO2CH3 E-isomer); 75.9 (=CCN); 112.1 (C≡N E-isomer);
120.7 (C≡N Z-isomer); 128.2 (3C); 128.9; 129.2 (2C);
129.4; 130.5; 133.0; 135.0 (2C); 144.5; 165.3 (C=O ester);
Ethyl (2E,2Z)-cyano[(5E,5Z)-4-oxo-5-(2-oxo-2-phenyl-
ethylidene)-3-phenyl-1,3-thiazolidin-2-ylidene]ethanoate
(7d). Yield 1.80 g (90%), pale-yellow crystals, mp 247–
249°C. IR spectrum, ν, cm–1: 3063 (=C–H), 2985 (C–H),
2214 (C≡N), 1732 (C=O), 1696 (C=O), 1642 (C=O), 726
1
and 695 (C–H Ph). H NMR spectrum, δ, ppm: 8.23–8.21
(3H, m, H-2,6, =CH); 7.92–7.44 (8H, m, H Ph, H-3,4,5);
4.28–4.22 (2H, m, OCH2CH3); 1.26–1.19 (3H, m,
999

Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
OCH2CH3). 13C NMR spectrum, δ, ppm: 14.5 (OCH2CH3);
A solution of chloroacetic acid (10 mmol, 0.94 g) in AcOH
(5 ml) was then added, and the reaction mixture was heated
at 80°C for 30 min. After cooling to room temperature,
concd HCl (2 ml) was added. The reaction mixture was
vigorously shaken and poured into cold H2O (50 ml). The
obtained solid was filtered off, washed with H2O (50 ml),
air-dried, and crystallized from 1,4-dioxane–PhMe, 2:3.
(4-Oxo-3-phenyl-1,3-thiazolidin-2-ylidene)propane-
dinitrile (8a). Yield 2.04 g (85%, method I), 0.85 g (35%,
method II), white crystals, mp 269–271°C (mp 273–275°C
(EtOH)6b). IR spectrum, ν, cm–1: 3058 (=CH), 2993 (C–H),
2942 (C–H), 2211 (C≡N), 1744 (C=O), 753 and 694 (C–H Ph).
1H NMR spectrum, δ, ppm (J, Hz): 7.60–7.44 (5H, m,
H Ph); 4.35 (2H, s, SCH2). Mass spectrum, m/z (Irel, %):
241 [M]+ (41), 167 [M−SCH2CO]+ (33), 77 [Ph]+ (100).
Ethyl (2E,2Z)-cyano(4-oxo-3-phenyl-1,3-thiazolidin-
2-ylidene)ethanoate (8b). Yield 2.43 g (85%), white waxy
flakes, mp 206–208°C (mp 208–210°C (EtOH)6b).
Synthesis of compounds (E,Z)-7a,d from 5-unsub-
stituted 1,3-thiazolidin-4-ones 8a,b. (Oxo)phenylacet-
aldehyde (1.07 g, 8 mmol) was added to a solution of
1,3-thiazolidin-4-one 8a (1.20 g, 5 mmol) or (E,Z)-8b (1.15 g,
4 mmol) and dried NaOAc (1.23 g, 15 mmol) in refluxing
glacial AcOH (30 ml). The reaction mixture was refluxed
for 20 min, cooled to room temperature, and poured into
cold H2O (50 ml). The obtained solid was filtered off,
washed with H2O (50 ml), air-dried, and crystallized from
glacial AcOH.
62.5 (OCH2CH3); 80.3 (=CCN); 112.0 (C≡N); 120.7
(CH=C); 129.3 (2C); 129.7 (2C); 129.9 (4C); 131.4; 134.7;
135.0; 136.5; 140.5 (C-5); 164.5 (C=O ester); 166.1; 167.1;
189.4 (C=O ketone). Mass spectrum, m/z (Irel, %): 404 [M]+
(30), 331 [M−CO2Et]+ (67), 214 (26), 190 [M−PhN=C=C
(CN)CO2Et]+ (26), 105 [PhC≡O]+ (97), 77 [Ph]+ (100).
Found, %: C 65.01; H 3.89; N 7.11. C22H16N2O4S.
Calculated, %: C 65.34; H 3.99; N 6.93.
Ethyl (2E,2Z)-cyano{(5E,5Z)-5-[2-(4-methylphenyl)-
2-oxoethylidene]-4-oxo-3-phenyl-1,3-thiazolidin-2-ylid-
ene}ethanoate (7e). Yield 2.00 g (95%), pale-yellow crystals,
mp 260–262°C. IR spectrum, ν, cm–1: 3063 (=C–H), 2985
(C–H), 2214 (C≡N), 1726 (C=O), 1697 (C=O), 1634
1
(C=O), 822 (C–H Ar), 748 and 691 (C–H Ph). H NMR
spectrum, δ, ppm (J, Hz): 8.20 (1H, s, =CH); 8.13 (2H, d,
J = 8.1, H-2,6); 7.57–7.54 (5H, m, H Ph); 7.42 (2H, d,
J = 8.1, H-3,5); 4.28–4.22 (2H, m, OCH2CH3); 2.49 (3H, s,
CH3); 1.26–1.20 (3H, m, OCH2CH3). 13C NMR spectrum,
δ, ppm: 14.5 (OCH2CH3); 21.8 (CH3); 62.4 (OCH2CH3);
80.2 (=CCN); 112.0 (C≡N); 120.9 (CH=C); 129.5 (2C);
129.8 (4C); 130.3 (2C); 131.3; 134.1; 134.7; 140.1; 145.8
(C-5); 163.9 (C=O ester); 165.5; 166.5; 188.3 (C=O
ketone). Mass spectrum, m/z (Irel, %): 418 [M]+ (3), 403
[M−CH3]+ (10), 204 [M−PhN=C=C(CN)CO2Et]+ (30), 119
[4-MeC6H4C≡O]+ (100), 91 [4-MeC6H4]+ (40), 77 [Ph]+
(19). Found, %: C 66.21; H 4.54; N 6.99. C23H18N2O4S.
Calculated, %: C 66.02; H 4.34; N 6.69.
Methyl (2E,2Z)-cyano{(5E,5Z)-5-[2-(4-methylphenyl)-
2-oxoethylidene]-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene}-
ethanoate (7g). Yield 1.80 g (90%), pale-yellow crystals,
mp 254–256°C. IR spectrum, ν, cm–1: 3061 (=C–H), 2985
(C–H), 2214 (C≡N), 1726 (C=O), 1697 (C=O), 1634 (C=O),
[(5E,5Z)-4-Oxo-5-(2-oxo-2-phenylethylidene)-3-phenyl-
1,3-thiazolidin-2-ylidene]propanedinitrile (7a). Yield
1.50 g (85%). 1H NMR spectrum, δ, ppm (J, Hz): 8.46 (1H,
s, =CH); 8.30 (2H, d, J = 8.0, H-2,6); 7.78 (1H, t, J = 8.0,
H-4); 7.66–7.61 (7H, m, C6H5, H-3,5). 13C NMR spectrum,
δ, ppm: 58.5 (=C(CN)2); 109.9 (C≡N); 113.6 (C≡N); 121.3
(CH=C); 129.6 (4C); 129.8 (2C); 130.16 (2C); 131.9;
133.2; 135.9; 139.2 (C-5); 165.5; 170.3; 189.4 (C=O
ketone).
1
822 (C–H Ar), 748 and 691 (C–H Ph). H NMR spectrum,
δ, ppm (J, Hz): 8.20 (1H, s, =CH); 8.14 (2H, d, J = 8.1, H-2,6);
7.55 (5H, br. s, H Ph); 7.42 (2H, d, J = 8.1, H-3,5); 3.80
(3H, s, CO2CH3); 2.42 (3H, s, CH3). Mass spectrum, m/z
(Irel, %): 404 [M]+ (11), 204 [M−PhN=C=C(CN)CO2Me]+
(22), 119 [4-MeC6H4C≡O]+ (100), 91 [4-MeC6H4]+ (48), 77
[Ph]+ (24), 65 [cycloC3H3CN]+ (20). Found, %: C 65.40;
H 3.87; N 6.73. C22H16N2O4S. Calculated, %: C 65.34;
H 3.99; N 6.93.
Synthesis of 5-unsubstituted 1,3-thiazolidin-4-ones
8a,b (General procedure). Method I.6b Propanedinitrile (2a)
(0.66 g, 10 mmol) or ethyl cyanoacetate (2b) (1.1 ml,
10 mmol) and phenyl isothiocyanate (1) (1.2 ml, 10 mmol)
were added to a solution of KOH (0.57 g, 10 mmol) in 95%
EtOH (30 ml). After stirring at room temperature for 30 min, a
solution of potassium chloroacetate (1.31 g, 10 mmol) in H2O
(20 ml) was added. The reaction mixture was stirred at
room temperature for 1 h, then poured into AcOH (50 ml)
and refluxed for 15 min. After cooling to room tempe-
rature, the mixture was poured into cold H2O (50 ml). The
obtained solid was filtered off, washed with H2O (50 ml),
air-dried, and crystallized from 1,4-dioxane.
Ethyl (2E,2Z)-cyano[(5E,5Z)-4-oxo-5-(2-oxo-2-phenyl-
ethylidene)-3-phenyl-1,3-thiazolidin-2-ylidene]ethanoate
(7d). Yield 1.38 g (85%).
Synthesis of compounds 6a,d from 1,3-thiazolidin-4-ones
(E,Z)-7a,d (General method). Zn dust (0.50 g, 8 mmol) was
added to a suspension of 1,3-thiazolidin-4-one (E,Z)-7a,d
(1 mmol), obtained from 5-unsubstituted 1,3-thiazolidin-
4-one 8a,b, in refluxing glacial AcOH (50 ml). The
reaction mixture was refluxed for 3 min, then filtered while
hot. The filtrate was cooled to room temperature and
poured into cold H2O (50 ml). The obtained solid was
filtered off, washed with H2O (50 ml), air-dried, and
crystallized from glacial AcOH.
[4-Oxo-5-(2-oxo-2-phenylethyl)-3-phenyl-1,3-thiazolidin-
2-ylidene]propanedinitrile (6a). Yield 0.36 g (92%).
Ethyl (2E,2Z)-cyano[4-oxo-5-(2-oxo-2-phenylethyl)-
3-phenyl-1,3-thiazolidin-2-ylidene]ethanoate (6d). Yield
0.35 g (90%).
Method II (compound 8a). A solution of ammonium
phenylcarbamodithioate (13) (1.86 g, 10 mmol), propane-
dinitrile (2a) (0.66 g, 10 mmol), and few drops of Et3N in
EtOH (40 ml) was stirred at room temperature for 2 h.
[(5E,5Z)-5-(4-Methoxybenzylidene)-4-oxo-3-phenyl-
1,3-thiazolidin-2-ylidene]propanedinitrile (7h). A suspen-
sion of powdered 5-unsubstituted 1,3-thiazolidin-4-one 8a
(1.20 g, 5.0 mmol), 4-methoxybenzaldehyde (0.7 ml,
1000

Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
5.0 mmol), and dried NaOAc (1.23 g, 15 mmol) in glacial
Synthesis of dimers (E,Z)-11a,b. 5-Bromo-1,3-thiazolidin-
4-one 10a,b (3 mmol) was dissolved in EtOH (10 ml)
(methods I and II) or glacial AcOH (10 ml) (method III).
Method I. KSCN (0.31 g, 3.2 mmol) was added to the
solution. The reaction mixture was refluxed for 10 min.
Method II. NaOCN (0.26 g, 3.2 mmol) was added to the
solution. The reaction mixture was refluxed for 10 min.
Method III. NaOAc (0.26 g, 3.2 mmol) was added to the
solution. The reaction mixture was refluxed for 10 min.
For methods I–III, the obtained solid was filtered off,
washed with H2O (50 ml), air-dried, and crystallized from
1,4-dioxane.
{(5E,5Z)-5-[2-(Dicyanomethylidene)-4-oxo-3-phenyl-
1,3-thiazolidin-5-ylidene]-4-oxo-3-phenyl-1,3-thiazolidin-
2-ylidene}propanedinitrile (11a). Yield 0.65 g (90%,
method I), 0.65 g (90%, method II), 0.70 g (95%, method III),
dark-orange flakes, mp >300°C. IR spectrum, ν, cm–1: 3063
(=C–H), 2210 (C≡N), 1711 (C=O), 739 and 693 (C–H Ph).
1H NMR spectrum, δ, ppm: 7.64 (10H, s, H Ph). Mass spectrum,
m/z (Irel, %): 478 [M]+ (53), 283 [M−PhN=C=C(CN)2−CO]+
(100), 88 [M−2(PhN=C=C(CN)2)−2CO)]+ (67), 77 [Ph]+
(51), 64 [cycloC3H2CN]+ (40). Found, %: C 60.45; H 2.17;
N 17.23. C24H10N6O2S2. Calculated, %: C 60.24; H 2.11;
N 17.56.
AcOH (10 ml) was refluxed for 30 min. After cooling to
room temperature, the reaction mixture was poured into
cold H2O (50 ml). The precipitate was filtered off, washed
with H2O (50 ml), air-dried, and crystallized from AcOH.
Yield 0.43 g (90%), yellow crystals, mp 278–280°C
(mp 275–278°C6b). IR spectrum, ν, cm–1: 3061 (=C–H), 3024
(=C–H), 2964 (C–H), 2217 (C≡N), 1718 (C=O), 838 (C–H Ar),
719 and 693 (C–H Ph). 1H NMR spectrum, δ, ppm (J, Hz):
Z-isomer (95%): 8.01 (1H, s, =CH); 7.71 (2H, d, J = 7.2,
H-2,6); 7.58 (5H, br. s, NPh); 7.20 (2H, d, J = 7.2, H-3,5);
3.90 (3H, s, OCH3); E-isomer (5%): 7.49 (1H, s, =CH);
7.20 (2H, d, J = 7.2, H-2,6); 7.58 (5H, br. s, NPh); 7.20
(2H, d, J = 7.2, H-3,5); 3.9 (3H, s, OCH3). Mass spectrum, m/z
(Irel, %): 359 [M]+ (59), 164 [M−C=(CN)2−PhNCO]+ (100),
149 [M−C=(CN)2−PhNCO−CH3]+ (49), 77 [Ph]+ (45).
Synthesis of 5-bromo-1,3-thiazolidin-4-ones 10a,b
(General method). A solution of Br2 (0.5 ml, 10 mmol) in
glacial AcOH (5 ml) was added portionwise to a
suspension of powdered 5-unsubstituted 1,3-thiazolidin-
4-one 8a,b (5 mmol) in refluxing glacial AcOH (50 ml).
The mixture was refluxed for 10 min till the color of
solution had changed to pale-yellow. After cooling to room
temperature, the reaction mixture was poured into cold
H2O (50 ml) and kept at room temperature for 1 h. The
obtained solid was filtered off, washed with H2O (50 ml),
air-dried, and crystallized from CHCl3 – petroleum ether,
3:2.
Ethyl (2E,2Z)-cyano[(5E,5Z)-5-{(2E,2Z)-2-[(cyano)-
ethoxycarbonylmethylidene]-4-oxo-3-phenyl-1,3-thiazo-
lidin-5-ylidene}-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene]-
ethanoate (11b). Yield 0.70 g (90%, method I), 0.70 g
(90%, method II), 0.75 g (95%, method III), dark-orange
flakes, mp >300°C. IR spectrum, ν, cm–1: 3063
(=C–H), 2215 (C≡N), 1698 (C=O), 1632 (C=O), 756 and 688
(5-Bromo-4-oxo-3-phenyl-1,3-thiazolidin-2-ylidene)-
propanedinitrile (10a). Yield 1.35 g (85%), cream-colored
granules, mp 212–214°C. IR spectrum, ν, cm–1: 3066 (=C–H),
2218 (C≡N), 1764 (C=O), 737 and 695 (C–H Ph). 1H NMR
spectrum, δ, ppm (J, Hz): 7.70–7.59 (3H, m, H-3,4,5);
7.36 (2H, d, J = 7.5, H-2,6); 5.96 (1H, s, CHBr). Mass
spectrum, m/z (Irel, %): 321 [M]+ (62), 320 [M]+ (48), 291
(37), 263 (62), 123 [M−PhNCO−CN−C≡CCN]+ (50), 69
[M−PhNCO−CN−CN−Br]+ (100). Found, %: C 44.82;
H 2.09; N 13.34. C12H6BrN3OS. Calculated, %: C 45.02;
H 1.89; N 13.12.
Ethyl (2E,2Z)-(5-bromo-4-oxo-3-phenyl-1,3-thiazolidin-
2-ylidene)(cyano)ethanoate (10b). Yield 1.55 g (85%),
cream-colored granules, mp 180–182°C. IR spectrum, ν, cm–1:
3063 (=C–H), 2210 (C≡N), 1753 (C=O), 1689 (C=O), 762
and 695 (C–H Ph). 1H NMR spectrum, δ, ppm (J, Hz): 7.65–
7.60 (3H, m, H-3,4,5); 7.37 (2H, d, J = 8.1, H-2,6); 4.29
(2H, q, J = 6.9, OCH2CH3); 3.85 (1H, s, CHBr); 1.31 (3H,
t, J = 9.6, OCH2CH3). 13C NMR spectrum, δ, ppm:
Z-isomer: 14.2 (OCH2CH3); 38.9 (OCH2CH3); 62.6 (C-5);
81.5; 110.9 (C≡N); 128.9; 130.0 (2C); 131.6 (2C);
133.8; 162.6 (C=O ester); 164.9; 167.8 (C=O ketone);
E-isomer: 14.1 (OCH2CH3); 40.4 (OCH2CH3); 63.0 (C-5);
80.9; 110.4 (C≡N); 128.2; 130.1 (2C); 131.9 (2C); 133.7;
164.8 (C=O ester); 165.3; 170.2 (C=O ketone). Mass
spectrum, m/z (Irel, %): 368 [M]+ (14), 366 [M]+ (13), 367
[M]+ (71), 365 [M−H]+ (67), 185 [M−Br−CO2Et−H−CO]+
(20), 169 [M−OEt−S−CHBrCO]+ 125 (57), 123
[M−PhNCO−CN−C≡CCO2Et]+ (56), 77 [Ph]+ (100).
Found, %: C 45.37; H 3.32; N 7.72. C14H11BrN2O3S.
Calculated, %: C 45.79; H 3.02; N 7.63.
1
(C–H Ph). H NMR spectrum, δ, ppm: 7.52–7.47 (10H, m,
H 2Ph); 4.22–4.15 (4H, m, 2OCH2CH3); 1.20–1.13 (6H, m,
2OCH2CH3). Mass spectrum, m/z (Irel, %): 572 [M]+ (28),
367 (13), 365 (67), 330 [M−PhNCO−CN−C≡CCO2Et]+
(31), 185 (20), 169 (22), 77 [Ph]+ (100). Found, %:
C 58.93; H 3.58; N 10.11. C28H20N4O6S2. Calculated, %:
C 58.73; H 3.52; N 9.78.
[5-(Benzylamino)-4-oxo-3-phenyl-1,3-thiazolidin-2-yl-
idene]propanedinitrile (12). A solution of 5-bromo-1,3-thi-
azolidin-4-one 10a (0.50 g, 1.5 mmol) in EtOAc (30 ml)
was added dropwise at room temperature over period of
20 min to a solution of benzylamine (0.17 g, 1.5 mmol) in
Et2O (30 ml). The reaction mixture was kept at room tempe-
rature for 24 h allowing to slowly evaporate. The obtained
solid was filtered off and crystallized from EtOH–PhMe,
2:3. Yield 0.46 g (85%), pale-gray flakes, mp 174–176°C.
IR spectrum, ν, cm–1: 3272 and 3062 (=C–H), 2972 (C–H),
2931 (C–H), 2215 (C≡N), 1664 (C=O), 748 and 694 (C–H Ph).
1H NMR spectrum, δ, ppm (J, Hz): 9.15 (1H, t, J = 6.3,
NHX); 7.47–7.44 (3H, m, H-3,4,5); 7.43–7.18 (5H, m,
CH2Ph); 7.07–7.04 (2H, m, H-2,6); 6.74 (1H, s, 5-CH);
4.33 (1H, dd, JAB = 15.0, JBX = 6.3, CHB); 4.23 (1H, dd,
J
AB = 15.0, JAX = 5.0, CHA). 13C NMR spectrum, δ, ppm: 43.1
(PhCH2); 47.5 (C-5); 66.5 (=C(CN)2); 112.4 (C≡N); 114.8
(C≡N); 125.4 (2C); 127.5; 127.6 (2C); 128.8 (2C); 129.5 (2C);
129.6; 136.7; 138.4; 163.3 (C-2); 174.4 (C=O). Mass spectrum,
m/z (Irel, %): 346 [M]+ (4), 106 [M−CHSC=(CN)2−PhNCO]+
(78), 104 [M−CHSC=(CN)2−PhNCO−H2]+ (100), 91
1001

Chemistry of Heterocyclic Compounds 2019, 55(10), 993–1003
[PhCH2]+ (49), 77 [Ph]+ (82). Found, %: C 66.18; H 4.27;
N 5.77. C26H18N2O3S3. Calculated, %: C 62.13; H 3.61;
N 5.57.
N 16.23. C19H14N4OS. Calculated, %: C 65.88; H 4.07;
N 16.17.
(5E,5Z)-5-(4-Methoxybenzylidene)-3-phenyl-2-thioxo-
3-Phenyl-2-thioxo-1,3-thiazolidin-4-one (14a). A solution
of phenyl isothiocyanate (1) (0.6 ml, 5 mmol), KOH
(0.28 g, 5 mmol), and 1,3-thiazolidine-2,4-dione 14b
(0.96 g, 5 mmol) in EtOH (15 ml) was stirred at 0°C for
30 min. A solution of potassium chloroacetate (0.66 g,
5 mmol) in EtOH (30 ml) was added to the reaction
mixture, and stirring at 0°C was continued for 30 min. The
reaction mixture was poured into glacial AcOH (25 ml) and
refluxed for 5 min. After cooling to room temperature, the
obtained solid was filtered off, washed with H2O (50 ml),
air-dried, and crystallized from glacial AcOH. Yield 0.91 g
(85%), pale-yellow crystals, mp 188–188°C (mp 192°C
(AcOH)10b). IR spectrum, ν, cm–1: 3046 (=C–H), 1736 (br,
1,3-thiazolidin-4-one (19). Yield 0.36 g (85%), yellow
crystals, mp 221–223°C (AcOH) (mp 223–225°C19).
IR spectrum, ν, cm–1: 3062 (=C–H), 1715 (C=O), 828
1
(C–H Ar), 753 and 686 (C–H Ph). H NMR spectrum,
δ, ppm (J, Hz): 7.81 (1H, s, =CH); 7.67 (2H, d, J = 8.7,
H-2,6); 7.56–7.39 (5H, m, H Ph); 7.15 (2H, d, J = 8.7, H-
3,5); 3.86 (3H, s, OCH3). Found, %: C 62.44; H 3.98; N 4.30.
C17H13NO2S2. Calculated, %: C 62.36; H 4.00; N 4.28.
Supplementary information file containing IR, 1H and 13
C
NMR, and mass spectra of compounds 6a–e,g, (E,Z)-7a–e,g,h,
8a, 10a,b, (E,Z)-11a,b, 12, (E,Z)-15, (E,Z)-18, and (E,Z)-19
and COSY spectrum of compound 12 is available at the
journal website at http://link.springer.com/journal/10593.
1
C=O), 751 and 693 (C–H Ph). H NMR spectrum, δ, ppm:
7.35–7.13 (5H, m, H Ph); 4.39 (2H, s, 5-CH2).
(5E,5Z)-5-(4-Oxo-3-phenyl-1,3-thiazolidin-2-ylidene)-
3-phenyl-2-thioxo-1,3-thiazolidin-4-one (15). A solution
of phenyl isothiocyanate (1) (0.6 ml, 5 mmol), KOH (0.28 g,
5 mmol), and 2-thioxo-1,3-thiazolidin-4-one 14a (1.05 g,
5 mmol) in EtOH (15 ml) was stirred at 0°C for 30 min. A
solution of potassium chloroacetate (0.66 g, 5 mmol) in
EtOH (30 ml) was added to the reaction mixture and
stirring at 0°C was continued for 30 min. The reaction
mixture was poured into glacial AcOH (25 ml) and
refluxed for 5 min. After cooling to room temperature, the
obtained solid was filtered off, washed with H2O (50 ml),
air-dried, and crystallized from glacial AcOH. Yield 1.60 g
(85%), pale-yellow crystals, mp 256–258°C. IR spectrum,
ν, cm–1: 3046 (=C–H), 1731 (C=O), 1671 (C=O), 750 and
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1002

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1003