Molecular modeling and cyclization reactions of 2-(4-oxothiazolidine-2-ylidene) acetonitrile

Article abstract of DOI:10.1007/s13738-018-1322-2

Diazotization of 2-(4-oxothiazolidine-2-ylidene) acetonitrile 1 with aryl diazonium chloride derivatives afforded 4-thiazolidinones 2a, b, whereas 3a, b derivatives produced through reaction of arylcarbonohydrazonoyl dicyanide with thioglycolic acid. Cyclization of 2a with aromatic aldehydes and malononitrile gave the expected substituted thiazolo [3,2-a] pyridines 4a, b. The reaction of 1 with anthraldehyde (1:1 molar ratio) gave the expected 4,5-dihydro-4-oxothiazole derivatives 5 which condensed with other mole p-chlorobenzaldehyde and gave the corresponding bisarylidine derivative 6. Thiazolo [3,2-a] pyridine enaminonitrile derivative 7 produced through addition of malononitrile to bisarylidine 6. Also, compound 7 reacted with other mole of malononitrile and furnished thiazolo [3,2-a] pyridine 12, furthermore, compound 7 refluxed with phenyl hydrazine, thiourea, and formic acid, to form the corresponding thiazolo [3,2-a] pyridines 13, 15 and 17, respectively. Also, compound 1 reacted with phNCS in presence of KOH and afforded 19. The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from calculation of the molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, electrophilicity index, HOMO and LUMO energy.

Full text of DOI:10.1007/s13738-018-1322-2

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1322-2
ORIGINAL PAPER
Molecular modeling and cyclization reactions
of 2‑(4‑oxothiazolidine‑2‑ylidene) acetonitrile
G. A. M. Elhagali1 · G. A. Elsayed2 · R. A. Eliswey1 · A. A. El‑Sherif3
Received: 7 September 2017 / Accepted: 7 February 2018
© Iranian Chemical Society 2018
Abstract
Diazotization of 2-(4-oxothiazolidine-2-ylidene) acetonitrile 1 with aryl diazonium chloride derivatives aforded 4-thiazoli-
dinones 2a, b, whereas 3a, b derivatives produced through reaction of arylcarbonohydrazonoyl dicyanide with thioglycolic
acid. Cyclization of 2a with aromatic aldehydes and malononitrile gave the expected substituted thiazolo [3,2-a] pyridines
4a, b. The reaction of 1 with anthraldehyde (1:1 molar ratio) gave the expected 4,5-dihydro-4-oxothiazole derivatives 5
which condensed with other mole p-chlorobenzaldehyde and gave the corresponding bisarylidine derivative 6. Thiazolo
[3,2-a] pyridine enaminonitrile derivative 7 produced through addition of malononitrile to bisarylidine 6. Also, compound 7
reacted with other mole of malononitrile and furnished thiazolo [3,2-a] pyridine 12, furthermore, compound 7 refuxed with
phenyl hydrazine, thiourea, and formic acid, to form the corresponding thiazolo [3,2-a] pyridines 13, 15 and 17, respectively.
Also, compound 1 reacted with phNCS in presence of KOH and aforded 19. The molecular modeling of the synthesized
compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from
calculation of the molecular parameters including electronegativity, net dipole moment of the compounds, total energy,
electronic energy, binding energy, electrophilicity index, HOMO and LUMO energy.
Keywords 4-Thiazolidinones · Thiazolo [3,2-a] pyridines · Thiazolo [3,2-a]1,8-naphthyridines · Molecular modeling
Introduction
the synthesis of pyridine derivatives, aiming to develop new
drugs, is an active research area. Recently, several research-
ers became interested to cyanopyridine derivatives [13–21].
The experimental studies have been accompanied by com-
putational studies, especially in recent years [22] due to their
important role in understanding of the probably behavior
of the compound during reactions and identifcation of the
important information about the compounds under investi-
gations, like total energy, binding energy, electronic energy,
dipole moment, bond lengths, HOMO, LUMO [23]. The
applicability of the semi-empirical methods PM3 for the cal-
culation of novel synthesized compounds has been evaluated
[24]. In a continuous of our research program directed toward
synthesis of some medicinally heterocyclic compounds
[25–31], we report here synthesis of some new series of thia-
zolidinones with pyridine moiety.
Thiazoles nucleus appears in the structure of antibiotics as
micrococcin [1] and they are synthetic intermediates and com-
mon substructures in numerous biologically active compounds
[2–5]. There has been considerable interest in the chemistry
of thiazolidin-4-one ring system, which is a core structure in
various synthetic pharmaceuticals displaying a broad spec-
trum of biological activities [6–8] and exhibits highly specifc
activity in vitro against mycobacterium tuberculosis [9–12].
Furthermore, the pyridine scafold is a wide spread structural
motif that can be found in many natural products and in sev-
eral pharmacologically interesting compounds. Therefore,
* G. A. M. Elhagali
elhag1970@yahoo.com
1
Chemistry Department, Faculty of Science(boys), Al-Azhar
University, Nasr City, Cairo, Egypt
2
Chemistry Department, Faculty of Science, Ain Shams,
Cairo, Egypt
3
Chemistry Department, Faculty of Science, Cairo University,
Giza, Egypt
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
1
attributed to imine, nitrile, and carbonyl moieties. Its H
Results and discussion
NMR spectrum (DMSO-d6) revealed singlet signal at δ
2.25 for methyl protons, singlet signal at 4.20 for methyl-
ene, multiple aromatic protons at 7.12–7.87 beside to NH
Chemistry
1
signal at 10.70 ppm, exchangeable with D2O. Also, H
2-(4-Oxothiazolidine-2-ylidene) acetonitrile 1 [32] used
as key starting material for synthesis many biologically
and pharmaceutically active heterocycles. Therefore,
when (1) coupled with either p-tolyldiazonium chloride
or p-methoxy benzene diazonium chloride in the presence
of ethanol having anhydrous sodium acetate with stirring
in ice bath produced the N-aryl-4-oxo-4,5-dihydrothia-
zole-2-carbohydrazonoyl cyanide. The structure of 2a, b
is confrmed by the help of analytical and spectroscopic
data. Thus, IR spectrum of 2a showed stretching signif-
cance absorption bands at 3240, 2214, and 1693 cm−1
NMR spectrum of 2b (DMSO-d6) showed characteristic
signals at δ 4.03 and 4.20 ppm which referred to (OCH3)
and (CH2) protons. 4-Oxothiazole derivatives 3a, b pro-
duced through refuxing of aryl carbohydrazonoyl with
thioglycolic acid. IR pattern displayed stretching frequen-
cies at 1713 and 1752 cm−1 which described 4-thiazoli-
dinone; Scheme 1. One pot reaction of 2a, malononitrile
and aromatic aldehydes in ethanol solution having a few
drops of piperidine yielded thiazolo [3,2-a] pyridines 4a,
b. The mechanistically equations which described thiazolo
pyridines production are illustrated in Scheme 1. Inferred
Scheme 1 Synthesis of 4-thiazolidinone derivatives 2a, b, 3a, b and 4a, b
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Journal of the Iranian Chemical Society
spectrum of 4b exhibited stretching bands at 3396, 3228
corresponding to (NH2), 3198 for (NH), (C≡N) stretching
frequency at 2204 cm−1, and carbonyl group at 1702 cm−1.
Its IH NMR spectrum (DMSO-d6) revealed singlet signal
for pyridine-4 H at δ 4.00 ppm; Scheme 1.
signals at 9.01, 9.05 ppm. In view of the growing biological
importance of fused cyanopyridones, particularly thiazolo
[1,2-a] pyridines [33–35] it was of interest to synthesize
some thiazolopyridines containing anthracenyl moiety on
the hope of obtaining more active compounds. Thiazolo
[3,2-a] pyridine derivative 7 obtained through refuxing of
6 with malononitrile for 6 h (Scheme 2). The analytical and
spectral data of 7 were agreement with the proposed struc-
ture, and its infrared spectrum assigned stretching bands
9-Anthraldehyde condensed with 1 (1:1 molar ratio) in
ethanol piperidine and gave the corresponding arylidene
derivative 5, which reacted with p-chlorobenzaldehyde and
formed the bisarylidine derivative 6. The obtained structures
5, 6 were confrmed by spectroscopic studies and elemental
analysis. The IR spectrum of compound 5 revealed absorp-
tion bands in the zone 3183, 2195 and 1707 cm−1 corre-
sponding to an imine, cyano and carbonyl, respectively. Its
1H NMR spectrum (DMSO-d6) showed signals at δ 5.16 for
methine-H and 11.49 ppm for NH proton disappeared with
D2O. Also, bisarylidene 6 revealed stretching frequencies at
3056, 2978, 2195 and 1709 cm−1 which referred to Ar–H,
Aliph-H, cyano and signifcant carbonyl for thiazolidinone.
1
at 1708 cm−1 for carbonyl moiety and HNMR spectrum
of 7 showed singlet signal at 4.70 ppm for pyridine-4H;
Scheme 2.
Refuxing of thiazolo [3,2-a] pyridine 7 with malononi-
trile in ethanol catalyzed with piperidine gave thiazol [3,2-a]
pyridine derivative 12, instead of thiazolopyridines structure
10, and 11. The structure of 12 was assured through spectro-
scopic and accurate elemental data. Its IR spectrum showed
any appearance of stretching carbonyl and this rejected
1
1
Its H NMR spectrum (DMSO-d6) revealed two methine
structure 10, whereas its H NMR spectrum revealed lack
Scheme 2 Synthesis of thiazolo [3,2-a] pyridine derivative 7
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Journal of the Iranian Chemical Society
Scheme 3 Synthesis of thiazolo [3,2-a] pyridine derivative 12
of respectable pyran-4H signal and this excluded pyrano
[2,3:4,5] thiazolo [3,2-a] pyridine structure 11 Scheme 3.
Enaminonitrile 7 used to form a novel thiazol [3,2-a]
pyridine derivatives through its reaction with diferent rea-
gents. Phenyl hydrazine condensed with thiazolo [3,2-a]
pyridine 7 in absolute ethanol and gave pyrazolo [3′,4′:4,5]
thiazolo [3,2-a] pyridine derivative 13 based on perfect
spectroscopic data IR spectrum of 13 showed absence of a
carbonyl stretching absorbing band and its mass spectrum
(13; C36H21ClN6S) showed a molecular ion peak at m/z
(604; 44.36%) and a base peak at m/z 54. Cyclization of 7
with thiourea produced derivative 15; Scheme 4, thiazolo
[3,2-a] pyridine structure 15 was confrmed by correct ele-
mental and spectral data, infrared spectrum of 15 showed
NMR spectrum exhibited two singlet signals at δ 4.19 and
9.64 ppm for pyridine-4-H and thiol proton. Furthermore,
7 was allowed to react with formic acid under refux condi-
tions to produce thiazolo [3,2-a]-3-aza-1,8-naphthyridine
17. IR spectrum of compound 17 showed an absorbing
1
band for cyano group, its HNMR spectrum assigned a
singlet signal for methine proton at δ 7.25 ppm.
When PhNCS reacted with 2-(4-Oxothiazolidine-
2-ylidene) acetonitrile 1 in the presence of KOH/DMF
solution with refuxing for 2 h, it is found that, opening of,
4-thiazolidinone ring was occurring rather than ketene for-
mation 18 and produced methyl 2-cyanoethanimidothioate
19 instead of 4-oxothiazole derivative 18 Scheme 5.
The mechanistic route for methyl 2-cyanoethanimidothio-
ate (19) production can be illustrated as follow.
1
presence of broad absorbing band for thiol group. Its H
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Journal of the Iranian Chemical Society
− 8.896, − 8.852 and − 8.923 eV corresponding to the
compounds 2b, 3b and 4b, while the other compounds
have low negative HOMO energy and compound 17 has
the least negative HOMO (− 3.841 eV). Further, discus-
sion about LUMO energy, the compound 7 showed most
negative LUMO energy value − 2.719 and − 2.301 eV was
the next lead LUMO energy was corresponded to the com-
pound 12. In case of 4f, 4g, 4h, 4j, 4l and 4m compounds,
their LUMO energy was in the order 5 > 13 > 15 > 12 > 4
a > 3b > 4b > 2a > 2b > 6 > 3a. The negative values of
the HOMO and LUMO (Table 4) indicate the title synthe-
sized compounds are stable molecules [38–40]. Literally,
the most essential stability index is ΔE between HOMO and
LUMO [41, 42]. The HOMO–LUMO energy separation has
been used as an important stability index and an indicator
for the chemical reactivity of the molecule. Generally, the
high chemical reactivity compounds have small ΔE and low
reactivity compounds have higher ΔE [43, 44]. The values
of the energy separation between the HOMO and LUMO for
the synthesized compounds lie in the range 2.317–7.951 eV.
This large HOMO–LUMO gap automatically means high
excitation energies for many of the excited states and good
stability for the title compounds. The low value of energy
gap may be due to the groups that enter into conjugation
[27].
This can attributed to broken of thiazolidine ring by OH
nucleophile easier than removal of hydrogen proton from
methylene group in position 5.
Methyl 2-cyanoethanimidothioate 19 obtained approved
by using adjusted elemental analysis and spectroscopic
techniques. IR spectrum of 19 assigned the presence of
stretching frequencies at 3431 and 2183 for NH, and cyano
bands and absence of thiazolidinone function, also 1H NMR
spectrum showed a lack of methine proton and presence
of methyl and methylene protons at δ 3.28 and 4.23 ppm,
respectively.
Simulation results
The electronic structural orientation and frontier molecu-
lar orbital location of synthesized compounds [36] along
with the calculated HOMO energy, LUMO energy,
HOMO–LUMO energy gap (ΔE), dipole moment and
heat of formation (HF) (Tables 1, 2). The electron densi-
ties and energies of frontier molecular orbital are important
electronic parameters. These were used to determine the
most reactive sites in the unsaturated system [37]. In fact,
the energy of the HOMO is related directly to the ioniza-
tion potential and it characterizes the susceptibility of the
molecule toward an attack by electrophiles. On the other
hand, the LUMO is related with electron afnity and gives
an idea of the susceptibility of the molecule toward attack
by nucleophiles. The synthesized heterocyclic compounds
used in this study according to the HOMO and LUMO data
are presented in Table 1. In this, the high negative HOMO
value − 9.055 eV was belonging to compound 2a. Moreo-
ver, the compound 3a has − 9.007 eV HOMO energy and
the compound 4a has − 8.952 eV. The HOMO values of
The reactivity index measures the energy stabilization
when the system acquires an additional electronic charge
(ΔNmax) from the environment. The electrophilicity index is
positive quantity and the direction of the charge transfer is
completely determined by the electronic chemical potential
(Pi) of the molecule because an electrophile is a chemical
species capable of accepting electrons from the environ-
ment and its energy must decrease upon accepting electronic
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Journal of the Iranian Chemical Society
Scheme 4 Synthesis of thiazolo [3,2-a] pyridine derivatives 13, 15 and 17
charge. Therefore, the electronic chemical potential must
be negative, exactly as supported by the values in Table 1.
The molecular stability and reactivity can be measured by
important properties like hardness (η) and softness (σ). Soft
molecules have small energy gap and more reactive than
hard molecules with a large energy gap. This can be attrib-
uted to the fact that soft molecules could easily ofer elec-
trons to an acceptor. Also, the reactivity of soft molecules
increases than hard molecules if electron transfer or rear-
rangement is necessary for the reaction.
The electrophilicity index (ω) which shows the abil-
ity of the molecule to accept electrons follows the trend;
7 (ω = 5.46) > 12 (ω = 4.71) > 5 (ω = 3.79) > 3a
(ω = 3.67) > 15 (ω = 3.65) > 3b (ω = 3.63) > 2a
(ω = 3.58) > 4b (ω = 3.57) > 13 (ω = 3.550) > 2b
(ω = 3.530) > 6 (ω = 3.400) > 3a (ω = 3.180) > 17
(ω = 3.110). Compound (7) exhibits the highest value of
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Journal of the Iranian Chemical Society
The dipole moment is frequently used to study the
intermolecular interactions involving the non-bonded-
type dipole–dipole interactions, because, higher the dipole
moment lead to stronger intermolecular interactions. The
dipole moment of the synthesized compounds was varied
from 1.86 to 11.57 Debye (Table 2).
Theoretical calculations have paid a considerable atten-
tion to the characterization and inferences of geometrical
optimization of the prepared compounds; therefore, we
could obtain the optimized structure for the prepared com-
pounds by computing the theoretical physical parameters,
such as, bond lengths and bond angles using the HyperChem
7.5 software. The optimized structure for the 2a, 2b, 3a and
3b with the atomic numbering scheme is shown in Figs. 1,
Scheme 5 Synthesis of methyl 2-cyanoethanimidothioate
electrophilicity (Table 1) which confrms its highest capacity
to accept electrons.
Table 1 The calculated quantum chemical parameters of the synthesized compounds
Compound
HOMO
LUMO
ΔE
x
η
σ
pi
− 5.2335
ω
S
ΔNmax
2a
3a
4a
2b
3b
4b
5
6
7
12
13
15
17
− 9.055
− 9.007
− 8.952
− 8.896
− 8.852
− 8.923
− 8.347
− 8.466
− 7.494
− 8.534
− 8.161
− 8.642
− 3.841
− 1.412
− 1.056
− 1.507
− 1.400
− 1.494
− 1.433
− 1.699
− 1.363
− 2.719
− 2.301
− 1.540
− 1.538
− 1.524
7.643
7.951
7.445
7.496
7.358
7.49
6.648
7.103
4.775
6.233
6.621
7.104
2.317
5.2335
5.0315
5.2295
5.148
5.173
5.178
3.8215
3.9755
3.7225
3.748
3.679
3.745
0.261677
0.251541
0.268637
0.266809
0.271813
0.267023
0.300842
0.281571
0.418848
0.320873
0.302069
0.281532
0.863185
3.583609
3.184001
3.673294
3.535473
3.636848
3.579664
3.795206
3.400297
5.461014
4.708697
3.553444
3.646974
3.105657
0.130839
0.12577
1.369488
1.265627
1.404835
1.373533
1.406089
1.382644
1.511131
1.383782
2.138848
1.738328
1.465187
1.432995
2.315494
− 5.0315
− 5.2295
− 5.148
− 5.173
− 5.178
− 5.023
− 4.9145
− 5.1065
− 5.4175
− 4.8505
− 5.09
0.134318
0.133404
0.135906
0.133511
0.150421
0.140786
0.209424
0.160436
0.151035
0.140766
0.431593
5.023
3.324
4.9145
5.1065
5.4175
4.8505
5.09
3.5515
2.3875
3.1165
3.3105
3.552
2.6825
1.1585
− 2.6825
HOMO and LUMO are given in eV
Table 2 Some energetic
properties of synthesized
compounds calculated by PM3
method
Compound Total energy kcal/mol Binding
Electronic
Heat of forma- Dipole moment
tion kcal/mol
energy kcal/ energy kcal/
mol
mol
2a
3a
4a
2b
3b
4b
5
− 62,297.3
− 62,295.6
− 106,141.2
− 69,057.8
− 69,056.2
− 106,144.2
− 77,370.4
− 104,839.3
− 121,172.8
− 130,050.2
− 139,706.1
− 128,948.7
− 132,439.7
− 3058.4
− 3057.9
− 5212.4
− 3147.6
− 3146.0
− 5210.5
− 4278.6
− 5618.8
− 6383.6
− 6969.9
− 7724.6
− 6767.7
− 6741.4
− 377,951.2 90.18
4.85
2.22
4.79
4.32
1.86
5.89
5.84
4.91
11.57
5.57
5.49
6.25
4.44
− 382,022.3 91.74
− 871,638.2 161.5
− 419,311.9 61.62
− 424,068.6 63.15
− 884,175.9 163.05
− 584,593.8 116.3
− 856,287.9 157.7
− 1,129,197.4 235.7
1,165,730.3 328.5
1,352,079.2 294.7
1,141,991.4 255.2
1,160,245.4 154.7
6
7
12
13
15
17
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Journal of the Iranian Chemical Society
Fig. 1 The molecular structure
of compound 2a along with the
atom numbering scheme
2, 3 and 4. The bond angles and bond lengths (Å) obtained
from the energy minimum optimized structures of 2a as a
representative example of the synthesized compounds are
given in Tables 3 and 4. In most of the cases, the actual bond
lengths and bond angles are close to the optimal values, and
thus the proposed structure of the compounds is acceptable.
Fig. 2 The molecular structure
of compound 2b along with the
atom numbering scheme
Fig. 3 The molecular structure
of compound 3a along with the
atom numbering scheme
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Journal of the Iranian Chemical Society
Table 3 Selected bond lengths (Å) of 2a compound
Bond length
Actual bond lengths
Optimal
bond
lengths
N(17)–H(28)
C(14)–N(18)
C(13)–H(27)
C(13)–H(26)
C(13)–C(14)
C(11)–C(13)
C(11)–N(12)
S(10)–C(11)
C(8)–O(15)
C(8)–N(12)
C(8)–C(9)
C(7)–H(25)
C(7)–H(24)
C(7)–H(23)
C(6)–H(22)
C(5)–H(21)
C(5)–C(6)
1.001
1.159
1.11
1.111
1.449
1.5
1.298
1.799
1.202
1.473
1.51
1.099
1.098
1.098
1.097
1.096
1.39
1.05
1.158
1.113
1.113
1.47
1.497
1.26
1.856
1.208
1.426
1.517
1.113
1.113
1.113
1.1
1.1
1.42
C(4)–C(7)
C(4)–C(5)
C(3)–H(20)
C(3)–C(4)
C(2)–H(19)
C(1)–N(17)
C(1)–C(2)
1.485
1.395
1.096
1.397
1.097
1.453
1.401
1.497
1.42
1.1
1.42
1.1
1.462
1.42
Fig. 4 The molecular structure of compound 3b along with the atom
numbering scheme
Experimental
Materials and methods
temperature for 2 h. The solid products formed were col-
lected by fltration and recrystallized from ethanol.
Melting points are uncorrected. IR spectra were recorded
on a Shimadzu 440 infrared spectrophotometer (υ; cm−1)
1
2‑(4‑oxo‑5‑(2‑(p‑tolyl)hydrazono)‑4,5‑dihydrothiazol‑2‑yl) ace‑
tonitrile (2a) Reddish browns crystals (EtOH); yield 72%;
m.p. 245–47 °C; IR (KBr, ̄ꢀ , cm−1): 3240 (NH), 3051(CH-
arom.), 2931 (CH-aliph.), 2214(C≡N) and 1693 (C=O
using the KBr technique (Shimadzu, Japan). H NMR
spectra were recorded on a Varian Gemini spectrometer (δ;
ppm) 200 MHz using TMS as internal standard. Mass spec-
tra were recorded on a Jeol-JMS-600 mass spectrometer.
13C NMR spectra were run out at 75 MHz Micro analyti-
cal data were obtained from the Micro analytical Research
Centre, Faculty of Science, Cairo University. The reactions
were monitored by thin layer chromatography (TLC) using
TLC sheets with UV fuorescent silica gel Merck 60f254
plates using UV lamp and diferent solvents as mobile
phases.
1
thiazolidinone) H NMR (DMSO-d6): δ/ppm 2.25 (s, 3H,
CH3), 4.20 (s, 2H, CH2), 7.12–7.87 (m, 4H, Ar–H),10.70(s,
1H, NH, canceled with D2O); Anal. Calcd. for C12H10N4OS
(258.30): C, 55.80; H, 3.90; N, 21.69 found: C, 56.12; H,
3.56, N, 21.72.
2‑(4‑oxo‑5‑(2‑(p‑methoxyphenyl) hydrazono)‑4,5‑dihydrothi‑
azol‑2‑yl) acetonitrile (2b) Reddish browns crystals (EtOH);
yield 88%; m.p. 210–12 °C; IR (KBr, ̄ꢀ , cm−1): 3181 (NH),
3040(CH-arom.), 2930 (CH-aliph.), 2212(C≡N) and 1697
(C=O thiazolidinone); 1H NMR (DMSO-d6):δ/ppm 4.03 (s,
3H, OCH3), 4.20 (s, 2H, CH2), 7.21–7.58 (m, 4H, Ar–H),
10.70(s, 1H, NH, canceled with D2O); Anal. Calcd. for
C12H10N4O2S (274.30): C, 52.54; H, 3.67; N, 20.43 found:
C, 52.77; H; 3.92; N, 20.72.
Chemistry
Synthesis of 2‑(4‑oxo‑5‑(2‑(aroyl hydrazono)‑4,5‑dihydro‑
thiazol‑2‑yl) acetonitrile (2a, b) Aryl diazonium chloride
(0.01 mol) in (20 mL) ethanol was stirred for ½ h with 1
(0.01 mol) in ice bath in the presence of anhydrous sodium
acetate (0.01 mol), then the stirring will continue in room
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Journal of the Iranian Chemical Society
Table 4 Selected bond angles (o) of 2a compound
CH2), 7.32–7.87(m, 5H, Ar–H + NH, canceled with D2O);
Anal. Calcd. for C12H10N4OS (258.30): C, 55.80; H, 3.90;
N, 21.69 found: C, 55.10; H, 3.65; N, 21.85.
Bond length
Actual bond angles
Optimal
bond
angles
Nʹ‑p‑methoxy phenyl‑4‑oxo‑4,5‑dihydrothiazole‑2‑carbo‑
hydrazonoyl cyanide (3b) Dark browns crystals (EtOH);
yield 79% m.p. 170–72 °C; IR (KBr, ̄ꢀ , cm−1): 3177
(NH), 3092(CH-arom.), 2119(C≡N) and 1752 (C=O thi-
H(28)–N(17)–N(16)
N(16)–N(17)–C(1)
N(18)–C(14)–C(13)
H(27)–C(13)–H(26)
H(27)–C(13)–C(14)
H(27)–C(13)–C(11)
H(26)–C(13)–C(14)
H(26)–C(13)–C(11)
C(14)–C(13)–C(11)
C(11)–N(12)–C(8)
C(13)–C(11)–S(10)
N(16)–C(9)–S(10)
N(16)–C(9)–C(8)
O(15)–C(8)–N(12)
O(15)–C(8)–C(9)
H(25)–C(7)–H(24)
H(25)–C(7)–H(23)
H(25)–C(7)–C(4)
H(24)–C(7)–H(23)
H(24)–C(7)–C(4)
H(23)–C(7)–C(4)
H(22)–C(6)–C(5)
H(22)–C(6)–C(1)
H(21)–C(5)–C(6)
H(21)–C(5)–C(4)
C(7)–C(4)–C(5)
115.364
116.89
113
124
180
109.4
109.41
109.41
109.41
109.41
110.2
115
120
126
120
124.3
123
109
109
110
109
110
110
120
120
120
120
121.4
121.4
120
120
120
120
120
120
120
120
179.508
106.798
109.047
110.113
108.798
111.179
110.797
113.598
120.697
130.69
119.237
120.642
129.169
107.517
107.551
110.621
107.61
1
azolidinone); H NMR (DMSO-d6):δ/ppm 3.82(s, 3H,
OCH3),4.25(s, 2H, CH2), 7.21–7.58 (m, 5H, Ar–H + NH,
canceled with D2O); Anal. Calcd. for C12H10N4O2S (274): C,
52.54; H, 3.67; N, 20.43 found: C, 52.12; H, 3.13; N, 20.10.
Synthesis of 5‑Amino‑7‑(aryl)‑3‑oxo‑2‑(2‑(p‑tolyl)
hydrazono)‑3,7‑dihydro‑2H‑thiazolo [3,2‑a] pyridine‑6,8‑di‑
carbonitrile (4a, b) A mixture of (2a), aromatic aldehyde
and malononitrile (1:1:1 molar ratio) was refuxed for 6 h in
absolute ethanolic piperidine solution. The solid products
formed were collected by fltration and recrystallized from
ethanol.
5 ‑ A m i n o ‑ 7 ‑ ( p ‑ c h l o r o p h e ny l ) ‑ 3 ‑ oxo ‑ 2 ‑ ( 2 ‑ ( p ‑ t o l y l )
hydrazono)‑3,7‑dihydro‑2H‑thiazolo [3,2‑a] pyridine‑6,8‑dicar‑
bonitrile (4a) Reddish browns crystals (EtOH); yield 62%;
m.p. 245–47 °C; IR (KBr, ̄ꢀ , cm−1): 3429, 3312, 3215 (NH2,
NH), 3034(CH-arom.), 2921 (CH-aliph.), 2222(C≡N) and
1701 (C=O thiazolidinone); 1H NMR (DMSO-d6): δ/ppm
2.25 (s, 3H, CH3), 4.10 (s, 1H, pyridine-H), 7.13–7.83 (m,
11H, Ar–H + NH2, canceled with D2O + NH, canceled with
D2O); Anal. Calcd. for C22H15ClN6OS (446.31): C, 59.12;
H, 3.38, N; 18.80 found: C, 59.77; H, 3.96; N, 18.52.
111.104
112.234
119.365
121.21
119.419
119.876
120.726
119.827
119.446
119.618
119.863
119.203
121.184
121.242
118.346
120.292
C(7)–C(4)–C(3)
C(5)–C(4)–C(3)
5 ‑ A m i n o ‑ 7 ‑ ( o ‑ c h l o r o p h e ny l ) ‑ 3 ‑ oxo ‑ 2 ‑ ( 2 ‑ ( p ‑ t o l y l )
hydrazono)‑3,7‑dihydro‑2H‑thiazolo [3,2‑a] pyridine‑6,8‑dicar‑
bonitrile (4b) Reddish browns crystals (EtOH); yield 66%;
m.p. 270–72 °C; IR (KBr, ̄ꢀ , cm−1): 3396, 3228, 3189 (NH2,
NH), 3037(CH-arom.), 2921 (CH-aliph.), 2204 (C≡N) and
H(20)–C(3)–C(4)
H(20)–C(3)–C(2)
H(19)–C(2)–C(3)
H(19)–C(2)–C(1)
N(17)–C(1)–C(6)
N(17)–C(1)–C(2)
C(6)–C(1)–C(2)
1
1702 (C=O thiazolidinone); H NMR (DMSO-d6):δ/ppm
2.25 (s, 3H, CH3), 4.00 (s, 1H, pyridine-H), 7.14–7.79
(m, 10H, Ar–H + NH2, canceled with D2O), 8.53 (s, 1H,
NH, canceled with D2O); Anal. Calcd. for C22H15ClN6OS
(446.31): C, 59.12; H, 3.38; N, 18.80 found: C, 59.45; H,
3.07; N, 19.32.
Synthesis of Nʹ‑aryl‑4‑oxo‑4,5‑dihydrothiazole‑2‑carbohydraz
onoyl cyanide (3a, b) A mixture of arylcarbonohydrazonoyl
dicyanide (0.01 mol) and thioglycolic acid was heated 2 h
in acetic acid. The solid products formed were collected by
fltration and recrystallized from ethanol.
Synthesis of 2‑[5‑(anthracen‑9‑ylmethylene)‑4‑oxothiazo‑
lidine‑2‑ylidene) acetonitrile (5) A mixture of anthralde-
hyde (0.01 mol) was heated under refux for 2 h with (1)
(0.01 mol) in absolute ethanol (20 mL) catalyzed piperidine.
The solid product formed was collected by fltration and
recrystallized from ethanol.
Nʹ‑p‑tolyl‑4‑oxo‑4,5‑dihydrothiazole‑2‑carbohydrazonoyl
cyanide (3a) Dark browns crystals (EtOH); yield 72%;
m.p. 180–82 °C; IR (KBr, ̄ꢀ , cm−1): 3235 (NH), 3059(CH-
Browns crystals; (EtOH); yield 72%; m.p. 125–27 °C; IR
(KBr, ̄ꢀ , cm−1): 3183 (NH), 3055(CH-arom.), 2923 (CH-
1
arom.), 2117(C≡N) and 1713 (C=O thiazolidinone); H
1
NMR (DM SO-d6): δ/ppm 2.35(s, 3H, CH3), 4.29(s, 2H,
aliph.), 2195 (C≡N) and 1707 (C=O thiazolidinone); H
1 3

Journal of the Iranian Chemical Society
NMR (DMSO-d6):δ/ppm 5.16 (s, 1H, methine-H), 7.51–
8.75 (m, 10H, Ar–H + methine-H) and 11.49 (s, 1H, NH,
canceled with D2O); 13C NMR 123.40, 124.99, 125.75,
126.66; 127.79, 129.05, 129.18, 129.27, 130.61, 130.74,
131.32, 135.16 and 160.00; Anal. Calcd. for C20H12N2OS
(328.39): C, 73.15; H, 3.68; N, 8.53 found: C, 73.52; H,
3.81; N; 8.85.
(565.06) C, 70.15; H; 3.03, N, 14.87 found: C, 70.21, H,
2.91; N; 14.92.
Synthesis of 8‑amino‑3‑(anthracen‑9‑yl)‑6‑(4‑chlorophenyl
)‑1‑phenyl‑1,6‑dihydropy‑ razolo‑[3′,4′:4,5] thiazolo [3,2‑a]
pyridine‑5,7‑dicarbonitrile (13) To a solution of 7(0.01 mol)
in absolute ethanolic solution (20 mL), phenyl hydrazine
(0.01 mol) was added. The reaction was heated for 6 h. The
solid product formed was collected by fltration and recrys-
tallized from ethanol.
Synthesis of 2‑[5‑(anthracen‑9‑ylmethylene)‑4‑oxo‑4,5‑dihy‑
drothiazolidin‑2‑yl)]‑3‑(p‑chlorophenyl) acrylonitrile (6) To
4-thiazolidinone derivative 5 (0.01 mol) in absolute ethanol
(20 mL) having little amount of piperidine, p-chlorobenza-
ldehyde (0.01 mol) was added and heated for 3 h. The solid
product formed was collected by fltration and recrystallized
from ethanol.
Brown powder, (EtOH); yield 59%; m.p. 190–92 °C; IR
(KBr, ̄ꢀ , cm−1): 3432, 3216 (NH2), 3056 (CH-arom.), 2928
(CH-aliph.) and 2211(C≡N); MS m/z (%): 604(m+), 44.36);
Anal. Calcd. for C36H21ClN6S (604.50) C, 71.40; H, 3.50,
N, 13.89. Found: C, 71.03, H, 3.71; N; 14.12.
Reddish brown crystals (EtOH); yield 67%; m.p. 150–
52 °C; IR (KBr, ̄ꢀ , cm−1): 3056 (CH-arom.), 2978 (CH-
Synthesis of 9‑amino‑4‑(anthracen‑9‑yl)‑7‑(4‑chloropheny
l)‑2‑mercapto‑7H‑pyrido [2′,1′:2,3] thiazolo [4,5‑d] pyrimi‑
dine‑6,8‑dicarbonitrile (15) Thiourea (0.01 mol) was fused
with 7 (0.01 mol) for ½ h. The reaction mixture was allowed
to cool. The solid product formed was collected by fltration
and recrystallized from ethanol.
1
aliph.), 2195(C≡N) and 1709 (C=O thiazolidinone); H
NMR (DMSO-d6):δ/ppm 6.58–8.66 (m, 13H, Ar–H), 9.01,
9.05 (2 s, 2H, methine-H); Anal. Calcd. for C27H15ClN2OS
(450.94) C, 71.91; H, 3.35; N, 6.21 found: C, 72.01; H, 3.89;
N, 6.19.
Yellow powder; (EtOH); yield 59%; m.p. 252–54 °C;
Synthesis of 5‑amino‑2‑(anthracen‑9‑ylmethylene)‑7‑(4‑chloro
phenyl)‑3‑oxo‑3,7‑dihydro‑2H‑thiazolo [3,2‑a] pyridine‑6,8‑di‑
carbonitrile (7) A mixture of 4-thiazolidinone derivative 6
(0.01 mol) and malononitrile (0.01 mol), in absolute ethanol
(20 mL) containing little quantity of piperidine, was refuxed
for 6 h. The solid product formed was collected by fltration
and recrystallized from ethanol.
IR (KBr, ̄ꢀ , cm−1): 3430, 3337 (NH2), 3056(CH-arom.),
1
2928(CH-aliph.) and 2209 (C≡N); H NMR (DMSO-d6),
4.19(s, 1H, pyridine-H), 7.20–8.22 (m, 15H, Ar–H + NH2;
Canceled with D2O), 9.64 (s, 1H, SH; Exchangeable with
D2O); Anal. Calcd. for C31H17ClN6OS2 (572.5.09) C, 64.97;
H, 2.99, N, 14.66 found: C, 64.21; H, 2.54; N, 15.02.
Brown powder, (EtOH); yield 73%; m.p. 160–62 °C; IR
(KBr, ̄ꢀ , cm−1): 3331, 3354 (NH2), 3051 (CH-arom.), 2200
(C≡N) and 1708 (C=O thiazolidinone); 1H NMR (DMSO-
d6): δ/ppm 4.70 (s, 1H, pyridine-H), 6.37–8.80 (m, 16H,
Ar–H + methine-H + NH2; Exchangeable with D2O); MS
m/z (%): 516, (m+, 6.89); Anal. Calcd. for C30H17ClN4OS
(517.00) C, 69.69; H, 3.31; N, 10.84 found: C, 70.12; H,
3.64; N; 10.37.
Synthesis of 8‑(anthracen‑9‑ylmethylene)‑5‑(4‑chlorophe
nyl)‑4,9‑dioxo‑4,5,8,9‑tetra‑hydro‑3H‑thiazolo [3′,2′:1,6]
pyrido [2,3‑d] pyrimidine‑6‑carbonitrile (17) A mixture of 7
(0.01 mol) was heated in enough quantity of formic acid for
6 h. The solid product formed was collected by fltration and
recrystallized from ethanol. Brown powder; yield 61%; m.p.
225–27 °C; IR (KBr, ̄ꢀ , cm−1): 3181 (NH), 2227 (C≡N) and
1
1712 (C=O); H NMR (DMSO-d6), 4.97(s, 1H, pyridine-
H), 5.20 (s, 1H, pyrimidine-H),7.20–8.22 (m, 13H, Ar–H),
8.88(s, 1H, methine-H), 9.64 (s, 1H, NH; exchangeable with
D2O); Anal. Calcd. for C31H17ClN4O2S (545.50) C, 68.32;
H, 3.14; N, 10.28 found: C, 68.21; H, 2.98; N, 10.52.
Synthesis of 6‑amino‑2‑(anthracen‑9‑ylmethylene)‑7‑(4‑chl
orophenyl)‑3‑(dicyanom‑ ethylene)‑3,7‑dihydro‑2H‑thiazolo
[3,2‑a] pyridine‑5,8‑dicarbonitrile (12) To a solution of thi-
azolo [3,2-a] pyridine derivative 7 (0.01 mol) in absolute
ethanol (20 mL) catalyzed with piperidine malononitrile
(0.01 mol) was added. The reaction mixture was heated for
6 h. The solid product formed was collected by fltration and
recrystallized from ethanol.
Synthesis of methyl 2‑cyanoethanimidothioate (19) To a
solution of 1 (0.01 mol) in DMF solution (20 mL), PhNCS
(0.01 mol) and KOH (0.01 mol) were added. The reaction
was heated for 3 h. The solid product formed was collected
by fltration and recrystallized from ethanol.
Yellow powder; (EtOH); yield 59%; m.p. 233–35 °C; IR
(KBr, ̄ꢀ , cm−1): 3373, 3216 (NH2), 3056 (CH-arom.), 2928
(CH-aliph.) and 2196 (C≡N); 1H NMR (DMSO-d6), 4.10
(s, 1H, pyridine-H), 7.50–8.19 (m, 16H, Ar–H +methine-
H + NH2, canceled with D2O) Anal. Calcd. for C33H17ClN6S
Brown powder; 74%; m.p. 225–27 °C; IR (KBr, ̄ꢀ , cm−1):
3381 (NH), 2216 (C≡N) and 1H NMR (DMSO-d6), 3.28(s,
3H, CH3), 3.65 (s, 1H, NH), 4.23 (s, 2H, CH2). Anal. Calcd.
for C5H6N2O2S (158.18) C, 37.96; H, 3.82; N, 17.71 found:
C, 38.23; H, 3.53; N, 17.21.
1 3

Journal of the Iranian Chemical Society
15. S.S. Mishra, K. Srivastava, S.D. Srivasta, Indian J. Chem. 36B,
826–830 (1997)
Molecular modeling studies
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An attempt to gain a better insight on the molecular struc-
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empirical method PM3 as implemented in HyperChem 7.5
[45]. The structures of synthesized reported compounds
were optimized with semi-empirical method PM3. A gra-
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in all the molecular mechanics and quantum calculations.
The lowest energy structure was used for each molecule
to calculate physicochemical properties.
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Conclusions
We reported herein a novel route for synthesis of some
thiazolidinone derivatives having diferent aroyl hydrazo-
noyl and aryl moieties. Also, this article include synthesis
of diferent thiazolo [3,2-a] pyridines and thiazolo [3,2-a]-
1,8-naphthyridine derivatives. To support the solid-state
structure, the molecular modeling optimization and elec-
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