A novel series of 1, 4-Dihydropyridine (DHP) derivatives bearing thiazolidin-4-one: From synthesis to structure

Article abstract of DOI:10.1016/j.molstruc.2017.03.005

A novel series of 1, 4-Dihydropyridine (DHP) thiazolidin-4-one compounds derived from dihydropyridine hydrazones Schiff bases with thioglycolic acid were synthesized through an efficient Hantzsch reaction and experimentally characterized by spectral methods using IR, ¹H NMR, ¹³C NMR, and mass spectroscopic methods. Herein, DHPs were synthesized by an improved Hantzsch procedure in the excellent yields by three different conditions including reflux condensation, fusion, and the microwave irradiation. An additional comparison of applied methodology routes was used to confirm the advantages including short reaction time, good yields, and operational simplicity. Furthermore, the structural and electronic properties of the studied molecules were theoretically investigated by performing density functional theory (DFT) to access reliable results to the experimental values. The molecular geometry, HOMO, and LUMO of the studied compounds were calculated. The theoretical ¹³C chemical shift results were also calculated using the gauge independent atomic orbital (GIAO) approach and their respective linear correlations were obtained.

Full text of DOI:10.1016/j.molstruc.2017.03.005

Accepted Manuscript
A novel series of 1, 4-Dihydropyridine (DHP) derivatives bearing thiazolidin-4-one:
From synthesis to structure
Tahseen S. Bade, Hossein Pasha Ebrahimi, Tahseen A. Alsalim, Salam J.J. Titinchi,
Hanna S. Abbo, Zeinab Bolandnazar, Amirpasha Ebrahimi
PII:
S0022-2860(17)30264-8
10.1016/j.molstruc.2017.03.005
MOLSTR 23501
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 16 October 2016
Revised Date: 25 February 2017
Accepted Date: 1 March 2017
Please cite this article as: T.S. Bade, H.P. Ebrahimi, T.A. Alsalim, S.J.J. Titinchi, H.S. Abbo,
Z. Bolandnazar, A. Ebrahimi, A novel series of 1, 4-Dihydropyridine (DHP) derivatives bearing
thiazolidin-4-one: From synthesis to structure, Journal of Molecular Structure (2017), doi: 10.1016/
j.molstruc.2017.03.005.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A Novel Series of 1, 4-Dihydropyridine (DHP) Derivatives
Bearing Thiazolidin-4-one: From Synthesis to Structure
Tahseen S. Bade a, Hossein Pasha Ebrahimi b, Tahseen A. Alsalim a*, Salam J. J. Titinchi c,
Hanna S. Abbo c, Zeinab Bolandnazar d, and Amirpasha Ebrahimi e
a Department of Chemistry, College of Education for pure science,
University of Basrah, Basrah 16001, Iraq
b Department of Chemistry and Biochemistry, California State University Dominguez Hills,
Carson, CA 90747, USA
c Department of Chemistry, University of the Western Cape,
Bellville, Cape Town 7535, South Africa
d David Geffen School of Medicine, University of California at Los Angeles,
Los Angeles, CA 90095, USA
e Department of Chemistry, Azad University, North Branch, Tehran, Iran
Tahseen A Alsalim
Department of Chemistry
University of Basrah
Basrah, Iraq
Tel: (964) 7801360990
*Corresponding Author. E-mail: tahseenalsalim@yahoo.com
Keywords: 1, 4-dihydropyridine, DHP, Thiozolidin-4-one, Hantzsch dihydropyridine synthesis,
Calcium channel blockers (CCBs), Microwave.
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Abstract
A novel series of 1, 4-Dihydropyridine (DHP) thiazolidin-4-one compounds derived from
dihydropyridine hydrazones Schiff bases with thioglycolic acid were synthesized through an
efficient Hantzsch reaction and experimentally characterized by spectral methods using IR, 1H
NMR, 13C NMR, and mass spectroscopic methods. Herein, DHPs were synthesized by an
improved Hantzsch procedure in the excellent yields by three different conditions including
reflux condensation, fusion, and the microwave irradiation. An additional comparison of applied
methodology routes was used to confirm the advantages including short reaction time, good
yields, and operational simplicity. Furthermore, the structural and electronic properties of the
studied molecules were theoretically investigated by performing density functional theory (DFT)
to access reliable results to the experimental values. The molecular geometry, HOMO, and
LUMO of the studied compounds were calculated. The theoretical 13C chemical shift results
were also calculated using the gauge independent atomic orbital (GIAO) approach and their
respective linear correlations were obtained.
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1. Introduction
1,4-Dihydropyridine derivatives (DHPs) are widely used clinically as L-type calcium
channel blockers (CCBs) in the treatment of hypertension and cardiovascular diseases1,2. Figure
1 represents some CCBs which prevent calcium from entering cardiac muscle cells and blood
vessels, resulting in bradycardia and vasodilation, respectively. In the past, DHPs were generally
synthesized by the classical Hantzsch reaction3–9, which involves the condensation of two
equivalents of a β-keto ester with one equivalent of an aldehyde and a nitrogen donor such as
ammonia or ammonium acetate10,11. A literature survey shows that a number of improved
methods have been recently reported to modify Hantzsch procedures either by using the β-
diketones instead of the β-keto esters or by replacing ammonia by an aromatic amine in
continuous flow condition12–14. However, some of these methods suffer from long reaction times,
low yields, and use of large quantities of volatile organic solvents, therefore, development of an
efficient and versatile method is still required.
N
O
N
NO2
O
CH3
O
O
CH3
O
CH3
CH3
H3C
O
O
H3C
O
O
H3C
N
CN
H3C
N
CN
H
H
Nilvadipine
Isradipine
Cl
Cl
NO2
Cl
O
O
O
O
O
O
CH3
H3C
CH3
CH
3
H3C
O
O
O
O
O
H C
O
O
3
H3C
N
H3C
N
CH3
H C
N
H
CH
3
3
NH2
H
H
Nifedipine
Felodipine
Amlodipine
Figure 1. Structures of the most known 1,4-DHP calcium channel blockers
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In addition, the occurrence of the nitrogen and sulfur containing heterocyclic ring systems
including thiazolidine as well as related cyclic systems in numerous biologically active
molecules has been importantly recognized with regards to the spectrum of activity in several
remarkable pharmacological drugs including antibiotics, antifungals, antiallergics, antiphlogistics
and antitumor substances15-26. In addition, the thiazolidine ring system represents a very
important structural unit in drug discovery27.
As a part of our endeavor toward the synthesis of new heterocyclic bioactive agents as
probes for biomolecules in medicinal, biophysical and bioanalytical chemistry to enhance many
physiological activities28-36, herein, we synthesized and characterized a new series of 1, 4-
Dihydropyridine derivatives bearing thiazolidin-4-one by three different conditions including
Hantzsch condensation, fusion and microwave irradiation methods. The synthesized compounds
were characterized on the basis of spectroscopic methods including IR, 1H and 13C NMR, as well
as mass spectroscopy. To additionally verify the proposed assignments, quantum chemical
calculations were performed. Therefore, the structural and electronic properties of the studied
compounds were theoretically investigated and the results were discussed. In the present study,
we have also extended the probing into the application of Density Functional Theory (DFT)
methods. The DFT methods are more advantageous owing to their accuracy and low
computational cost. These properties make DFT more practical and feasible for the computations
of different molecules. Therefore, these synthesized compounds were theoretically investigated
by B3LYP, as the more popular DFT methods. Thus, a comparison was made between the
theoretically calculated 13C chemical shift constants and the experimentally measured 13C
chemical shifts. GIAO (Gauge Including Atomic Orbital) as the most widely used approach for
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calculating NMR shielding tensors were applied37–42. The Gaussian 09 package was employed to
perform optimization of structures and all the calculations43.
2. Results and discussion
All the intermediate and the target compounds (DHPs thiazolidine-4-one derivatives)
were synthesized according to the methods summarized in scheme 1 and 2. As outlined in
Scheme 1 and 2, the reaction included several steps which the dihydropyridine 1 was synthesized
in a general Hantzsch procedure by the condensation of two equivalents of ethyl acetoacetate
with one equivalent of p-hydroxybenzaldehyde and ammonium solution under ethanol medium.
O H
O H
H
H
3 C
O
C H O
C H
O
3
O
O
E t O H / r e f l u x e
H
3 C
O
O
3
C H
3
O
O
O
O
H
3 C
N
C H
H
C H
3
3 C
1
N H 4 O A c
C l C H 2C O O C 2 H
5
K
2 C O
3
D M F / 8 0 o C
O
C H
3
O
H
N
O
N H
2
O
O
N H 2 N H
O
O
2
H
3 C
O
O
3
C H
3
O
O
E t O H / r e f lu x e
H
3 C
N
H
C H
H
3 C
O
O
3
C H
3
H
3 C
N
H
C H
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
=
=
=
=
=
=
=
=
=
=
=
=
4 - c h lo r o p h e n y l
4 - n itr o p h e n y l
3 , 4 - d im e t h o x y p h e n y l
3 , 4 , 5 - tr i m e th o x y p h e n y l
4 - N , N - d im e t h y la m in o p h e n y l
4 - m e t h o x y p h e n y l
3 - in d o ly l
4 - h y r o x y p h e y l
p h e n y l
H
N
R
N
O
O
O
O
H
O
O
3
C H
3
3
C
4 - e th y l p h e n y l
2 - t h io p h e n y l
4 - b r o m o p h e n y l
H
3 C
N
C H
H
4 - 1 5
Scheme 1. Preparation procedure of DHPs hydrazone (Schiff bases) with general structure
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The solid product was converted to ester 2 by using ethyl chloroacetate in DMF medium. The
only hydroxyl group of DHP ring undergoes alkylation during this step. A nucleophilic
substitution reaction converted ester 2 to its hydrazide 3 by refluxing it with hydrazine
monohydrate in ethanol. DHP Schiff bases (hydrazone) 4-15 were synthesized by the
condensation of an aromatic aldehyde with prepared hydrazide using different methods reflux,
fusion and MW irradiation. The yield and reaction time of different methods for newly
synthesized compounds are collected in Table 1.
Table 1. The yield and reaction time of prepared DHPs Hydrazone in different methods
Reflux
Time (hr)
MW irradiation
Time (min) Yield % Time (min) Yield %
Fusion
Compound
Yield %
76
4
4
4
4
4
4
6
6
4
4
6
4
13
13
13
13
13
9
15
15
9
87
92
86
83
80
92
79
87
84
87
85
87
15
15
15
15
15
10
15
15
10
10
10
15
85
91
85
87
83
91
81
85
89
90
87
91
4
5
6
7
8
81
78
80
72
81
63
61
78
9
10
11
12
13
14
15
75
77
76
9
9
13
As is clear from Table 1, the maximum time of fusion and MW methods measured about 15 min
while reflux takes 4-6 hrs. DHP Schiff bases (hydrazone) 4-15 were converted to the
corresponding DHPs thiadiazolin-4-one 4a-15a by the condensation reaction of the obtained
Schiff bases with thioglycolic acid and hydrazone under reflux. The synthetic route of
compounds is outlined in Scheme 2. As can be concluded from Table 1, microwave irradiation
has major advantages over the classical approach (Method A) since shorter reaction time (from
hours to mins) are required and significantly improved yields are observed. For instance,
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compound 11 was synthesized in 61% yield, after 6 hours in ethanol at the reflux method. In
contrast, the microwave assisted reaction, on neutral alumina, affords an 87% yield in just 15
minutes.
R
H
H
H
N
R
N
N
O
N
S
O
O
O
O
HS
O
OH
O
O
O
O
ZnCl2
H3C
O
O
CH3
H3C
O
O
CH3
H3C
N
H
CH3
H3C
N
H
CH3
4 -15
4a -15a
4a = 4-chloro phenyl
6a = 3,4-dimethoxy phenyl
7a = 3,4,5-trimethoxy phenyl
8a = 4- N,N-dimethylamino phenyl
9a = 4-methoxy phenyl
10a = 3- indolyl
11a = 4-hyroxy pheyl
12a = phenyl
13a = 4-ethyl phenyl
14a = 2-thiophenyl
15a = 4-bromo phenyl
Scheme 2. Preparation of DHPs Thiazolidin-4-one
2.1 Spectral characterization
In this section, spectral studies including the observed spectroscopic results for the title
compounds are discussed. Newly synthesized target compounds were characterized by FTIR, 1H
NMR, 13C NMR as well as mass spectral techniques. All the synthesized compounds gave
satisfactory analyses for the proposed structures, which were confirmed on the basis of their
spectral data. A complete set of spectral data of the complexes is given in Supplementary data.
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IR spectra analysis
The IR spectra of the prepared compounds exhibit characteristic bands of the expected functional
groups. The spectral data of compounds 1-3 are in a good agreement with the literature44. As
shown in Figure 2, the presence of bands 1740 and 3340 cm-1 due to carbonyl stretching and NH2
stretching respectively indicates the condensation of ester 2 and hydrazine in 1:1 mol ratio.
Figure 2. IR spectra of compounds 2 and 3.
The IR spectrum of DHPs hydrazone derivatives 4-15 shows a strong bond at 1612-1604 cm-1
that attributed to the stretching vibration of azomethine as the main characteristic band which
obviously confirms the formation of Schiff base.
1H and 13C NMR spectra analysis
1
The H NMR spectral data of all compounds at ambient temperature in DMSO-d6 confirms the
proposed structural elucidation. The spectra of all compounds show the azomethine proton
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(CH=N) as singlet signal at δ ~ 7.91–8.37 ppm. The 1H NMR spectra of Schiff bases display the
NH proton (-CO-NH=N-) as singlet signal at δ ~ 11.86–11.27 ppm.
Figure 3. 1H NMR spectra of compound 2
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The spectra of DHPs 4-thiazolidinone compounds 4a-15a show the heterocyclic proton -CH (-
SCHN-) appear at a region between 5.16 and 6.65 ppm as a two signal. They also display a
signal at δ ~ 3.51–4.60 ppm which is attributed to the methylene group (-CH2-S). The
disappearance of proton signals attributed to NH2 in the 1H NMR spectra of DHPs 4-15 supports
the condensation of aromatic aldehydes with prepared hydrazides. As it can be observed in
Figures 3 and 4, all protons of cyclic, aromatic ring and methyl groups are observed in their
expected region for compounds 2 and 12a, respectively.
Figure 4. 1H NMR spectra of compound 12a
Also, the 13C NMR spectra of compounds were recorded in DMSO-d6. All spectra exhibited
signals from azomethine carbon at δ ~ 170 ppm as the highest chemical shift in our synthesized
Schiff bases. The carbons of the thiazolidine-4-one system appear between δ ~ 59.1-59.4 ppm
and 28.0-28.8 ppm which are attributed to the carbon of SCHN and -CH2-S, respectively. All
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assignments for other carbon were found as expected. In addition, 13C DEPT NMR and 15N
NMR of compounds 9a and 10a are presented in Figures 5 and 6, respectively.
Figure 5. 13C NMR and DEPT spectrum of compound 9a
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Figure 6. 15N NMR spectrum of compound 10a
These spectra also support the proposed structure for compounds.
Mass spectra analysis
Mass spectrometry as a powerful structural characterization technique in coordination chemistry
has been successfully used to confirm the molecular ion peaks of all compounds. The peaks
intensity gives an idea about the stability of fragments, especially with the base peak. The
electron impact spectrum of the studied compounds is characterized by high relative intensity
molecular ion peaks. The mass spectrum of compound 7a is presented in Fig. 7 as a case study.
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Figure 7. Mass spectrum of compound 7a
In addition, as can be concluded from Table 2, the ESI reveals the observed [M+H] is in good
agreement with calculated [M+H].
Table 2. ESI mass spectra data for DHPs thiazolidin-4-one derivatives
Compound
4a
Structure
C30H32ClN3O7S
C32H37N3O9S
C33H39N3O10S
C32H38N4O7S
C31H35N3O8S
C32H34N4O7S
C30H33N3O8S
C30H33N3O7S
C32H37N3O7S
C28H31N3O7S2
C30H32BrN3O7S
Calc. [M+H]
615.1096
640.6682
670.7428
623.7327
610.6909
619.7009
596.6643
580.6649
608.7180
586.6936
659.5569
Found. [M+H]
615.2225
640.1580
670.3013
623.0603
610.2073
6192239
6a
7a
8a
9a
10a
11a
12a
13a
14a
15a
596.2102
580.2907
608.2568
586.2485
659.0400
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2.2 Computational study
In present work, a non-local DFT method, B3LYP, was used to perform theoretical
calculations on the studied compounds. The geometry of all compounds was fully optimized at
the B3LYP level of theory along with standard 6-311+G(d,p) basis set which has amply been
proven to give very good ground-state geometries. Also, no constraints were imposed on the
structure during the geometry optimizations. The vibrational frequency analyses, calculated at
the same level of theory, indicate that the optimized structures are at the stationary points
corresponding to local minima without any imaginary frequency. The electronic properties were
calculated using B3LYP/6-311+G(d,p) based on the optimized structures. The Gaussian 09
package was employed to perform optimization of structures and all the calculations. The results
are discussed for compound 12 and the corresponding thiazolidin-4-one derivative, compound
12a as cases study. The geometry optimization yields nonplanar structures.
2.2.1 Electronic properties
The frontier molecular orbitals, as the most important orbitals in a molecule, play a significant
role in the electronic properties and determine the way the compound interacts with other species
and provide useful information about the biological mechanism45. The HOMO (the highest
occupied molecular orbital) represents the ability to donate an electron and LUMO (the lowest-
lying unoccupied molecular orbitals) as an electron acceptor represents the ability to receive an
electron. The frontier orbital gap, the energy gap between HOMO and LUMO represents the
stability of structures and helps to characterize some significant issues including the kinetic
stability as well as chemical reactivity of the compound. In order to evaluate the energetic
behavior of the title compounds, we carried out calculations for compounds 12 and 12a. Taking
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the DFT result, the shapes of frontier molecular orbitals for these compounds have been
demonstrated in Fig. 8.
LUMO PLOT
LUMO PLOT
(EXCITED STATE)
(EXCITED STATE)
ELUMO = 0.168 a.u.
ELUMO = 0.183 a.u.
∆E = -0.412 a.u.
∆E = -0.383 a.u.
EHOMO = -0.229 a.u.
EHOMO = -0.215 a.u.
HOMO PLOT
HOMO PLOT
(GROUND STATE)
(GROUND STATE)
Figure 8. The atomic orbital compositions of the frontier molecular orbital of 12 and 12a
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It is seen that the HOMO of two compounds is mostly located on the benzene ring, azomethine
group and partly related to acetate group. It is seen that for compound 12, while the HOMO is
localized on whole the pyridine ring, almost the benzene ring, and a part of azomethine group,
the LUMO is localized mainly on the pyridine ring, almost the azomethine group. Also, for
compound 12a the benzene ring and thiazolidin-4-one has no contribution to the orbitals. High
instability of this compound 12a is due to the thiazolidin-4-one specific structural and electronic
features. This small energy gap confirms high chemical reactivity as well as high polarizability.
2.2.2 NMR analysis
In order to a comparison between the experimental and theoretical NMR data, which may
be helpful in making correct assignments and understanding the relationship between chemical
shift and molecular structure, 13C NMR chemical shifts calculation for further clarification of
synthesized compounds are reported. To clarify the relation between theoretical and
experimental values of NMR chemical shift constants, the experimental data are plotted vs.
13
computed values. The C NMR chemical shifts of all carbons were calculated on the optimized
structures of compounds using B3LYP method employing 6-31+G(d,p) basis set for all atoms.
In order to compute the 13C NMR chemical shifts, each couple of carbon atoms on equivalent
locations of the compound was considered as equivalent and their average of chemical shifts
were calculated.
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180
160
140
120
100
80
B3LYP/6-31+G(d,p)
δexp=0.9837 δcalc+ 1.489
r=0.9990
60
40
20
0
0
20
40
60
80
100
120
140
160
180
Theoretical chemical shift (ppm)
Figure 9. Experimental values vs. theoretical 13C NMR chemical shifts of compound 10
The statistical parameters of computed 13C NMR chemical shifts along with experimental data
for compound 10 are given in Fig. 9. As can be seen, the results are in reasonable agreement with
experimental values.
3. Conclusion
Calcium channel blockers (CCBs) were developed in the 1970s and are now widely used.
CCBs are drugs that block the entry of calcium into cardiac muscle and arteries. Among
pharmacologically important heterocyclic compounds, 1,4-Dihydropyridine derivatives (DHPs)
have long been used as CCBs in pharmacology. The biological activity of these compounds is
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enhanced on undergoing bearing containing heterocyclic rings, particularly, the agents within the
thiazolidine system have been of great scientific exploitation and interest as these are
accompanied by almost all the biological profiles and pharmacological activities. In summary, a
new series of 1, 4-Dihydropyridine derivatives bearing thiazolidin-4-one has been synthesized by
three different conditions including Hantzsch condensation, fusion and microwave irradiation
methods and characterized by structural, analytical and detailed spectroscopic methods. All
newly synthesized compounds were structurally characterized by different spectroscopic
1
methods including IR, H and 13C NMR, as well as mass analysis which they were used to
identify the products. To additionally verify the proposed assignment, quantum chemical
calculations were performed. Therefore, the structural and electronic properties of the studied
compounds were theoretically investigated and the results were discussed.
4. Experimental protocols
4.1 Materials, instrumentation and spectral measurements
All starting materials were purchased from Merck, Sigma, Scharlau, Aldrich, J. S. Baker and
used as received. 4-(dimethylamino) benzaldehyde, 4-methoxybenzaldehyde, benzaldehyde, 4-
ethylbenzaldehyde, 4-hydoxybenzaldehyde, 4-nitrobenzaldehyde, 3, 4-dimethoxybenzaldehyde,
4-bromobenzaldehyde, 3, 4, 5-trimethoxybenzaldehyde were supplied from Aldrich. Hydrazine,
ethylacetoacetate, thiophene -2-carbaldehyde, 2-mercaptoacetic acid, indol-3-carbaldehyde, 2-
chloroethylacetate, 4-chlorobenzaldehyde were obtained from Merck. All solvents employed in
synthesis were of extra-pure grade and used as received without further purification. Thin-layer
chromatography (TLC) was carried out by using aluminum sheet coated with silica gel 60F254
(Merck), iodine and ultraviolet (UV) light was used for visualized TLC plates.
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IR spectra were recorded by using Shimadzu FTIR-Affinity spectrophotometer in the region
4000–400 cm-1 in KBr pellet. The spectra were collected with a resolution of 2 cm-1 with 15
scans. The mass spectra were scanned by the EI technique at 70 eV with an Agilent
1
13
Technologies 5975C spectrometer. The experimental values of H and C NMR spectra for the
studied compounds were scanned on a Bruker Avance 400 MHz spectrometer with a field
gradient operating at 400.122 MHz for proton observation and 100.61 MHz for carbon
observation. TMS as the internal standard was used as referenced to 0.0 ppm and DMSO-d6 was
used as the solvent. The experiments were run in unlock mode, with sufficient a number of scans
to achieve S/N ratios 200:1 (ca.). NMR spectra were obtained at a probe temperature of about
298 K. Melting points were recorded on a Fisher-Johns melting point apparatus.
4.2 Preparation methods
Two series of compounds were derived from DHPs. The first series of DHPs Schiff bases were
synthesized from DHPs hydrazide with different aromatic aldehydes (Scheme 1). In the second
series, the DHPs thiazolidinone were derived by hetero cyclization of the DHPs Schiff bases by
using the cyclization agent (mercapto acetic acid) as an efficient route to synthesize substituted
DHPs thiazolidin-4-one derivatives (Scheme 2).
1,1'-(4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-diyl)dipropan-1-one (1) was
prepared by mixing (10.0 g, 81.8 mmol) of p-hydroxy benzaldehyde and (16.0 g, 123 mmol) of
ethyl acetoacetate with (16.5 g, 123 mmol) of ammonium acetate in 100.0 mL of ethanol. The
solution was refluxed for 16 h and poured on to crush ice. Then, it was filtered, washed with
water and dried at room temperature. Recrystallization from ethanol/DMF afforded the purified
crystals.
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(Yield, 60%); mp 239-241°C; IR (KBr, cm-1) 3348, 3101, 2985, 1661, 1612, 1591, 1510, 1489,
1
1369, 1226, 1130, 1022; H NMR (DMSO-d6, δ/ppm) 1.13 (t, 6H, J=8, CH2CH3), 2.23 (s, 6H,
CH3), 3.98 (q, 4H, J=8, OCH2CH3), 4.74 (s, 1H, CH), 6.57 (d, 2H, J=8, Ar-H), 6.92 (d, 2H, J=8,
Ar-H), 8.70 (s, 1H, NH), and 9.08 (s, 1H, OH); 13C NMR (DMSO-d6, δ/ppm), 167.5, 155.8,
145.2, 139.3, 128.7, 114.8, 102.7, 59.3, 38.2, 18.6, 14.6.
ethyl 2-(4-(2,6-dimethyl-3,5-dipropionyl-1,4-dihydropyridin-4-yl) phenoxy)acetate (2) was
prepared by the addition of compound 1 (8.0 g, 23 mmol) to chloroethyl acetate (4.2 g, 34 mmol)
o
and K2CO3 (4.6 g, 34 mmol) in 125 mL of DMF. The resulting mixture was stirred at 80 C for
20 h. The reaction mixture was cooled down to room temperature and poured onto ice-water.
The precipitate was filtered, washed with cold ethanol, and then dried in air.
(Yield 74%); mp 239-241oC; IR (KBr, cm-1) 3249, 3228, 3101, 2976, 1691, 1662, 1612, 1570,
1
1508, 1305, 1211, 1118, 1022; H NMR (DMSO-d6, δ/ppm) 8.77 (S, 1H, NH), 7.04 (d, 2H, J =
8.6, Ar-H), 6.7 (d , 2H, J = 8.6, Ar-H), 4.79 (S, 1H, CH), 4.68 (S, 2H, OCH2CO), 4.15 (q, 2H, J
= 8, OCH2CH3), 3.98 (q, 4H, J = 4, OCH2CH3), 2.24 (S, 6H, CH3), 1.20 (t, 6H, J=8, CH3), 1.13
(t, 6H, J = 8, OCH2CH3); 13C NMR (DMSO-d6, δ/ppm): 169.3, 167.4, 156.2, 145.6, 141.6,
128.7, 114.2, 102.4, 65.0, 61.0, 59.4, 38.2, 18.6, 14.6.
2-(4-(2,6-dimethyl-3,5-dipropionyl-1,4-dihydropyridin-4-yl) phenoxy)acetohydrazide (3): An
ethanolic solution (75 mL) of compound 2 (6.5 g, 15 mmol) was added to hydrazine
monohydrate (2.4 g, 75 mmol). Then, the solution was heated under reflux for 4 h. The reaction
mixture was cooled down to room temperature and poured on to crush ice. Recrystallization
from ethanol/DMF afforded the purified white precipitate.
20

ACCEPTED MANUSCRIPT
o
(Yield 81%); mp 191-192 C; IR (KBr, cm-1) 3346, 3254, 3102, 2981, 1743, 1689, 1624, 1504,
1
1366, 1305, 1276, 1205, 1089; H NMR (DMSO-d6, δ/ppm): 9.20 (S, 1H, NH-NH2), 8.77 (S,
1H, NH), 7.04 (d, 2H, J = 8.2, Ar-H), 6.75 (d, 2H, J = 8, Ar-H), 4.79 (S, 1H, CH), 4.40 (S, 2H,
OCH2CO), 4.30 (S, 2H, NHNH2), 3.98 (q, 4H, J=4, OCH2CH3), 2.24 (S, 6H, CH3), 1.13 (t, 6H,
J=4, OCH2CH3); 13C NMR (DMSO-d6, δ/ppm): 167.4, 167.2, 156.5, 145.6, 141.6, 128.7, 114.3,
102.5, 66.7, 59.4, 38.2, 18.68, 14.6.
4.3 General procedure for the synthesis of DHP- hydrazone (Schiff bases) (4-15)
Method A (Reflux Condensation method)
An ethanolic solution (25 mL) of Hydrazone 3 (0.5 g, 1.2 mmol) was mixed with (1.2 mmol) of
aldehyde. The solution was acidified by adding 2 drops of glacial acetic acid and refluxed for 8
h. Then, the reaction mixture was concentrated by evaporation, and the precipitate of Schiff base
complexes was collected by filtration, washed with hot water, ethanol and finally with a small
portion of diethyl ether to extract all organic impurities solvent.
Method B (Fusion)
Compound (3) (1 mmol) was mixed with appropriate aldehydes (1 mmol). Then, the mixture was
inserted into a pyrex beaker which was placed in an oil bath heat to fusion for the specified time
Table 1). The progress of the reaction was monitored by TLC on completion the resulting
mixture. The reaction mixture was extracted with ethyl acetate. The ethereal layer was dried over
anhydrous sodium sulfate and the solvent was removed under reduced pressure. The Extracts
were dried over anhydrous sodium sulfate, evaporated and recrystallized with a suitable solvent.
Method C (Microwave irradiation):
A simple and fast synthesis of DHPs hydrazone Schiff bases was performed by the microwave-
assisted reaction, on neutral alumina. A mixture of compound 3 (1 mmol, 0.417 g) and
21

ACCEPTED MANUSCRIPT
appropriate aldehydes (1 mmol) was inserted into a 200-ml pyrex beaker filled with neutral
alumina and subjected to microwave irradiation for the specified time at its full power of 900
watts (Table 1). The completion of the reaction was monitored by TLC. The mixture was then
cooled to room temperature and extracted with ethyl acetate. The concentration of the combined
extracts under reduced pressure and recrystallization of the residue (EtOH) provided the title
compounds (Table 2).
The physical properties and spectral data of prepared DHPs hydrazone are given below.
(E)-diethyl 4-(4-(2-(2-(4-chlorobenzylidene)hydrazinyl)-2-oxoethoxy)phenyl)-2,6-dimethyl-1,4
dihydropyridine-3,5-dicarboxylate (4): recrystallized from DMF/EtOH; mp 246-248oC; IR (KBr,
cm-1) 3298, 3234, 3099, 2980, 2900, 1691, 1660, 1612, 1506, 1490, 1215. 1H NMR (DMSO-d6,
δ/ppm): 11.62 (S, 1H, CONH), 8.77 (S, 1H, NH), 8.31 (S, 1H, CH=N), 7.7-6.8 ( m, 8H, Ar-H),
5.06 (S, 1H, CH) , 4.8 (S, 2H, OCH2CO), 3.9 (m, 4H, OCH2CH3), 2.5 (S, 6H, CH3), 1.1 (t, 6H,
OCH2CH3); 13C NMR (DMSO-d6, δ/ppm): 169.7, 167.5, 156.8, 156.4, 147.0, 145.5, 142.8,
141.7, 141.1, 138.6, 129.3, 129.0, 114.4, 114.2, 102.5, 66.9, 59.4, 43.1, 18.6, 14.6.
(E)-diethyl
4-(4-(2-(2-(4-nitrobenzylidene)hydrazinyl)-2-oxoethoxy)phenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (5): recrystallized from DMF/EtOH; mp 244-245oC; IR (KBr,
cm-1) 3298, 3234, 3099, 2980, 2900, 1691, 1660, 1612, 1506, 1490, 1215. 1H NMR (DMSO-d6,
δ/ppm): 11.86 (S, 1H, CONH), 8.7 (S, 1H, NH), 8.3 (S, 1H, CH=N), 8.1- 6.76 (m, 8H, Ar-H),
5.11 (S, 1H, CH), 4.80 (S, 2H, OCH2CO), 3.98 (m, 4H, OCH2CH3), 2.24 (S, 6H, CH3), 1.14 (t,
13
6H, OCH2CH3); C NMR (DMSO-d6, δ/ppm): 167.4, 165.4, 148.2, 145.5, 141.8, 130.0, 128.8,
128.4, 114.2, 102.5, 66.8, 59.4, 43.6, 18.6, 14.6.
22

ACCEPTED MANUSCRIPT
(E)-diethyl 4-(4-(2-(2-(3,4-dimethoxybenzylidene)hydrazinyl)-2-oxoethoxy)phenyl)-2,6-dimethyl-
o
1,4-dihydropyridine-3,5-dicarboxylate (6): recrystallized from DMF/EtOH; mp 214-215 C; IR
1
(KBr, cm-1) 3346, 3186, 3086, 2945, 2843, 1710, 1689, 1678, 1593, 1489, 1290. H NMR
(DMSO-d6, δ/ppm): 11.52 (S, 1H, CONH), 8.82 (S, 1H, NH), 8.37 (S, 1H, CH=N), 7.36- 6.89
(m, 7H, Ar-H), 5.12 (S,1H, CH), 4.85 (S, 2H, OCH2CO), 4.63 (m, 4H, OCH2CH3), 3.85 (S, 3H,
OCH3), 3.83(S, 3H, OCH3), 2.3(S, 6H, CH3), 1.16 (t, 6H, OCH2CH3); 13C NMR (DMSO-d6,
δ/ppm): 168.5, 167.1, 149.3, 128.4, 114.5, 111.8, 102.8, 59.3, 55.8, 50.1, 42.8, 18.6, 14.6.
(E)-diethyl 2,6-dimethyl-4-(4-(2-oxo-2-(2-(3,4,5-trimethoxybenzylidene) hydrazinyl) ethoxy)
phenyl) - 1,4-dihydropyridine-3,5-dicarboxylate (7): recrystallized from DMF/EtOH; mp 212-
1
214oC; IR (KBr, cm-1) 3298, 3234, 3099, 2980, 1689, 1678,1647, 1506, 1492,1215; H NMR
(DMSO-d6, δ/ppm): 11.59 (S, 1H, CONH), 8.76 (S, 1H, NH), 7.91 (S, 1H, CH=N), 7.0-6.7 (m,
6H, Ar-H), 5.07 (S, 1H, CH), 4.8 (S, 2H, OCH2CO),3.82 (m, 4H, OCH2CH3), 3.8(S, 6H, OCH3) ,
3,69(S, 3H, OCH3), 2.24(S, 6H, CH3), 1.16 (t, 6H, OCH2CH3);13C NMR (DMSO-d6, δ/ppm):
169.7, 167.4, 164.8, 156.9,153.6, 130.0, 128.8, 128.6, 114.5, 114.2, 104.6, 102.9, 60.6, 59.4,
56.3, 18.6, 14.5.
(E)-diethyl 2,6-dimethyl-4-(4-(2-oxo-2-(2-(4-dimethylaminobenzylidene) hydrazinyl) ethoxy)
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (8): recrystallized from DMF/EtOH; mp 217-218
1
oC; IR (KBr, cm-1) 3290, 3232, 3099, 2980, 1676, 1660, 1604,1504, 1442, 1220; H NMR
(DMSO-d6, δ/ppm): 11.27 (S, 1H, CONH), 8.76 (S, 1H, NH), 7.86 (S, 1H, CH=N), 7.5-6.7 (m,
8H, Ar-H), 5.01 (S, 1H, CH), 4.8 (S, 2H, OCH2CO), 4.0 (m, 4H, OCH2CH3), 2.96 (S, 6H, N-
13
CH3), 2.24 (S, 6H, CH3), 1.16 (S, 6H, OCH2CH3); C NMR (DMSO-d6, δ/ppm): 169.0, 167.4,
156.6,152.0, 151.8, 145.50, 144.9, 128.9, 128.7, 128.6, 121.9, 114.3, 112.4, 102.6, 59.3, 18.7,
14.6.
23

ACCEPTED MANUSCRIPT
(E)-diethyl 2,6-dimethyl-4-(4-(2-oxo-2-(2-(4-methoxybenzylidene) hydrazinyl) ethoxy) phenyl)-
1,4-dihydropyridine-3,5-dicarboxylate (9): recrystalized from DMF/EtOH; mp 222-224oC; IR
(KBr, cm-1) 3315, 3095, 2926, 1678,1643,1608,1504, 1444, 1215. 1H NMR (DMSO-d6, δ/ppm):
11.43(S, 1H, CONH), 8.76(S, 1H, NH), 8.3(S, 1H, CH=N),7.9-6.7(m, 8H, Ar-H), 5.0(S, 1H,
CH), 4.8(S, 2H, OCH2CO),4.0(m, 4H, OCH2CH3), 3.98(S, 3H, OCH3), 2.24(S, 6H, CH3),1.16(S,
6H, OCH2CH3).13C NMR (DMSO-d6, δ/ppm): 169.3, 167.5, 156.8, 145.5, 141.1, 129.1, 128.60,
127.8, 114.2, 102.4, 64.9,59.4, 55.7, 43.9,18.6, 14.6.
(E)-diethyl 4-(4-(2-(2-((1H-indol-3-yl)methylene)hydrazinyl)-2-oxoethoxy)phenyl)-2,6-dimethyl-
o
1,4-dihydropyridine-3,5-dicarboxylate (10). recrystallized from MeOH; mp 230-232 C; IR
(KBr, cm-1) 3334, 3223, 3095, 2978, 1689, 1656, 1604, 1506, 1444, 1213; 1H NMR (DMSO-d6,
δ/ppm): 11.56 (S, 1H, CONH), 11.25 (S, 1H, NH-indol), 8.76 (S, 1H, NH), 8.32 (S, 1H, CH=N),
7.9-6.7 (m, 8H, Ar-H), 5.09 (S, 1H, CH), 4.8 (S, 2H, OCH2CO), 3.97 (m, 4H, OCH2CH3),
13
2.24(S, 6H, CH3), 1.15 (S, 6H, OCH2CH3); C NMR (DMSO-d6, δ/ppm): 168.8, 167.4, 145.5,
137.7, 137.4, 137.1, 131.0,128.7, 114.5,114.0, 102.4, 59.4, 43.7, 18.6, 14.6.
(E)-diethyl 2,6-dimethyl-4-(4-(2-oxo-2-(2-(4-hydroxybenzylidene) hydrazinyl) ethoxy) phenyl)-
o
1,4-dihydropyridine-3,5-dicarboxylate (11): recrystallized from MeOH; mp 237-239 C; IR
1
(KBr, cm-1) 3334,3223, 3095, 2978, 1689, 1658, 1604,1506, 1444, 1213; H NMR (DMSO-d6,
δ/ppm): 11.4 (S, 1H, CONH), 9.6 (S, 1H, OH), 8.8 (S, 1H, NH), 7.9 (S, 1H, CH=N), 7.58-6.77
(m,8H, Ar-H), 5.07 (S, 1H, CH), 4.85 (S, 2H, OCH2CO), 4.06 (m, 4H, OCH2CH3), 1.2(t, 6H,
OCH2CH3); 13C NMR (DMSO-d6, δ/ppm): 169.1, 167.4, 148.6, 145.5, 144.5, 141.6, 129.4,
129.0, 128.77, 128.6, 116.3, 114.5, 114.2, 102.5, 56.0, 59.4, 118.7, 14.6.
24

ACCEPTED MANUSCRIPT
(E)-diethyl
4-(4-(2-(2-benzylidenehydrazinyl)-2-oxoethoxy)phenyl)-2,6-dimethyl-1,4-
o
dihydropyridine-3,5-dicarboxylate (12): recrystallized from DMF/EtOH; mp 234-236 C; IR
(KBr, cm-1) 3277, 3234, 3097, 2926, 1687, 1658, 1604, 1504, 1419, 1228; 1H NMR (DMSO-d6,
δ/ppm): 11.61 (S, 1H, CONH), 8.8 (S, 1H, NH), 8.0 (S, 1H, CH=N), 7.75-6.80 (m, 9H, Ar-H),
5.12 (S, 1H, CH), 4.86 (S, 2H, OCH2CO), 4.06 (m, 4H, OCH2CH3), 2.3 (S, 6H, CH3), 1.2 (t, 6H,
OCH2CH3). 13C NMR (DMSO-d6, δ/ppm): 169.6, 167.4, 164.8, 156.8, 156.4, 148.3, 145.5,
144.1, 141.2, 134.6, 134.4, 130.3, 130.4, 129.2, 128.8, 128.6, 127.5, 127.3, 102.4, 66.9, 65.08,
59.44, 18.6, 14.6.
(E)-diethyl
4-(4-(2-(2-(4-ethylbenzylidene)hydrazinyl)-2-oxoethoxy)phenyl)-2,6-dimethyl-1,4-
o
dihydropyridine-3,5-dicarboxylate (13): recrystallized from MeOH; mp 231-232 C; IR (KBr,
1
cm-1) 3286, 3238, 3099, 2972, 1676, 1660, 1504, 1232; H NMR (DMSO-d6, δ/ppm): 11.56 (S,
1H, CONH), 8.82 (S, 1H, NH), 8.03 (S, 1H, CH=N), 7.67-6.80 (m, 8H, Ar-H), 5.1 (S, 1H, CH),
4.86 (S, 2H, OCH2CO), 4.05 (m, 4H, OCH2CH3), 2.7 (m,2H, CH2CH3), 2.3 (S, 6H, CH3), 1.2 (t,
13
6H, OCH2CH3), 1.19 (t, 3H, CH2CH3); C NMR (DMSO-d6, 100 MHz, δ/ppm): 176.6, 146.5,
144.4, 132.0, 128.7, 128.7, 127.6, 127.4, 114.2, 102.5, 59.4, 28.5, 18.6, 14.7.
(E)-diethyl 2,6-dimethyl-4-(4-(2-oxo-2-(2-(thiophen-3-ylmethylene)hydrazinyl)ethoxy) phenyl)-
o
1,4-dihydropyridine-3,5-dicarboxylate (14): recrystallized from DMF/ EteOH; mp 262-263 C;
1
IR (KBr, cm-1) 3388, 3284, 3228, 3099, 2974, 1666, 1608, 1583, 1508, 1444, 1228; H NMR
(DMSO-d6, δ/ppm): 11.51 (S, 1H, CONH), 8.77 (S, 1H, NH), 8.1 (S, 1H, CH=N), 7.66-6.65 (m,
7H, Ar-H), 4.96(S,1H, CH), 4.8 (S, 2H, OCH2CO), 4.0 (m,4H, OCH2CH3), 2.24(S, 6H, CH3),
1.52 (t, 6H, OCH2CH3); 13C NMR (DMSO-d6, δ/ppm): 167.4, 164.6, 145.7, 143.5, 139.3, 132.3,
129.5, 128.7, 128.6, 128.4, 114.4, 114.1, 102.5, 59.6, 18.6, 14.8.
25

ACCEPTED MANUSCRIPT
(E)-diethyl 2,6-dimethyl-4-(4-(2-oxo-2-(2-(4-bromobenzylidene) hydrazinyl) ethoxy) phenyl)-1,4-
o
dihydropyridine-3,5-dicarboxylate (15): recrystallized from DMF/ EteOH; mp 235-237 C; IR
(KBr, cm-1) 3311, 3275, 3097, 2981, 1676, 1647, 1604, 1506, 1489, 1226; 1H NMR (DMSO-d6,
δ/ppm): 11.63 (S, 1H, CONH), 8.77 (S, 1H, NH), 7.97 (S, 1H, CH=N), 7.64-6.33 (m, 8H, Ar-H),
5.06 (S, 1H, CH), 4.8(S, 2H, OCH2CO), 4.0(m, 4H, OCH2CH3), 2.24 (S, 6H, CH3), 1.14 (t, 6H,
OCH2CH3); 13C NMR (DMSO-d6, δ/ppm): 173.8, 165.2, 158.5, 151.8, 142.9, 135.4, 132.7,
131,2, 126.4, 114.7, 102.3, 68.7, 62.9, 42.8, 18.2, 16.6.
4.4 General procedure for the synthesis of DHP- Thiazolidin-4-one (4a-15a)
To the clear solution of dihydropyridine hydrazones of 4-15 (0.001 mol) in 20ml DMF,
thioglycolic acid (0.001mol, 0.184 g) was added and zinc chloride ( 0.001 mmol) , the reaction
mixtures was heated at 80–85 °C for 16 using an oil bath, After the completion of the reaction
(TLC ) monitoring using Hexane: EtOAc, 7:3, v/v. The mixture was poured in crash ice 150ml,
the mixture neutralized with a saturated solution of sodium carbonate. After stirring for few
minutes organic layer was separated and washed twice time with distilled water, recrystalized
from suitable solvents.
diethyl
4-(4-(2-(2-(4-chlorophenyl)-4-oxothiazolidin-3-ylamino)-2-oxoethoxy)
phenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4a): recrystallized from ethanol, Yield 53%,;
mp 230-232 oC; IR (KBr, cm-1) 3300, 3234, 3099, 2981, 1672. 1645, 1506, 1490, 1226; 1H NMR
(DMSO-d6, δ/ppm) 11.62 (S, 1H, CONH), 8.76 (S, 1H, NH), 7.72-6.74 (m, 8H, Ar-H), 5.9/5.45
(S, 1H, N-CH-S), 5.06 (S, 1H, CH), 4.8 (S, 2H, OCH2CO), 3.99 (m, 4H, OCH2CH3), 3.88 (m,
13
1H, SCH2), 3.65 (d, 1H, SCH2), 2.24 (S, 6H, CH3), 1.16 (t, 6H, OCH2CH3); C NMR (DMSO-
d6, δ/ppm), 169.7, 167.4, 166.5, 147.0, 145.5, 130.5, 129.3, 129.2, 129.0, 128.8, 128.6, 114.5,
26

ACCEPTED MANUSCRIPT
114.2, 102.4, 79.6, 74.9, 59.4, 43.2, 29.1, 28.7, 14.6; HRMS (ESI), C30H32ClN3O7S, calculated
[M+H] 615.1096, observed [M+H] 615.2225.
diethyl 4-(4-(2-(2-(3,4-dimethoxyphenyl)-4-oxothiazolidin-3-ylamino)-2-oxoethoxy) phenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (6a): recrystallized from CHCl3, (Yield 54%);
o
mp 228-229 C; IR (KBr, cm-1) 3346, 3186, 3086, 2945, 2843, 1710, 1689, 1678, 1593, 1489,
1
1290; H NMR (DMSO-d6, δ/ppm), 11.52/11.44 (d,1H, CONH), 8.84(S, 1H, NH), 7.21-6.91
(m,7H, Ar-H), 5.52 (S,1H, N-CH-S), 5.16 (S, 1H, CH), 4.80 (S, OCH2CO), 3.65 (d, 1H, S-CH2),
3.74(d, 1H, S-CH2), 4.43 (m, 4H, OCH2CH3), 4.04 (S, 3H, OCH3), 3.86 (S,3H, OCH3), 2.3(S,
6H, CH3), 1.19 (t, 6H, OCH2CH3); 13C NMR (DMSO-d6, δ/ppm), 168.7, 167.3, 165.0, 145.6,
139.4, 129.4, 128.8, 128.4, 114.5, 102.6, 79.8, 74.3, 67.7, 59.3, 50.2, 44.3, 28.7, 14.5; HRMS
(ESI), C32H37N3O9S, calculated [M+H] 640.6682, observed [M+H] 640.1580.
diethyl
2,6-dimethyl-4-(4-(2-oxo-2-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-
ylamino)ethoxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (7a): recrystallized from CHCl3,
(Yield 47%); mp 215-217 oC; IR (KBr, cm-1) 3339, 3172, 3083, 2947, 2883, 1711, 1681, 1675,
1
1590, 1487, 1290; H NMR (DMSO-d6, δ/ppm), 11.59/11.49 (S, 1H, CONH), 8.76 (S, 1H,NH),
7.0-6.73 (m, 6H, Ar-H), 6.54/ 5.65 (S, 1H, N-CH-S), 5.07 (S, 1H , CH), 4.84 (S, 2H, OCH2CO),
4.80 (S, 2H, S-CH2), 3.88 (m, 4H, OCH2CH3), 3.8 (S, 6H, OCH3), 3.69 (S, 3H, OCH3), 3.66 (m,
1H, S-CH2), 3.51 (m, 1H, S-CH2), 2.24 (S, 6H, CH3), 1.14 (t, 6H, OCH2CH3); 13C NMR
(DMSO-d6, δ/ppm), 167.7, 166.4, 165.0, 146.7, 139.4, 129.4, 127.9, 127.4, 114.6, 102.7, 8.9,
75.6, 67.8, 59.3, 50.3, 44.3, 28.8, 14.5; HRMS (ESI), C33H39N3O10S, calculated [M+H]
670.7428, observed [M+H] 670.3013.
diethyl 4-(4-(2-(2-(4-(dimethylamino)phenyl)-4-oxothiazolidin-3-ylamino)-2-oxoethoxy) phenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (8a): recrystallized from CHCl3, (Yield
27

ACCEPTED MANUSCRIPT
o
42%); mp 207-208 C; IR (KBr, cm-1) 3277, 3086, 3017, 2984, 2931, 1684, 1668, 1648, 1506,
1
1447, 1213; H NMR (DMSO-d6, δ/ppm), 11.27/11.19 (S, 1H, CONH), 8.76 (S, 1H, NH), 8.0-
6.8 (m, 8H, Ar-H), 6.41/5.65 (S, 1H, N-CH-S), 4.79(S, 1H, CH), 4.5 (S, 2H, OCH2CO), 3.98 (m,
4H, OCH2CH3), 3.78 (d, 1H, S-CH2), 3.76 (d, 1H, S-CH2), 3.1(S, 6H, N-CH3), 2.24(S, 6H, CH3),
1.16 (t, 6H, OCH2CH3, J =7 MHz);13C NMR (DMSO-d6, δ/ppm), 170.9, 167.4, 164.4, 145.6,
129.4, 129.0, 128.2, 114.3, 102.4, 79.78, 74.8, 59.1, 43.7, 28.0, 18.7, 14.6; HRMS (ESI),
C32H38N4O7S, calculated [M+H] 623.7327, observed [M+H] 623.0603.
diethyl
4-(4-(2-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-ylamino)-2-oxoethoxy)phenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (9a): recrystallized from CHCl3, (Yield 49%);
o
mp 190-192 C; IR (KBr, cm-1) 3300, 3087, 3029, 2981, 2929, 1691, 1668, 1660, 1508, 1438,
1207; 1H NMR (DMSO-d6, δ/ppm), 11.43/11.38 (d, 1H, CONH), 8.76 (S, 1H,NH), 7.03-6.7 (m,
8H, Ar-H), 6.5/5.6 (S, 1H, N-CH-S), 5.03 (S, 1H, CH), 4.8 (S, 2H, OCH2CO), 4.0 (m, 4H,
OCH2CH3), 3.8(S, 3H, OCH3), 3.63(d, 1H, S-CH2), 3.52(d, 1H, S-CH2), 2.24(S, 6H, CH3),
13
1.14(t,6H, OCH2CH3). C NMR (DMSO-d6, δ/ppm), 169.3, 167.5, 156.8, 145.5, 141.1, 129.4,
128.8, 128.6, 127.7, 114.6, 102.4, 64.9, 59.4, 55.7, 43.9, 28.6, 14.6; HRMS (ESI), C31H35N3O8S,
calculated [M+H] 610.6909, observed [M+H] 610.2073.
diethyl
4-(4-(2-(2-(1H-indol-3-yl)-4-oxothiazolidin-3-ylamino)-2-oxoethoxy)phenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (10a): recrystallized from ethanol, (Yield 45%,);
o
mp 221-222 C; IR (KBr, cm-1) 3267, 3086, 3027, 2980, 2931, 1689, 1678, 1658, 1506, 1442,
1
1215; H NMR (DMSO-d6, δ/ppm), 11.61 (S, 1H, CONH), 11.25 (S, 1H, NH-indol), 8.76 (S,
1H, NH), 7.81-6.75 (m, 9H, Ar-H), 6.56/5.21 (S, 1H, N-CH-S), 5.06 (S, 1H, CH), 4.80 (S, 2H,
OCH2CO), 4.02 (m, 4H, OCH2CH3), 3.80 (d, 1H, S-CH2), 3.72 (d, 1H, S-CH2), 2.24 (S, 6H,
28