H5BW12O40-Catalyzed syntheses of 1,4-dihydropyridines and polyhydroquinolines via Hantzsch reaction: Joint experimental and computational studies

Article abstract of DOI:10.1016/j.molstruc.2019.127011

A series of polyhydroquinoline derivatives were effectively synthesized via Hantzsch reaction in high yields in the presence of catalytic amounts of a highly negatively charged borotungstic acid H5BW12O40 in refluxing EtOH under green and mild reaction co

Full text of DOI:10.1016/j.molstruc.2019.127011

Journal of Molecular Structure 1199 (2020) 127011
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
H BW O -Catalyzed syntheses of 1,4-dihydropyridines and
5
12 40
polyhydroquinolines via Hantzsch reaction: Joint experimental and
computational studies
a
a
,
**
a
b, *
Tayebeh Momeni , Majid M. Heravi
, Tayebeh Hosseinnejad , Masoud Mirzaei
,
a
Vahideh Zadsirjan
Department of Chemistry, Alzahra University, Vanak, Tehran, Iran
a
b
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2019
Received in revised form
A series of polyhydroquinoline derivatives were effectively synthesized via Hantzsch reaction in high
yields in the presence of catalytic amounts of a highly negatively charged borotungstic acid H5BW12O40
in refluxing EtOH under green and mild reaction conditions. It is a Keggin-type heteropoly acid with a
higher negative charge and strong Brønsted acidity. Moreover, a comparative mechanistical analysis of
Hantzsch reaction was made based on the structural, thermodynamical and electronic properties along
the reaction pathway using density functional theory (DFT) and quantum theory of atoms in molecules
30 August 2019
Accepted 31 August 2019
Available online 4 September 2019
(
QTAIM) approaches.
Keywords:
©
2019 Elsevier B.V. All rights reserved.
1,4-Dihydropyridines
Keggin
Hantzsch reaction
Dimedone
1,3-Cyclohexanediones
Polyhydroquinoline
DFT
1
. Introduction
and their derivatives, several of them were found being biologi-
cally, pharmacologically and medicinally are very important com-
pounds. As a matter of fact, nowadays, some important prescribed
drug such as nifedipine A (with the brand name of Adalat) as well as
Multicomponent reactions (MCRs) have attracted much atten-
tion and stirred up the interest of synthetic organic chemists as well
as those who are engaged in combinatorial chemistry due to their
broad increment of molecular diversity and high atom economy
effectiveness [1,2]. Although, MCRs can provide a library of inter-
esting organic compounds and conducted in a one pot fashion, they
still agonize from several drawbacks, such as usage of excessive
amount of reagents and toxic solvents, some should have been
performed under harsh reaction conditions and requiring long re-
action time [3].
2
þ
amlodipine and B, nicardipine C (Fig. 1) are known as a major Ca
channels blockers, that are extensively used for treatment of
several conditions such as hypertension and angina (Fig. 1) [4,5].
4-Aryl-1,4-dihydropyridines are found being analogues of NADH
coenzymes, which have been known for acting as calcium channel
blockers. Their unique heterocyclic moieties are found in a several
bioactive compounds such as bronchodilator, antiatherosclerotic,
antitumor, vasodilator, antidiabetic, geroprotective, and heptapro-
tective agents [6]. Due to these biological importance, poly-
hydroquinoline derivatives not only have stirred up the interest of
organic synthetic chemists but also represent a challenging
research area. Thus, several approaches have been achieved and
reported for their synthesis. Among them, the most familiar and
frequently operated is the classical Hantzsch MCR including, an
appropriate aldehyde, ethyl acetoacetate, and ammonia as source of
nitrogen in AcOH or alcohols under reflux conditions [7,8]. Never-
theless, these methods show their merits as well suffer from many
The Hantzsch pseudo-four-component reaction is the oldest
(
this reaction was reported by Arthur Rudolf Hantzsch in 1881) and
most generally established strategy for the synthesis of 1,4-DHPs
*
Corresponding author.
*
* Corresponding author.
E-mail addresses: mmheravi@alzahra.ac.ir (M.M. Heravi), mirzaeesh@um.ac.ir
(
M. Mirzaei).
https://doi.org/10.1016/j.molstruc.2019.127011
022-2860/© 2019 Elsevier B.V. All rights reserved.
0

2
T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
Fig. 1. Selected examples of 1,4-dihydropyridines (DHPs) demonstrating pharmacological activity.
drawbacks such as a being done in long reaction times, requiring an
excess of organic solvent, giving low product yields, and under
harsh refluxing conditions. Thus, introductions of other alternative
methods for the synthesis of polyhydroquinoline derivatives, which
are more effective, being performed under milder reaction condi-
tions and giving higher product yields [9] are still in much demand.
Keggin type heteropoly acids (HPAs) are the most effective and
promising solid acid as proton donors. HPAs are hydrous acids
which retain the highest proton conductivity at ambient temper-
ature in comparison with other inorganic solid acids as proton
were known, thus the synthesis of the products were convention-
ally confirmed by comparison of their melting points, measured by
using the capillary tube method with an electro thermal 9200
apparatus, and FTIR spectra with authentic samples. As a matter of
certainty, the H NMR spectra of compounds 5c and 5f were
measured and the for some selected products, NMR spectra are also
given with the related references.
1
2.1. Synthesis of 1,4-dihydropyridines and 4-Aryl-1,4-
dihydropyridines: General Procedure.
doners [10e14]. HPAs are placed in to
metaleoxygen clusters of early transition metals with general for-
mula of H [X ], in which M is the addenda atom and X is the
heteroatom [14e16]. Two acquainted HPAs are silicotungstic acid
SiWA, H SiW12 40) and phosphotungstic acid (PWA, H
a large family of
A mixture of an appropriate aldehyde (1 mmol), ammonium
acetate (1 mmol) and ethylacetoacetate (2 mmol) or dimedone
(1 mmol), ethylacetoacetate (1 mmol) in the presence of catalytic
z
x m y
M O
(
4
O
3
PW12
O
40
)
amount of (H BW12O40) (10 mol %) was refluxed in EtOH (5 ml) for
5
which both have the same Keggin structure (i.e. x ¼ 1, m ¼ 12, and
y ¼ 40). A Keggin-type heteropoly acid has a higher negative charge
and strong Brønsted acidity. An increase in the number of protons
in Keggin heteropolyanions decreases the acidic strength [17,18].
We are interested in the catalytic activity of HPAs in organic
transformations [19e21] especially those leading to construction of
different heterocycles via MCR [23]. In this regard we have
reviewed the applications of HPAs as effective catalysts, from
different points of view [24,25]. In continuation of theses interests,
in this paper we successfully examined a highly negatively charged
borotungstic acid H5BW12O40 (hereafter denoted as BWA), where
the indicated reaction time. The progress of the reaction was
monitored by TLC (7:3 n-hexane/ethylacetate). After the comple-
tion of the reaction, water (5 ml) was added to the mixture. The
organic layer was extracted with ethyl acetate, dried over anhy-
drous sodium sulphate and filtered using an ordinary funnel and
filter paper by gravity. The filtrate was evaporated under reduced
pressure and the crude products were purified by recrystallization
from a mixture of ethylacetate/n-hexane to give the corresponding
products. These products were identified by comparison of their
melting points along with their FTIR spectra and in two cases (5c
1
and 5f) H NMR.
3þ
B
is the central heteroatom, as an effective catalyst in the syn-
thesis of a series of polyhydroquinoline derivatives via the Hantzsch
pyridine synthesis. Concentrated on joint experimental and
computational methods, as the authors we have recently reviewed
the synthesis and properties of Hantzsch-type compounds via
combined experimental and computational viewpoints [26].
In continuation of our recent interest in joint experimental and
computational investigations on the synthesis and design of het-
erogeneous catalysts [27e30] and also mechanistical properties of
catalyzed organic reactions [31e33], In this respect, we applied
quantum chemistry approaches to obtain accurate computational
information on the energetics and electronic aspects of reaction
pathways and present sound interpretations on the priority of its
mechanistically aspects and feature.
2
2
.2. Selected spectral data
.2.1. Ethyl-2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline- 3-carboxylate (5a):[35]
FT-IR (KBr):
max ¼ 3288, 3218, 3080, 3029, 2959, 2930, 1871,
699, 1610, 1484 cm ; H NMR (CDCl
eCH ), 1.04 (3H, s, eCH
), 1.21 (3H, t, J ¼ 7.20 Hz, eCH
4H, m, eCH ), 2.30 (3H, s, eCH
), 4.06 (2H, q, J ¼ 7.20 Hz, eOCH
.66 (1H, s, eCH) 5.05 (NH, s), 7.11e7.31 (5H, m, AreH). C NMR
, 75 MHz):
¼ 14.42, 19.55, 27.33, 29.77, 32.93, 36.88, 41.02,
1.04, 60.03, 106.17, 112.13, 126.22, 128.18, 128.23, 144.08, 147.33,
y
ꢀ
1 1
1
3
, 300 MHz):
d
¼ 0.92 (3H, s,
), 2.10e2.26
),
3
3
3
(
4
2
3
2
13
(CDCl
3
d
5
149.26, 167.73, 196.09.
2.1.2. Ethyl-2,7,7-trimethyl-5-oxo-4-p-tolyl-1,4,5,6,7,8-
2
. Experimental
hexahydroquinoline-3-carboxylate (5b) [35]
FT-IR (KBr):
max ¼ 3275, 3206, 3022, 2930, 1702, 1647,
1492 cm ; H NMR (CDCl , 300 MHz): ), 1.06
¼ 0.94 (3H, s, eCH
(3H, s, eCH ), 2.11e2.21 (4H, m,
), 1.22 (3H, t, J ¼ 6.40 Hz, eCH
eCH ), 2.25 (3H, s, eCH ), 2.33 (3H, s, eCH ), 4.07 (2H, q,
J ¼ 6.40 Hz, eOCH ), 5.00 (1H, s, eCH), 6.49 (NH, s), 7.00 (2H, d,
J ¼ 7.60 Hz, AreH), 7.19 (2H, d, J ¼ 8.0 Hz AreH). C NMR (CDCl
75 MHz):
y
ꢀ
1 1
All chemicals employed to study of the catalytic behavior of the
3
d
3
BWA were purchased from Aldrich Merck Company and used as
received without further purification. Heteropoly acid, H
BWA) was prepared, following the literature [34]. Melting points
3
3
5
BW12
O
40
2
3
3
(
2
13
were measured by an electrothermal 9200 apparatus. IR spectra
were recorded on the FT-IR Tensor Spectrophotometer. Nuclear
magnetic resonance (NMR) spectra were recorded on a Bruker
3
,
d
¼ 14.51, 19.52, 21.36, 27.43, 29.79, 32.93, 36.39, 41.14,
51.09, 60.04, 106.36, 112.39, 128.13, 128.80, 135.63, 143.82, 144.51,
148.94, 167.87, 195.92.
3
AVANCE 400 MHz Spectrometer in CDCl as a solvent. All products

T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
3
2.2.3. Ethyl-2,7,7-Trimethyl-5-oxo-4-(4-methoxyphenyl)-1,4,5,6,7,8
128.06, 128.21, 144.45, 148.02, 168.09.
hexahydroquinoline ꢀ3 -carboxylate (5c) [36]
FT-IR (KBr):
y
max ¼ 3276, 2957, 1701, 1648, 1605, 1494, 1380,
2.2.9. Diethyl 2,6-dimethyl-4-(4-methoxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (6b) [38]
ꢀ
1 1
1
215, 1033 cm ; H NMR(CDCl
3
, 300 MHz)
d
¼ 0.94 (3H, s, eCH
3
),
1
.07 (3H, s, eCH
eCH ), 2.31e2.37 (4H, m, 2CH
J ¼ 7.2 Hz, OCH
m, AreH), 7.20e7.26 (2H, m, AreH). C NMR (CDCl
¼ 14.2, 16.3, 27.2, 27.2, 31.7, 41.7, 43.5, 51.3, 55.9, 61.7, 102.3, 111.9,
14.2, 130.1, 134.5, 149.5, 150.7, 157.7, 167.2, 198.9.
3
), 1.21 (3H, t, J ¼ 7.2 Hz, eCH
3
), 2.13e2.27 (3H, m,
FT-IR (KBr):
1251, 1198, 1041, 568 cm , H NMR: (DMSO, 300 MHz):
1H, NH), 7.03 (d, 2H, J ¼ 8.4 Hz, AreH), 6.74 (d, 2H, J ¼ 8.4 Hz, AreH),
4.78 (s, 1H), 397 (m, 4H, 2CH ), 3.66 (s, 3H, eOCH ), 2.23 (s, 6H,
2CH ); C NMR (DMSO, 100 MHz):
y
max ¼ 3233, 2933, 2804, 1656, 1609, 1489, 1515,
ꢀ
1 1
2
2
), 3.74 (3H, s, eCH
3
), 4.06 (2H,q,
d
¼ 8.73 (s,
2
), 5.00 (1H, s, CH), 6.01 (1H, s, NH), 6.72e6.75 (2H,
13
3
, 75 MHz):
2
3
13
d
1
3
), 1.12 (t, 6H, J ¼ 7.2 Hz, 2CH
3
d
1
¼ 166.9, 157.4, 144.9, 140.4, 128.2, 113.1, 102.1, 58.9, 54.8, 37.9, 18.1,
4.1.
2
1
.2.4. Ethyl-2,7,7-trimethyl-4-(3-nitrophenyl)-5-oxo-
,4,5,6,7,8hexahydroquinoline-3-carboxylate (5d) [35]
FT-IR (KBr):
max ¼ 3283, 3210, 3076, 2957, 1704, 1643, 1534,
485, 1380, 1351, 1210 cm
1H, t, J ¼ 1.8 Hz, AreH), 8.02e7.94 (1H, m, AreH), 7.73 (1H, d,
2.2.10. Diethyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (6c) [38]
y
ꢀ1
1
1
(
;
H NMR (400 MHz, CDCl
3
)
d
¼ 8.11
FT-IR (KBr):
1214, 1044, 788 cm ; H NMR: (DMSO, 300 MHz):
NH), 7.98 (dd, 1H, J ¼ 2.1 Hz, AreH), 7.55 (m, 3H), 4.94 (s, 1H), 3.97
y
max ¼ 3345, 2988, 1707, 1645, 1528, 1486, 1352,
ꢀ
1 1
d
¼ 8.99 (s, 1H,
J ¼ 7.7 Hz), 7.37 (1H, t, J ¼ 7.9 Hz), 6.39 (1H, d, J ¼ 6.6 Hz, eNH), 5.16
1
3
(
(
1H, s, eCH), 4.07 (2H, q, J ¼ 7.1 Hz, eOCH
3H, t, J ¼ 7.1 Hz, eCH ), 1.09 (3H, s, eCH
, 75 MHz):
1.2; 104.8; 111.2; 121.3; 122.6; 128.7; 134.7; 144.7; 148.3; 164.7;
67.3; 195.5.
2
), 2.42e2.11 (7H, m), 1.20
(m, 4H, 2CH
NMR (DMSO, 75 MHz):
121.8, 121.0, 101.0, 59.1, 39.2, 18.1, 14.0.
2
), 2.27 (s, 6H, 2CH
3
), 1.10 (t, 6H, J ¼ 7.2 Hz, 2CH
3
);
C
13
3
3
), 0.93 (3H, s, eCH
3
).
C
d
¼ 166.4, 150.2, 147.3, 146.3, 134.1, 129.5,
NMR (CDCl
5
1
3
d
¼ 19.5; 27.0; 29.3; 32.7; 36.7; 40.9; 50.5;
2.2.11. Diethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro
pyridine-3,5-dicarboxylate (6d) [39]
2
.2.5. Ethyl-2,7,7-trimethyl-4-(4-nitrophenyl)-5-oxo-1,4,5,6,7,8
hexahydroquinoline - 3-carboxylate (5e) [35]
FT-IR (KBr):
max ¼ 3275, 3190, 3073, 2965, 1703, 1648, 1517,
492, 1376, 1344, 1279 cm
3H, s, eCH ), 1.08 (3H, s, eCH
.16e2.36 (4H, m, eCH ), 2.40 (3H, s, eCH
), 5.15 (1H, s, eCH), 6.31 (NH, s), 7.50 (2H, d, J ¼ 7.80 Hz,
FT-IR (KBr):
y
max ¼ 3248, 3102, 1647, 1518, 1488, 1347, 1252, 863.
cm ; H NMR (DMSO, 400 MHz): ),
¼ 1.27 (t, 6H, J ¼ 7.3 Hz, eCH
2.13 (s, 6H, eCH ), 4.85 (1H,
), 4.35 (m, 4H, J ¼ 5.9 Hz, eOCH
ꢀ1 1
d
3
y
3
2
ꢀ
1
1
1
(
2
;
H NMR (CDCl
), 1.82 (3H, t, J ¼ 7.10 Hz, eCH
), 4.04 (2H, q, J ¼ 7.80 Hz,
3
, 300 MHz):
d
¼ 0.90
eNHe), 5.79 (s, 1H, eCH), 7.51 (d, 2H, J ¼ 7.8 Hz, AreH), 7.59 (d, 2H,
13
3
3
3
),
J ¼ 7.8 Hz, AreH); C NMR (DMSO, 100 MHz):
d
¼ 15.1, 17.8, 45.7,
2
3
63.3, 96.6, 128.1, 128.7, 132.5, 145.2, 148.3, 167.5.
eOCH
2
1
3
AreH), 8.09 (2H, d, J ¼ 7.8 Hz, AreH). C NMR (CDCl
¼ 14.33, 18.97, 27.03, 29.57, 32.54, 37.29, 50.74, 59.79,103.47,
10.27, 123.14, 129.03, 145.99, 146.04, 150.294, 155.23,167.14, 195.47.
3
,75 MHz):
2.2.12. Diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (6e) [40]
d
1
FT-IR (KBr):
y
max ¼ 3345, 1707, 1645, 1486, 1214, 1044, 788 cm
H NMR (CDCl , 250 MHz): CH ),
¼ 1.25 (t, 6H, J ¼ 7.1 Hz, 2CH
2.29 (s, 6H, 2CH CH ), 4.96 (s, 1H, CH),
), 4.10 (q, 4H, J ¼ 7.1 Hz, 2CH
6.47 (s, 1H, NH), 7.16 (d, 2H, J ¼ 8.4 Hz, AreH), 7.33 (d, 2H, J ¼ 8.4 Hz,
ꢀ
1; 1
3
d
3
2
2
.2.6. Ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (5f). [37]
FT-IR (KBr):
max ¼ 3274, 3206, 3076, 2934, 2871, 1706, 1604,
491, 1381, 1214, 1108, 856. cm
¼ 0.84 (s, 3H, eCH ), 0.99 (s, 3H, eCH
eCH ), 2.06 (dd, 2H, eCH ), 2.13 (dd, 2H, eCH
.99 (q, 2H, J ¼ 7.3 Hz, eOCH ), 4.95 (s, 1H, eCH), 7.08 (d, 2H,
J ¼ 9.3 Hz, AreH), 7.18 (d, 2H, J ¼ 9.4 Hz, AreH), 7.93 (1H, eNHe).
3
3
2
13
y
AreH); C NMR (CDCl
3
, 62.9 MHz):
d
¼ 14.2, 19.3, 39.3, 59.8, 103.4,
ꢀ
1
1
1
d
;
H NMR (DMSO, 400 MHz):
), 1.14 (t, 3H, J ¼ 7.2 Hz,
), 2.28 (s, 3H, eCH ),
119.8, 130.0, 130.8, 144.5, 146.9, 167.6.
3
3
3
2
2
3
2.2.13. Diethyl 4-(4-chlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate (6f) [39]
3
2
FT-IR (KBr):
y
max ¼ 3357, 2987, 1694, 1486, 1461, 1333, 1261,
H NMR (DMSO, 400 MHz):
¼ 1.23 (t, 6H, J ¼ 7.1 Hz,
), 2.27 (s, 6H, eCH ), 4.87 (1H,
), 4.17 (m, 4H, J ¼ 5.7 Hz, eOCH
1
3
ꢀ1
1
C NMR (DMSO, 100 MHz):
0.8, 51.2, 60.1, 77.8, 105.3, 111.5, 128.2, 129.8, 131.7, 146.5, 150.1,
67.8, 195.7;
d
¼ 14.8, 19.2, 27.4, 29.9, 32.8, 36.6,
881 cm
eCH
;
d
4
1
3
3
2
eNHe), 5.68 (s, 1H, eCH), 7.41 (d, 2H, J ¼ 7.9 Hz, AreH), 7.57 (d, 2H,
13
J ¼ 7.8 Hz, AreH); C NMR (DMSO, 100 MHz):
d
¼ 14.3, 14.9, 45.9,
2
.2.7. Ethyl-4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate (5g) [35]
FT-IR (KBr):
max ¼ 3275, 3242, 3075, 2959, 2935, 1703, 1648,
604, 1421, 1380, 1279, 1214, 1071, 842, 533. cm ; H NMR (CDCl
00 MHz): ), 1.06 (3H, s, eCH ), 1.19 (3H, t,
¼ 0.91 (3H, s, eCH
J ¼ 7.10 Hz,eCH ), 2.14e2.32 (4H, m, eCH ), 2.35 (3H, s, eCH ), 4.05
2H, q, J ¼ 7.10 Hz, eOCH ), 5.00 (1H, s, eCH), 6.58 (NH, s), 7.19 (2H,
61.3, 97.6, 127.1, 128.3, 134.8, 143.2, 147.1, 167.
y
3. Results and discussion
ꢀ1 1
1
3
3
,
d
3
3
We recently reviewed the applications of dimedone in the
synthesis of various hetrocyclic systems including the synthesis of
polyhydroquinoline via Hantzsch reaction [41]. During our last
longing experiences (about 2 decades) a specific HPA so-called
3
2
3
(
2
13
d, J ¼ 7.60 Hz, AreH), 7.30 (2H, d, J ¼ 7.70 Hz, AreH). CNMR (CDCl
3
,
7
6
1
5 MHz):
0.14, 105.89, 111.84, 120.09, 130.04, 131.10, 144.14, 146.46, 149.06,
67.54, 195.98.
d
¼ 14.44, 19.63, 27.35, 29.74, 32.98, 36.54, 41.18, 50.98,
5
H BW12O40 (BWA), has attracted our special attention. Since this
3
þ
heteropoly acid has B as the central heteroatom, we thought it is
worthy to test its catalytic activity as an easily accessible (inex-
pensively) catalyst and compare it with that of known but expen-
sive and not easily to handle boron tetrafluoride etherate [42e44]
as a strong Lewis acid in the synthesis of different heterocycles via
MCR which has been our ever interest for the years.
2
.2.8. Diethyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate (6a) [35]
FT-IR (KBr):
max ¼ 3342, 2934, 1689, 1651, 1489, 1247, 1123,
090, 701 cmꢀ1; H NMR (CDCl
J ¼ 7.05 Hz, eCH ), 2.31 (6H, s, eCH
eOCH ), 4.99 (1H, s, eCH), 5.81 (NH, s), 7.14e7.25 (5H, m, AreH).
NMR (CDCl , 75 MHz):
¼ 14.52, 19.81, 39.84, 60.02, 104.12, 126.31,
y
1
1
3
, 300 MHz):
d
¼ 1.22 (6H, t,
To obtain the polyhydroquinoline derivatives via Hantzsch re-
3
3
), 4.09 (4H, q, J ¼ 6.80 Hz,
action, different Lewis acids such as TiCl
[Ce(SO $4H O] [46], Zr-SBA-16 [47], and Brønsted acids such
[(CH SO HMIM][HSO ] [48], MIL-101-SO H [49], ([DDPA][HSO ])
2 2 3
/Nano-g-Al O [45],
1
3
2
C
4
)
2
2
3
d
2
)
4
3
4
3
4

4
T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
[
50] have been used as effective catalysts.
Armed with these experiences, initially, in the presence of BWA
conditions provided the corresponding products in 72% yield
(Table 1, entries 6). Particularly, the best results (94% yields) was
obtained when the model reaction was conducted in EtOH at reflux
temperature (Table 1, entry 7). Thus, EtOH was selected as the
solvent of choice. In order to find the influence of temperature, the
as an acidic catalyst, in ethanol as solvent, at reflux condition, a
four-component reaction (as a model reaction) involving, benzal-
dehyde, ethylacetoacetate, dimedone, and ammonium acetate was
performed. The progress of reaction was monitored by TLC (using
5 40
model reaction was conducted in the presence of H BW12O
7
:3 n-hexane/ethylacetate as eluent). This reaction was proceeded
(BWA) in EtOH at ambient temperature giving only 50% yield
(Table 1, entry 8). This model reaction then was refluxed in EtOH
which resulted in the desired products in highest yield (94% yield)
(Table 1, entry 6). At last, to optimize the catalyst loading we con-
ducted the model reaction in the presence of 5 mol%, BWA. The
expected product was isolated at 85%, showing the importance of
the presence of a catalyst particularly a one such as BWA, (Table 1,
entry 9). Then, traditionally, we increased the amount gradually
from 5 mol% to 10 mol%. The yield of reactions was increased from
85% to 94% (Table 1, entry 7). The improvement of the yield by
increasing the BWA quantity can be rationalized to the possible
increase in the number of available active sites, as well as increasing
the amount of contact and collision chance between the BWA
surface with the molecules of the starting materials. Notably, that
further increase in the loaded BWA amount from 10 mol% to 15 mol
% the yields and reaction times did not change, significantly.
(Table 1, entry 10). Thus, 10 mol% of catalyst selected as the optimal
catalyst loading (Table 1, entry 7). The best results were obtained
when 1 mmol of aldehyde, 1 mmol of dimedone, 1 mmol of
smoothly and cleanly, to completion to give the corresponding
polyhydroquinoline derivative in satisfactory yield (Scheme 1).
The reaction conditions were optimized using the aforemen-
tioned model reaction comprising benzaldehyde, ethyl-
acetoacetate, dimedone, and ammonium acetate. The results are
shown in Table 1. We performed the model reaction by grinding,
under solvent-free conditions, the reaction proceeded, insignifi-
cantly. Then, we added our catalyst to the above system. By
grinding the mixture, the reaction proceeded, sluggishly. Thus, we
then examined the effects of solvents, both, polar and nonpolar. To
select the best solvent, the model reaction was run in refluxing
water as the green and plentiful solvent which gave the desired
compound 5a in 27% yield (Table 1, entry 1).
In addition to water, we examined, EtOH/H
COOCH CH3. As indicated in Table 1, when the model reaction
was run in EtOH/H O at reflux temperature, gave the expected
product 5a in only 63% yield (Table 1, entry 3). When CH Cl was
used product 5a was obtained in 20% yield (Table 1, entry 2).
CH COOCH CH and CH CN gave the respective products in, 13 and
2 2 2 3
O, CH Cl , CH CN,
CH
3
2
2
2
2
3
2
3
3
ammonium acetate and 10 mol% H
5
BW12O40 (BWA) in EtOH was
57% yield respectively (Table 1, entries 4 and 5) and in solvent-free
refluxed to give the corresponding desired product in 94% yield
5
Scheme 1. H BW12O40 catalyzed symmetrical and unsymmetrical Hantzsch reaction.
Table 1
Optimization of reaction conditions for Hantzsch reaction.
Entry
Solvent
Temperature
Time (min)
Catalyst amount (mol%)
Yield (%)
1
2
3
4
5
6
7
8
9
H
CH
EtOH/H
CH
CH
Non-solvent
EtOH
EtOH
EtOH
EtOH
2
O
Cl
2 2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Room
Reflux
Reflux
600
720
240
420
120
120
45
120
60
45
10
10
10
10
10
10
10
10
5
27
20
63
13
57
72
94
50
85
94
2
O
3
COOEt
CN
3
10
15

T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
5
Table 2
BW12O40 catalyzed Hantzsch reaction under reflux condition in EtOH.
H
5
Entry
Product
R1
Yield (%)
Time (min)
mp (ºC) Found
mp (ºC) Lit
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
6d
6e
6f
H
4-CH
4- OCH
3-NO
4-NO
4-Cl
4-Br
2-OCH
H
94
91
92
93
98
90
90
88
87
85
88
89
84
84
45
60
60
50
45
45
45
60
90
100
90
90
90
90
195e199
255e257
255e257
180e183
235e240
240e242
253e255
238e240
135e140
160e161
158e160
124e127
160e164
140e143
202-204 [36]
259-261 [36]
255-257 [35]
173-177 [36]
241-243 [36]
244-246 [35]
254-256 [38]
e
3
3
2
2
3
140-142 [40]
163-168 [40]
163-164 [40]
128-132 [40]
162-164 [39]
145-147 [40]
10
11
12
13
14
4-OCH
3
3-NO
4-NO
4-Br
4-Cl
2
2
after 45 min (Table 1, entery 7).
Under the optimal conditions, we investigated the substrate
scopes and limitations of this MCR Various aromatic aldehydes
containing both electron-releasing or electron-withdrawing sub-
stituents on the aromatic ring in the ortho, meta, and para posi-
tions, gave the corresponding products in high yields as indicated in
Table 2.
To compare the advantages of this catalyst, its catalytic activity
was compared by those other catalyst, previously reported, such as
silica coated nano-Fe
36], -Al -nanoparticles [42], molecular sieve supported
lanthanum [43], Bakers’ yeast [47], Ionic liquid (TBA-AMPS) [44]
Table 3). As can be seen in Table 3, the catalytic activity of BWA was
3 4
O supported basic ionic liquid (BIL@MNP)
[
g
2 3
O
(
compared with diverse catalysts such as which have been previ-
ously employed as catalysts in our model reaction. As it can
compared BWA is doing best among others, catalyst can mediate. In
addition, it provides the corresponding products in short reaction
time.
Fig. 2. Recyclability of catalyst for Hantzsch reaction.
3.1. Catalyst reusability
could be removed easily by evaporation of the solvent. After re-
covery of the catalyst, it was washed with EtOAc, dried at 130 C for
Noticeably, as it can be realized from Fig. 2, we studied the
ꢁ
reusability of the catalyst. Initially, the model reaction was done in
the presence of the freshly prepared BAW under the already
secured optimal reaction. The catalyst was soluble in EtOH and
1
h, and re-used in the same model reaction. The recycled catalyst
and recycled catalyst were used for three consecutive reactions
Table 3
The comparison of the catalytic activity of H
5
BW12
O40 with formerly reported catalysts.
Entry Catalyst
Time
Catalyst Amount Temperature
Solvent
Yield (%) Ref.
ꢁ
ꢁ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
silica coated nano-Fe
-Al -nanoparticles
Ionic liquid (TBA-AMPS)
Molecular sieve supported lanthanum
Tetrabutylammonium hexatungstate [TBA]
3
O
4
supported basic ionic liquid (BIL@MNP)
15 min 0.25 mmol%
10 min 0.2 mg
70
90
C
C
Solvent free
Solvent free
CH OH
3
EtOH
Solvent free
CH CN
3
phosphate buffer 79
EtOH
EtOH
perfluorodecalin 95
92
92
97
99
95
85
[36]
[42]
[43]
[44]
[51]
[45]
[46]
[47]
[10]
[35]
[48]
[49]
[41]
[50]
[52]
g
2 3
O
8 min
4 h
10 mmol%
10 mg
reflux
reflux
110
reflux
r.t.
ꢁ
2
[W
6
O
19
]
20 min 7 mmol%
25 min 10 mmol%
C
K
7
[PW11CoO40
]
Bakers' yeast
LiBr
24 h
4 h
200 mg
10 mol%
r.t.
r.t.
60
25
r.t.
70
93
92
Ceric Ammonium Nitrate (CAN)
Hafnium (IV) bis(perfluorooctanesulfonyl)imide Hf(NPf
60 min 0.05 mmol%
3 h 1 mol%
90 min 30 mol%
20 min 10 mol%
120 min 0.2 g
ꢁ
ꢁ
0
1
2
3
4
5
2
)
4
C
C
I
2
EtOH
Solvent-free
MeOH
93
98
92
95
96
ZnO-nanoparticle
Alumina sulfuric acid (ASA)
Ni nanoparticle
nickel containing alkyl-imidazolium ionic liquid based ordered mesoporous 15 min 0.5 mol%
organosilica (Ni@ILOMO)
ꢁ
C
1 min
10 mol%
microwave (540 W) Neat
ꢁ
70
C
C
Solvent-free
ꢁ
16
17
18
19
20
PdRuNi nanoparticles furnished with graphene oxide (PdRuNi@GO NPs)
(SnO ) nanoparticles
Mesoporous vanadium ion doped titania nanoparticles (VeTiO
Yb(OTf)
BW12
45 min 6 mg
70
r.t.
r.t.
r.t.
DMF
EtOH
Solvent-free
EtOH
EtOH
93
94
85
90
94
[53]
[37]
[54]
[55]
2
9 min
1 mol%
2
)
10 min 2 mol%
3
5 h
5 mol%
H
5
O
40
45 min 10 mol%
reflux
This work

6
T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
without appreciable loss in its catalytic activities.
mentioned that in our previous researches, we have mechanisti-
cally studied the origins of regio-selectivity in the sonogashira and
click synthesis of triazoles and tetrazoles [31e33] via density
functional theory (DFT) computations.
4
. Computational section
In this line, we first designed two different reaction pathway
models to investigate the reaction energetics that led to generate
two different products entitled as product-1 and product-2,
respectively, as was illustrated in Scheme 2.
All calculations were performed using GAMESS suite of pro-
grams [57] via DFT approach, based on M08-HX functional in
In the present section, we have concentrated to assess compu-
tationally two mechanistical pathways of Hantzsch reaction that
lead to produce 1,4-dihydropyridine and 2-arylpyridine as has been
reported experimentally [56]. In this respect, we have presented
accurate computational information on the energetics of these two
reaction pathways using quantum chemistry methods. It should be
Scheme 2. Plausible mechanisms for the synthesis of 1,4-dihydropyridine and 2-arylpyridines via two reaction paths.

T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
7
account using the polarized continuum model (PCM) computa-
tions. In Fig. 3, we have displayed the optimized structure of
product-1 and product-2, calculated at M08-HX/6-311 þ G** level
of theory. The calculated thermochemical data, including reaction
energies, Enthalpies and Gibbs free energies at M08-HX/6-
3
11 þ G** in the gas and two solution phases are presented in
Tables 4 and 5, respectively.
The comparative survey in the reported results of Tables 4 and 5
revealed that the production of product-1 in the gas and solution
phases should be more favorable thermodynamically than product-
ꢀ1
2
about 7e8 kcal mol . Expectedly, at both reaction pathways,
thermochemistry in the solution phase is more stable than the gas
phase with the corresponded more negative calculated Gibbs free
energy values and also both solvents, DMSO and EtOH have a near
and similar effect on the reaction thermochemical properties.
Moreover, the calculated Gibbs free energy values become more
positive than those obtained for enthalpy calculated values that
could be assigned to the negative values of the reaction entropy
change.
In order to explain the formation of the different products, 1,4-
DHPs and 2-arylpyridines, two mechanistical pathways are sug-
gested in Scheme 2. The initial step is the same in two reaction
paths. At this stage, the reaction involves
a Knoevenagel
Fig. 3. The optimized structure of product-1 and product-2, calculated at M08-HX/6-
11 þ G** level of theory.
3
connection with 6-311 þ G** orbital basis sets [58]. We have
determined the ground state structures of all reagents and products
through the geometry optimization procedure. The harmonic fre-
quency analysis was then performed to confirm that the found
optimized geometries correspond to the true minima and also to
obtain enthalpies and Gibbs free energies. Furthermore, the effect
of solvation on the reaction thermochemistry in the presence of
Dimethyl sulfoxide (DMSO) and ethanol (EtOH) was taken into
Table 4
Thermochemistry of two reaction pathways, calculated at M08-HX/6-311 þ G** level
of theory in the gas phase.
DEe is the reaction energy, DH and DG are the reaction
enthalpy and Gibbs free energy, respectively. Note that the conversion energy
ꢀ
1
change values are in kcal.mol
M08-HX/6-311 þ G**
Isomers
.
Gas phase
D
E
e
D
H
DG
Product-1
Product-2
ꢀ1.67
5.88
ꢀ4.15
2.38
10.28
Fig. 4. Optimized structures of TS-1 and TS-2, calculated at M08-HX/6-311 þ G** level
3.56
of theory.
Table 5
The same as Table 4, calculated in the presence of DMSO and ethanol as solvents via PCM method.
M08-HX/6-311 þ G**
Isomers
DMSO solvent
Ethanol solvent
D
E
e
DH
DG
DE
e
DH
DG
Product-1
Product-2
ꢀ5.33
ꢀ7.74
ꢀ0.74
ꢀ1.27
ꢀ5.26
ꢀ7.74
ꢀ0.66
ꢀ1.20
1.58
5.98
1.66
6.06

8
T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
Table 6
The Gibbs free energy differences between two transition states (denoted as
the gas and two solution phases, DMSO and ethanol.
D
GTS) corresponded to two reaction pathways, calculated at M08-HX/6-311 þ G** level of theory in
M08-HX/6-311 þ G**
Gas phase
DMSO solvent
25.34
Ethanol solvent
25.42
TS (kcal.mol 1
ꢀ
)
28.44
D
G
Table 7
Mathematical properties of BCPs associated to some selected bonds in product-1 and product-2. The properties have been obtained via QTAIM analysis on the M08-HX/6-
11 þ G** calculated wave function of electron density. Note that numbering of atoms is in accordance with Fig. 5.
3
Product-1
Bonded atoms
r
V
2
r
Gb
Vb
Hb
jV j =Gb
b
b
b
C
C
N
11eC13
11eC12
16eC15
0.241
0.241
0.295
0.294
ꢀ0.543
ꢀ0.542
ꢀ0.686
ꢀ0.685
0.057
0.058
0.239
0.238
ꢀ0.251
ꢀ0.251
ꢀ0.650
ꢀ0.649
ꢀ0.193
ꢀ0.193
ꢀ0.411
ꢀ0.410
4.342
4.339
2.715
2.717
C
14eN16
Product-2
C
C
N
6
eC
eC
21eC
7
0.267
0.323
0.320
0.252
ꢀ0.658
ꢀ0.907
ꢀ0.712
ꢀ0.615
0.072
0.121
0.290
0.153
ꢀ0.308
ꢀ0.470
ꢀ0.759
ꢀ0.460
ꢀ0.231
ꢀ0.348
ꢀ0.468
ꢀ0.306
4.245
3.863
2.613
3.005
7
8
5
C
9
eN21
Table 8
The same as Table 5 for TS-1 and TS-2. Note that numbering of atoms is in accordance with Fig. 6.
TS-1
Bonded atoms
r
V
2
r
Gb
Vb
Hb
jV j =Gb
b
b
b
N
26eC
eC
eC11
eC
3
0.318
0.232
0.238
0.231
ꢀ0.777
ꢀ0.491
ꢀ0.535
ꢀ0.491
0.264
0.055
0.054
0.055
ꢀ0.722
ꢀ0.233
ꢀ0.242
ꢀ0.232
ꢀ0.458
ꢀ0.178
ꢀ0.187
ꢀ0.177
2.732
4.210
4.478
4.235
C
C
C
6
8
8
8
9
TS-2
eC
N
3
7
0.313
0.233
0.241
0.345
ꢀ0.785
ꢀ0.508
ꢀ0.549
ꢀ1.026
0.249
0.050
0.054
0.145
ꢀ0.694
ꢀ0.228
ꢀ0.247
ꢀ0.547
ꢀ0.445
ꢀ0.177
ꢀ0.192
ꢀ0.402
2.788
4.497
4.504
3.761
C
C
C
6
eC
eC
9
4
9
20eC11
condensation of 1,3-dicarbonyl compound with the aldehyde to
give an -unsaturated carbonyl compound 4 and a condensation
of ammonia with another equivalent of the 1,3-dicarbonyl com-
pound to afford an enamine 3. The rate determining step is the
mechanistical priority in the synthesis of product-1, compared with
product-2. In another hand, it was also demonstrated that the
calculated stability difference between two transition state struc-
tures decreases in the solution phases in comparison with the gas
phase.
a,b
Michael addition of the enamine to the a,b-unsaturated carbonyl
compound. However, unlike the previously known mechanism of
the Hantzsch reaction, the enamine intermediate can attack on the
In the next step, we concentrated on topological analysis of
electron density functions via QTAIM calculations to investigate the
mechanistical features of two reaction paths [59e61].
carbon atom of the C]O double bond (carbon
carbon atom of the C]C double bond (carbon
b
of 4) instead of the
a
of 4). Subsequently,
All topological analysis of electron density was performed at
DFT optimized structures of products and transition states along
the reaction pathways via QTAIM computations using AIM2000
the intermediate 7 undergoes an intramolecular addition of the
amino to the carbon-carbon double bond to afford the 1,2-
dihydropyridine.
5
7
program .
In this mechanistical context, we studied comparatively the
thermochemical properties of transition states species in two
above-mentioned mechanistic reaction pathways via saddle point
computations. In Fig. 4, the obtained M08-HX/6-311 þ G** opti-
mized structures of transition states, corresponded to two reaction
routes have been represented (denoted as TS-1 and TS-2, respec-
tively). In Table 6, we have listed the difference of Gibbs free energy
values for TS-1 and TS-2, calculated at M08-HX/6-311 þ G** levels
in the gas and two solution phases, respectively. As it can be
deduced from the calculated results of Table 6, TS-1 is more stable
In this respect, resulting M08-HX/6-311 þ G** wave function
files for the optimized structures of products and transition states
were applied as inputs to AIM2000 program. In Tables 7 and 8, we
have reported the calculated values of electron density,
rb, its
Laplacian, V2 , electronic kinetic energy density, Gb, electronic
r
potential energy density, Vb, total electronic energy density, Hb and
ratio of jVbj/Gb, for some selected BCPs of product-1 and product-2
and their corresponded transition states, respectively. The QTAIM
molecular graphs of product-1, product-2 and their corresponded
transition states have been displayed in Figs. 5 and 6, respectively.
It should be mentioned that the aforementioned properties of
ꢀ
1
than TS-2 by around 27 kcal mol
that strictly approves the

T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
9
Fig. 5. QTAIM molecular graphs of product-1 and product-2 calculated at M08-HX/6-311 þ G** level of theory.
electron density at BCPs can be regarded as the regions of con-
5. Conclusion
centration and depletion of electron charge density and a basis for
classifying the interatomic interactions [60,61].
In summary, in this paper, we reported an effective, versatile
and facile strategy for the synthesis of polyhydroquinoline de-
rivatives via Hantzsch MCR employing BWA as a green, reusable
and homogeneous catalyst in refluxing EtOH. This strategy not only
demonstrates significant improvements in the rate of reaction and
provide higher yields, but also circumvents the utilization of haz-
ardous catalysts or solvents. The gifted points for the presented
strategy are competence, and generality, obtaining high yields in
relatively short reaction time, clean reaction profile, simplicity of
product isolation, uncomplicatedness, latent for recycling of the
catalyst. In the other hand, we investigated the energetics of two
different reaction pathways that lead to generate the different
products, 1,4-DHPs and 2-arylpyridines, using quantum chemistry
methods. In this line, thermochemical and electronic features of
two reaction pathways and their corresponded transition states
were analyzed via DFT and QTAIM approaches. The calculated
thermochemical and electronic results clearly demonstrated the
mechanistical priority in the synthesis of 1,4-DHPs than 2-
arylpyridines. Notably, the purpose of this work, is presenting a
green, homogenous catalyst with potential usage for improving
organic reactions and synthesis of 1,4-DHPs is just particular as a
model organic transformation.
The comparative investigation of the reported results in Tables 7
and 8 clearly show the following facts: (i) the negative values of V2
r
and also H(r) at all selected BCPs determine the presence of cova-
lent bond critical points and consequently charge concentration in
the bonded region, (ii) comparison between the calculated electron
density properties and indicators on C11eC13 and N16eC14 as
newly formed covalent bonds in product-1 with the corresponded
C6eC7 and N21eC9 bonds in product-2 shows that C11eC13 in
product-1 is more strongly than C6eC7 in product-2, while there is
an inverse trend in the bond strength of N16eC14 in product-1
compared with N21eC9 in product-2. In the other point, it can be
claimed that product-2 is more stable electronically based on the
formation of more ring critical points (RCP) around the pyridine
ring, (iii) comparative assessment on the near value of electron
density for C6eC8 and C6eC9 in TS-1 and TS-2, respectively, reveals
no preference from the electronic viewpoint while in QTAIM mo-
lecular graph of TS-1, it has been displayed more RCPs around
C6eC8 that leads to the more electronic stability of TS-1. This
feature can be regarded as the main electronic origin for the pri-
ority of reaction path-1 in comparison with reaction path-2.

10
T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
Discov. Today 14 (2009) 1058e1066;
d) M. Mirela Filipan-Litvíc, M. Litvíc, I. Cepanec, V. Vinkovíc, Hantzsch Syn-
(
thesis of 2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-methoxyphenyl)-1,4-
dihydropyridine; a Novel cyclisation leading to an unusual formation of 1-
amino-2-methoxycarbonyl-3,5-bis(o-methoxyphenyl)-4-oxa-cyclohexan-1-
ene, Molecules 12 (2007) 2546e2558.
[
[
5] M.G. Dekamin, S. khanizadeh, Z. Latifidoost, H. Daemi, Z. Karimi, M. Barikani,
Alginic acid: a highly efficient renewable and heterogeneous biopolymeric
catalyst for one-pot synthesis of the Hantzsch 1,4-dihydropyridines, RSC Adv.
4
(2014) 56658e56664.
6] (a) T. Godfraid, R. Miller, M. Wibo, Calcium antagonism and calcium entry
blockade, Pharmacol. Rev. 38 (1986) 321e416;
(
b) A. Sausins, G. Duburs, Synthesis of 1, 4-dihydropyridines by cyclo-
condensation reactions, Heterocycles 27 (1988) 269e289;
c) P.P. Mager, R.A. Coburn, A.J. Solo, D.J. Triggle, H. Rothe, QSAR, diagnostic
(
statistics and molecular modelling of 1, 4-dihydropyridine calcium antago-
nists: a difficult road ahead, Drug Des. Discov. 8 (1992) 273e289;
(d) R. Mannhold, B. Jablonka, W. Voigdt, K. Schoenafinger, K. Schravan, Cal-
cium-and calmodulin-antagonism of elnadipine derivatives: comparative SAR,
Eur. J. Med. Chem. 27 (1992) 229e235.
[
7] B. Love, K.M. Sander, The Hantzsch reaction. I. Oxidative dealkylation of
certain dihydropyridines, J. Org. Chem. 30 (1965) 1914e1916 (Cover letter).
8] (a) A. Hantzsch, Synthese von thiazolen und oxazolen, Ber. Dtsch. Chem. Ges.
[
2
1 (1888) 942e946;
b) A. Hantzsch, Neue bildungsweise yon pyrrolderivaten, Ber. Dtsch. Chem.
Ges. 23 (1890), 1747-1476;
c) R.H. Wiley, D.C. England, L.C. Behr, in: Organic Reactions vol. 1, Wiley,
Toronto, 1951, p. 367, 6;
d) A. Dondoni, A. Massi, E. Minghini, V. Bertolasi, Multicomponent Hantzsch
cyclocondensation as route to highly functionalized 2- and 4-
(
(
(
a
dihydropyridylalanines, 2- and 4-pyridylalanines, and their N-oxides: prepa-
ration via a polymer-assisted solution-phase approach, Tetrahedron 60 (2004)
2311e2326.
[9] Sh Ko, Ch-F. Yao, Ceric Ammonium Nitrate (CAN) catalyzes the one-pot syn-
thesis of polyhydroquinoline via the Hantzsch reaction, Tetrahedron 62 (2006)
7
293e7299.
þ
[
10] A. Hardwick, P.G. Dickens, R.C.T. Slade, Investigation of H motion in the 21-
hydrates of 12-tungstophosphoric and 12-molybdophosphoric acids by ac
conductivity and pulsed 1H NMR measurements, Solid State Ion. 13 (1984)
345e350.
[
[
[
[
11] K.D. Kreuer, M. Hampele, K. Dolde, A. Rabenau, Proton transport in some
heteropolyacidhydrates a single crystal PFG-NMR and conductivity study,
Solid State Ion. 28e30 (1988) 589e593.
12] R.C.T. Slade, H.A. Pressman, E. Skou, Ac and dc conductivity studies of pelle-
tised 12-tungstophosphoric acid and 12-tungstosilicic acid hexahydrates,
Solid State Ion. 38 (1990) 207e211.
Fig. 6. QTAIM molecular graphs of TS-1 and TS-2 calculated at M08-HX/6-311 þ G**
level of theory.
13] R.C.T. Slade, J. Barker, H.A. Pressman, Studies of protonic self-diffusion and
conductivity in 12-tungstophosphoric acid hydrates by pulsed field gradient
Acknowledgements
1
H NMR and ac conductivity, Solid State Ion. 28e30 (1988) 594e600.
14] U.B. Mi oꢀ c, M.R. Todorovíc, M. Davidovíc, P. Colomban, I. Holclajtner-Antu-
The authors are thankful from Alzahra Research Council for the
partial financial support. MMH is also thankful to Iranian National
Science Foundation (INSF) for partial financial support. MM is
thankful to research council of Ferdowsi University of Mashhad,
Mashhad, Iran.
novíc, Heteropoly compounds-From proton conductors to biomedical agents,
Solid State Ion. 176 (2005) 3005e3017.
15] M. Sadakane, E. Steckhan, Electrochemical properties of polyoxometalates as
electrocatalysts, Chem. Rev. 98 (1998) 219e238.
16] D.E. Katsoulis, A survey of applications of polyoxometalates, Chem. Rev. 98
(1998) 359e388.
[
[
[
17] R.S. Drago, J.A. Dias, T.O. Maier, An acidity scale for Br o€ nsted acids including
3
H PW12O40, J. Am. Chem. Soc. 119 (1997) 7702e7710.
[18] F. Lefebvre, F.X. Liu-Cai, A. Auroux, Microcalorimetric study of the acidity of
Appendix A. Supplementary data
tungstic heteropolyanions, J. Mater. Chem. 4 (1994) 125e131.
[
[
[
5 30
19] M.M. Heravi, F.K. Behbahani, F.F. Bamoharram, H14[NaP W O110]: a heter-
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2019.127011.
opoly acid catalyzed acetylation of alcohols and phenols in acetic anhydride,
J. Mol. Catal. A Chem. 253 (2006) 16e19.
20] M.M. Heravi, Kh Bakhtiari, F.F. Bamoharram, An efficient and chemoselective
synthesis of acylals from aromatic aldehydes and their regeneration, catalyzed
by 12-molybdophosphoric acid, Catal. Commun. 7 (2006) 499e501.
21] M.M. Heravi, Kh Bakhtiari, T. Benmorad, F.F. Bamoharram, H.A. Oskooie,
M.H. Tehrani, Nitration of aromatic compounds catalyzed by divanadium-
References
[
[
1] B.B. Toure, D.G. Hall, Natural product synthesis using multicomponent reac-
tion strategies, Chem. Rev. 109 (2009) 4439e4486.
2] A. Shaabani, A. Sarvary, S. Ghasemi, A.H. Rezayan, R. Ghadari, S.W. Ng, An
environmentally benign approach for the synthesis of bifunctional
sulfonamide-amide compounds viaisocyanide-based multicomponent re-
actions, Green Chem. 13 (2011) 582e585.
5 2
substituted molybdophosphoric acid, H [PMo10V O40], Monatshefte Chem.
138 (2007) 449e452.
[23] M.M. Heravi, M. Mirzaei, S.Y. Shirazi Beheshtiha, V. Zadsirjan, F. Mashayekh
Ameli, M. Bazargan, H BW12 40 as a green and efficient homogeneous but
5
O
recyclable catalyst in the synthesis of 4H-Pyrans via multicomponent reac-
tion, Appl. Organomet. Chem. 32 (2018) e4479.
[
[
3] A. Zhu, R. Liu, Ch Dua, L. Lia, Betainium-based ionic liquids catalyzed multi-
component Hantzsch reactions for the efficient synthesis of acridinediones,
RSC Adv. 7 (2017) 6679e6684.
4] (a) D.J. Triggle, 1,4-dihydropyridine calcium channel ligands: selectivity of
action. The roles of pharmacokinetics, state-dependent interactions, channel
isoforms, and other factors, Drug Dev. Res. 58 (2003) 5e17;
[24] M.M. Heravi, Z. Faghihi, Applications of heteropoly acids in multi-component
reactions, J. Iran. Chem. Soc. 11 (2014) 209e224.
[25] M.M. Heravi, M. Vazin Fard, Z. Faghihi, Heteropoly acids-catalyzed organic
reactions in water: doubly green reactions, Green Chem. 6 (2013) 282e300.
[26] T. Hosseinnejad, M. Omrani-Pachin, M.M. Heravi, Joint computational and
experimental investigations on the synthesis and properties of Hantzsch-type
compounds: an Overview, Curr. Org. Chem. 23 (2019) 1e18.
[27] M. Malmir, M.M. Heravi, S. Sadjadi, T. Hosseinnejad, Ultrasonic and bio-
assisted synthesis of Ag@HNTs-T as a novel heterogeneous catalyst for the
green synthesis of propargylamines: a combination of experimental and
computational study, Appl. Organomet. Chem. 32 (2018), e4291.
(
b) J.-C. Liang, J.-L. Yeh, C.-S. Wang, S.-F. Liou, C.-H. Tsai, I.-J. Chen, The new
generation dihydropyridine type calcium blockers, bearing 4-phenyl oxy-
propanolamine, display -/ -Adrenoceptor antagonist and long-Acting anti-
hypertensive activities, Bioorg. Med. Chem. 10 (2002) 719e730;
c) N. Edraki, A.R. Mehdipour, M. Khoshneviszadeh, R. Miri, Dihydropyridines:
evaluation of their current and future pharmacological applications, Drug
a
b
(

T. Momeni et al. / Journal of Molecular Structure 1199 (2020) 127011
11
[
[
[
28] T. Baie Lashaki, H.A. Oskooie, T. Hosseinnejad, M.M. Heravi, CuI nanoparticles
(73) (2008) 1628e1630.
[45] B.B.F. Mirjalili, A. Bamoniri, L. Asadollah Salmanpoor, TiCl
novel lewis acid catalyst for promotion of one-pot synthesis of 1,4-
dihydropyridines, J. Nanostruct. 8 (2018) 276e287.
[46] E. Mosaddegh, A. Hassankhani, One-pot synthesis of polyhydropyridine de-
rivatives via Hantzsch four component condensation in water medium: use of
a recyclable Lewis acid [Ce(SO ) .4H O] catalyst, Bull. Chem. Soc. Ethiop. 26
4 2 2
(2012) 461e465.
[47] M. Maheswari, V. Vasudevan Srinivasan, A. Ramanathan, M.P. Pachamuthu,
R. Rajalakshmi, G. Imran, Preparation and characterization of mesostructured
Zr-SBA-16: efficient Lewis acidic catalyst for Hantzsch reaction, J. Porous
Mater. 22 (2015) 705e711.
on modified poly (styrene-co-maleic anhydride) as an effective catalyst in
regioselective synthesis of 1, 2, 3-triazoles via click reaction: a joint experi-
mental and computational study, J. Coord. Chem. 70 (2017) 1815e1834.
29] V. Zadsirjan, M.M. Heravi, M. Tajbakhsh, H.A. Oskooie, M. Shiri,
T. Hosseinnejad, Hydroarylation of cinnamic acid with phenols catalyzed by
2
/Nano-
g-Al
2
O
3
as a
acidic ionic liquid [H-NMP]HSO
4
: computational assessment on substituent
effect, Res. Chem. Intermed. 42 (2016) 6407e6422.
30] M.M. Heravi, T. Hosseinnejad, N. Nazari, Computational investigations on
structural and electronic properties of CuI nanoparticles immobilized on
modified poly(styrene-co-maleic anhydride) leading to an unexpected but
efficient catalyzed synthesis of 1,4-dihydropyridine via Hantzsch pyridine
synthesis, Can. J. Chem. 92 (2017) 530e536.
[48] M.M. Heravi, M. Saeedi, N. Karimi, M. Zakeri, Y.S. Beheshtih, A. Davoodnia,
[
[
[
31] T. Hosseinnejad, S. Mahdavian, Quantum chemistry study on regioselectivity
in ruthenium catalyzed synthesis of 1,5-disubstituted 1,2,3-triazoles, Comput.
Theor. Chem. 1143 (2018) 29e35.
32] T. Hosseinnejad, M. Dinyari, Computational study on stereoselective synthesis
of substituted 1H-tetrazoles via a click reaction: DFT and QTAIM approaches,
Comput. Theor. Chem. 1071 (2015) 53e60.
33] T. Hosseinnejad, M.M. Heravi, R. Firouzi, Regioselectivity in Sonogashira
synthesis of 6-(4-nitrobenzyl)-2-phenylthiazolo[3,2-b]1,2,4-triazole: a quan-
tum chemistry study, J. Mol. Model. 19 (2013) 951e961.
2 4 3 4
Brønsted acid ionic liquid [(CH ) SO HMIM][HSO ] as novel catalyst for one-
pot synthesis of Hantzsch polyhydroquinoline derivatives, Synth. Commun.
40 (2010) 523e529.
3
[49] N. Devarajana, P. Suresh, MIL-101-SO H metal-organic framework as a
Brønsted acid catalyst in Hantzsch reaction: an efficient and sustainable
methodology for one-pot synthesis of 1,4-dihydropyridine, New J. Chem. 43
(2019) 6806e6814.
[50] X. Liu, B. Liu, Hantzsch reaction starting directly from alcohols through a
tandem oxidation process, J. Chem. 2017 (2017) 1e5.
[34] H. Gao, A. Virya, K. Lian, Proton conducting H
5
BW12O
40 electrolyte for solid
[51] A. Davoodnia, M. Khashi, N. Tavakoli-hoseini, Tetrabutylammonium hex-
supercapacitors, J. Mater. Chem. A. 3 (2015) 21511e21517.
2 6
atungstate [TBA] [W O19]: novel and reusable heterogeneous catalyst for
[
35] T. Demirci, B. Çelik, Y. Yıldız, S. Eri s¸ , M. Arslan, F. Sen, B. Kilbas, One-pot
synthesis of Hantzsch dihydropyridines using a highly efficient and stable
PdRuNi@GO catalyst, RSC Adv. 6 (2016) 76948e76956.
rapid solvent-free synthesis of polyhydroquinoline via unsymmetrical
Hantzsch reaction, Chin. J. Catal. 34 (2013) 1173e1178.
[52] D. Elhamifar, H. Khanmohammadia, D. Elhamifar, Nickel containing ionic
liquid based ordered nanoporous organosilica: a powerful and recoverable
[
[
36] M. Hong, Ch Cai, W.-B. Yi, Hafnium (IV) bis(perfluorooctanesulfonyl)imide
complex catalyzed synthesis of polyhydroquinoline derivatives via unsym-
metrical Hantzsch reaction in fluorous medium, J. Fluorine Chem. 131 (2010)
catalyst for synthesis of polyhydroquinolines, RSC Adv.
7
(2017)
54789e54796.
111e114.
[53] T. Demirci, B. Çelik, Y. Yıldız, S. Eris, M. Arslan, F. Sen, B. Kilbas, One-pot
synthesis of Hantzsch dihydropyridines using a highly efficient and stable
PdRuNi@GO catalyst, RSC Adv. 6 (2016) 76948e76956.
[54] G.B. Dharma Rao, S. Nagakalyan, G.K. Prasad, Solvent-free synthesis of poly-
hydroquinoline derivatives employing mesoporous vanadium ion doped
titania nanoparticles as a robust heterogeneous catalyst via the Hantzsch
reaction, RSC Adv. 7 (2017) 3611e3616.
37] Q. Zhang, X.-M. Ma, H.-X. Wei, X. Zhaoa, J. Luoc, Covalently anchored tertiary
amine functionalized ionic liquid on silica coated nano-Fe3O4 as a novel,
efficient and magnetically recoverable catalyst for the unsymmetrical
Hantzsch reaction and Knoevenagel condensation, RSC Adv.
3861e53870.
7 (2017)
5
[38] H. Niaz, H. Kashtoh, J.A.J. Khan, A. Khan, A.-T. Wahab, M. Tanveer Alam,
Kh Mohammed Khan, Sh Perveen, M. Iqbal Choudhary, Synthesis of diethyl 4-
[55] L.-M. Wang, J. Sheng, L. Zhang, J.-W. Han, Zh-Y. Fan, H. Tiana, Ch-T. Qian, Facile
substituted-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates as
series of inhibitors against yeast -glucosidase, Eur. J. Med. Chem. 95 (2015)
99e209.
a
new
3
Yb(OTf) promoted one-pot synthesis of polyhydroquinoline derivatives
a
through Hantzsch reaction, Tetrahedron 61 (2005) 1539e1543.
[56] L. Shen, S. Cao, J. Wu, J. Zhang, H. Li, N. Liu, X. Qian, A revisit to the Hantzsch
reaction: unexpected products beyond 1,4-dihydropyridines, Green Chem. 11
(2009) 1414e1420.
[57] W. Schmidt, M.K. Baldridge, K.A. Boatz, J.T. Elbert, S.S. Gordon, M.H. Jensen,
J. Koseki, S. Matsunaga, N.A. Nguyen, K.J. Su, S.L. Windus, T. Dupuis,
M.A. Montgomery, General atomic and molecular electronic structure system,
J. Comput. Chem. 14 (1993) 1347e1363.
[58] Y. Zhao, D.G. Truhlar, Exploring the limit of accuracy of the global hybrid meta
density functional for main-group thermochemistry, kinetics, and non-
covalent interactions, J. Chem. Theory Comput. 4 (2008) 1849e1868.
[59] R.F.W. Bader, AIM2000 Program, Mc Master University, Hamilton, 2000,
version 2.0.
1
[
[
39] S.M. Vahdat, F. Chekin, M. Hatami, M. Khavarpour, S. Bagheri, Z. Roshan-kouhi,
Synthesis of polyhydroquinoline derivatives via a four-component Hantzsch
condensation catalyzed by tin dioxide nanoparticles, Chin. J. Chem. 34 (2013)
758e763.
40] A. Debache, W. Ghalem, R. Boulcina, A. Belfaitah, S. Rhouati, B. Carboni, An
efficient one-step synthesis of 1,4-dihydropyridines via a triphenylphosphine-
catalyzed three-component Hantzsch reaction under mild conditions, Tetra-
hedron Lett. 50 (2009) 5248e5250.
41] M.M. Heravi, V. Zadsirjan, B. Fattahi, N. Nazari, Applications of dimedone in
the synthesis of heterocycles: an update, Curr. Org. Chem. 20 (2016)
[
[
1676e1735.
42] U.C. Reddy, S. Bondalapati, A.K. Saikia, Stereoselective One-Pot, three-
component synthesis of 4-aryltetrahydropyran via Prins-Friedel-Crafts reac-
tion, J. Org. Chem. 74 (2009) 2605e2608.
[60] E. Espinosa, I. Alkorta, J. Elguero, E. Molins, From weak to strong interactions:
a comprehensive analysis of the topological and energetic properties of the
electron density distribution involving XeH/FeY systems, J. Chem. Phys. 117
(2002) 5529.
[61] R.G. Bone, R. F Bader, Identifying and analyzing intermolecular bonding in-
teractions in van der Waals molecules, J. Chem. Phys. 100 (1996)
10892e10911.
[
43] U.C. Reddy, A.K. Saikia, One-pot, three-component synthesis of 4-aryl-5,6-
dihydropyran via prins-friedel-crafts reaction, Synlett 7 (2010) 1027e1032.
44] U.C. Reddy, B. Rama Raju, E.K. Pramod Kumar, A.K. Saikia, Stereoselective one-
pot, three-component synthesis of 4-amidotetrahydropyran, J. Org. Chem. 73
[