USY-zeolite catalyzed synthesis of 1,4-dihydropyridines under microwave irradiation: structure and recycling of the catalyst

Article abstract of DOI:10.1016/j.molstruc.2020.129430

The Hantzsch three-component reaction is the best-known multicomponent reaction, affording dihydropyridines which have been employed therapeutically and also as visible‐light photoredox catalysts. In this work we report the application of an ultra-stable

Full text of DOI:10.1016/j.molstruc.2020.129430

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Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
USY-zeolite catalyzed synthesis of 1,4-dihydropyridines under
microwave irradiation: structure and recycling of the catalyst
Leonardo H.R. Alpontia, Monize Picininib, Ernesto A. Urquieta-Gonzalezb,∗
,
Arlene G. Corrêaa,∗
a Centre of Excellence for Research in Sustainable Chemistry, Department of Chemistry, Brazil
b Department of Chemical Engineering, Federal University of São Carlos, 13565-905 São Carlos, SP - Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The Hantzsch three-component reaction is the best-known multicomponent reaction, affording dihy-
dropyridines which have been employed therapeutically and also as visible-light photoredox catalysts.
In this work we report the application of an ultra-stable (US) Y zeolite as a promising green catalyst in
the synthesis of a series of 1,4-dihydropyridines under microwave irradiation. Using the optimized reac-
tion conditions, 21 compounds were prepared in 64-96% isolated yields. The recovery and recycle of the
USY zeolite are also reported as well as its fully characterization.
Received 12 September 2020
Revised 6 October 2020
Accepted 7 October 2020
Available online xxx
Keywords:
multicomponent reaction
Green synthesis
Zeolite
© 2020 Elsevier B.V. All rights reserved.
Heterogenous catalysis
Microwave
1. Introduction
mechanisms. The recent advances in the chemistry of Hantzsch es-
ters in photoredox catalyzed organic synthesis have been reviewed
Important factors associated with the development of greener
processes are atom economy, efficiency, elimination of toxic inter-
mediates/products and generation of as minimum waste as pos-
sible [1]. In this sense, multicomponent reactions (MCRs) have
emerged as an interesting tool that allows for the straightforward
synthesis of intricate molecules in a one-pot fashion without the
isolation and purification of intermediates, therefore leading to
lower costs, time and energy consumption. Additionally, MCRs are
modular and convergent in nature and also an important source of
molecular diversity [2].
[5].
Several mechanisms have been reported for the Hantzsch 3CR.
Depending on the reaction conditions and substrates selected for
the transformation, side reactions may take place in competition
with the Hantzsch ester formation [6]. Due to its importance,
literature survey discloses numerous synthetic protocols for 1,4-
dihydropyridines synthesis [7], including green solvents such as
water [8] or sodium acetate trihydrate–urea deep eutectic solvent
(DES) [9], as well as solvent-free conditions [10], under infrared
[11] or UV irradiation [12], microwave heating [13], and the use of
citric acid as organocatalyst [14].
The 1,4-dihydropyridine synthesis using β-ketoesters, aldehydes
and ammonia, reported by A. R. Hantzsch in 1881, is the best-
known three-component reaction (3CR) [3]. This class of com-
pounds has been extensively studied due to their potent biological
activities [4]. Illustrative examples are nifedipine and nimodipine,
that are employed therapeutically to reduce blood pressure and
treat neurological deficits, respectively (Scheme 1). Hantzsch esters
have also proven to be a useful class of electron donors and proton
sources in photoredox catalyzed processes. Moreover, under pho-
toredox catalytic conditions, alkyl-1,4-dihydropyridines can serve
as versatile types of alkylation reagents via oxidative fragmentation
In the last decades, catalytic processes have unquestionably be-
come a cornerstone within the Green Chemistry perspective, and
their continuous advances have enabled the discontinuation of out-
dated stoichiometric methodologies to give place to more sustain-
able ones [15]. Among the major current challenges in this area
is the replacement of conventional homogeneous catalysts by het-
erogeneous ones, which are easy to handle and usually recyclable,
since they can be readily recovered. Recently, we have reviewed
the applications of zeolites [16] as catalysts in multicomponent re-
actions [17].
The synthesis of 1,4-dihydropyridines using heterogeneous
catalysis have been reported employing for example silica-
supported sulphuric acid [18], silica gel/NaHSO4 [19], sulfated zir-
conia [20], nano-crystalline solid acid catalyst [21], supported ionic
∗
Corresponding authors.
E-mail
addresses:
urquieta@ufscar.br
(E.A.
Urquieta-Gonzalez),
agcorrea@ufscar.br (A.G. Corrêa).
https://doi.org/10.1016/j.molstruc.2020.129430
0022-2860/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: L.H.R. Alponti, M. Picinini, E.A. Urquieta-Gonzalez et al., USY-zeolite catalyzed synthesis of 1,4-dihydropyridines
under microwave irradiation: structure and recycling of the catalyst, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.
2020.129430

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Scheme 1. The Hantzsch MCR and examples of dihydropyridines as commercially available drugs.
Table 1
Catalyst testing for 1,4-dihydropyridine synthesis.
Entrya
Catalyst
Catalyst (mg)
Time (min)
4a yield (%)b
1
-
-
120
180
120
120
120
120
120
120
120
10
12
18
70
90
82
87
82
83
96
96
95
82
96
63
71
2
-
-
3
CuCl2.2H2O
CuCl2.2H2O
mordenite
ferrierite
ZSM-5
BETA
USY
3
4
7
5
100
100
100
100
100
100
100
50
50
25
25
6
7
8
9
10c
11c
12c
13c
14c
15c
USY
USY
15
USY
15
USY
20
USY
20
USY
25
a
reactions were carried out using benzaldehyde 1 (0.5 mmol), dimedone 2 (1.0 mmol), ammonium ac-
etate 3 (1.25 mmol) and EtOH (0.5 mL) in an oil bath at 110°C;
b
isolated yield after column chromatography;
c
performed under MW irradiation (110°C, 300 W).
liquid phase catalyst [MerImi]PF6 under ultrasonication [22], and
5 (Zeolite Socony Mobil – 5), ferrierite, mordenite and beta [31],
having the Si/Al ratios shown in Table 2, where tested as catalyst
in its protonic form in the described MCR at 110°C for 2 h using
conventional heating (Table 1, entries 5-9).
a negatively charged borotungstic acid H5BW12O40 [23]. In this re-
gard, zeolites, in particular, have received increasing attention ow-
ing to their efficiency and selectivity in organic transformations, as
consequence of attractive properties, i.e. tunable acidity and pore
size; still, an important feature of such materials is the possibil-
ity of inserting additional metals into their framework [24–26].
Nikpassand et al. reported the use of HY zeolite (Si/Al = 2.54) as
catalyst for the Hantzsch synthesis using dimedone and 9 different
aromatic aldehydes, under reflux of ethanol (2.5-3.5 h) [27]. The
desired products were obtained in good yields (70-90%), although
no information on the recycling of the catalyst was described.
Continuing our interest on the use of zeolites as green cat-
alysts [28], in this work we report the promising application of
an ultra-stable (US) Y zeolite in the synthesis of a series of 1,4-
dihydropyridines.
As can be seen from Table 1, the USY zeolite showed to be the
most suitable for the studied MCR, providing compound 4a in 96%
yield (entry 9). Looking for a more efficient protocol, microwave
(MW) irradiation was tested, and for our delight, the desired prod-
uct was still obtained on the USY zeolite in the same yield in only
10 min (entry 10). We then evaluated the catalyst loading (entries
12-15), using 50 or 25 mg of the USY zeolite under MW irradiation
for 15, 20 or 25 min., and the best result was that of the entry 13,
where the Hantzsch ester 4a (Table 1), was isolated in 96% yield.
For the catalyst recycling study, the USY zeolite was separated
from the reaction mixture and washed 4-5 times with ethanol fol-
lowed by centrifugations for 5 min at 5000 W, and then reused. As
shown in Fig. 1, the yield was still very good (> 90%) up to the 4th
cycle.
2. Results and discussion
The zeolites were characterized by XRD, SEM analyses and N2
physisorption measurements. The XRD diffractograms of the ze-
olites in their protonic form, prepared as reported in previous
works [32], confirmed its respective type FAU crystalline struc-
ture (Fig. 2a) [33]. Coherent with their crystal sizes of about 1
μm or higher (Fig. 3), the USY, mordenite, ferrierite and ZSM-
5 zeolites present well resolved XRD patterns evidencing sam-
ples with high crystallinity (Fig. 4). The zeolite beta, constituted
by agglomerates of nanosized crystals, generated a less resolved
XRD pattern [34,35]. The textural properties of the studied zeolites
We initiated our study using dimedone, benzaldehyde, ammo-
nium acetate in ethanol as solvent and evaluating different cata-
lysts (Table 1) [29]. Through the data obtained in entries 1 and 2,
it is possible to notice that the reaction needs a catalyst to inten-
sify its performance. As copper has been reported to catalyze this
reaction [30], we tested CuCl2.2H2O (entries 3 and 4) and obtained
product 4a in good yields. However, aiming to develop more sus-
tainable synthetic methods, a metal-free condition would be de-
sired. Taking this into account, different zeolites, such as USY, ZSM-
2

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Table 2
Si/Al ratio and textural properties of the used zolites.
Microporeb Externalb
Structure, Micropore
system and pore
diameterc (nm)
volume
surface area
(m2ꢀg−1
)
Zeolite
Si/Ala
10
(cm3ꢀg−1
)
mordenite
0.159
0.118
0.159
0.160
0.273
53.4
MOR
1D–12/8-ring
0.71 × 0.62 / 0.48 × 0.38
ferrierite
ZSM-5
Beta
10
20
15
2.9
39.3
24.4
228
FER
2D–10/8-ring
0.42 × 0.54 / 0.35 × 0.48
MFI
3D–10-ring
0.56 × 0.53 / 0.55 × 0.51
BEA
3D–12-ring
0.66 × 0.77 / 0.56 × 0.56
USY
22.9
FAU
3D–12-ring
0.74
a
Si/Al ratio determined by EDX;
b
c
Calculated using the t-plot method [39];
Data from the International Zeolite Association [40].
(Table 2) clearly show a superior microporous volume for the USY
zeolite.
In order to better understanding its role of as heterogeneous
catalyst in the Hantzsch 3CR, the USY zeolite was also analysed
by in situ FTIR of adsorbed pyridine. The obtained results showed
that besides its 3D microporous structure [31] (Table 2) and the
above commented higher microporous volume (Table 2) and high
specific surface area (Table 3), the acidic nature of the USY active
sites (Table 3), was another important contributing factor on its
best catalytic behavior [37]. In this way, the USY zeolite, because
its lower Si/Al ratio, shows a high amount of active acid sites with
Brønsted nature (Fig. 2b and Table 3) [38].
Moreover, the high stability of the USY zeolite as catalyst is
demonstrated by XRD (Fig. 2a), textural (Table 3), and in situ
FTIR of adsorbed pyridine (Fig. 2b and Table 3) data, which were
Fig. 1. Yield of compound 4a for each reaction cycle using the USY zeolite as cata-
lyst.
Fig. 2. Fresh USY zeolite (in red) and USY zeolite recovered from the reaction mixture (in blue): (a) XRD diffractograms; (b) in-situ DRIFTS spectra of adsorbed pyridine [36].
Brønsted acid sites band at ~1545 cm−1, Lewis acid sites band at ~1450 cm−1
.
3

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Fig. 3. SEM micrograph of the used commercial zeolites: (a) ZSM-5; (b) USY; (c) ferrierite; (d) mordenite; (e) beta.
Fig. 5. MEV images showing the USY zeolite: (a) before (fresh) and (b) after (spent)
reaction.
(spent USY zeolite). As can be seen in Fig. 5, coherently with
the commented XRD and acidic properties stability, MEV images
did not show any changes in the original morphology of the USY
zeolite.
We then turned our attention for the evaluation of the scope
and limitation of this method using different aldehydes and dime-
done or ethyl acetoacetate. As can be observed on Table 4, in
general the best yields were obtained with dimedone probably
due to its higher acidity. It is worth to mention that pentan-
2,4-dione and heptan-3,5-dione have been tested as well, how-
ever the desired products were not obtained recovering the start-
ing material. Aromatic aldehydes containing both electron donor
and withdrawing groups were successfully employed furnishing
good to excellent isolated yields (entries 1-4), excepting for 4-
nitrobenzaldehyde as only traces of the desired product was ob-
served (entry 5). In order to obtain compounds 4e and 4o, we
have also tested the reactions under MW irradiation at 90 and 100
°C without success. When aliphatic aldehydes were tested, once
again the corresponding 1,4-dihydropyridines were obtained in
good yields (entries 6-8), including the new derivative 4h. Further-
more, heteroaromatic aldehydes could also be employed affording
the corresponding products in good yields (entries 9-10). Finally,
we have tested this protocol in the synthesis of acridinediones
using p-toluidine instead of ammonium acetate [16], and for our
delight the desired product 5 was obtained in 64% isolated yield
(Scheme 2).
Fig. 4. XRD diffractograms of the used protonic beta, ferrierite, mordenite and ZSM-
5 zeolites.
Table 3
Textural and acid properties of the USY zeolite.
Sample
1BET area (m2.g−1
)
2CBrønsted (μmol.g−1
)
3CLewis (μmol.g−1
)
4USYfresh
5USYspent
679
669
446
482
<15
<15
1
Specific surface area;
2
3
4
5
Brønsted acid sites;
Lewis acid sites
Before reaction;
After reaction.
obtained before (fresh USY) and after (spent USY) reaction. As
can be evidenced, the FAU structure (Fig. 2a), the specific sur-
face area (Table 3) and acidic properties (Table 3 and Fig. 2b),
of the fresh USY zeolite are practically preserved after reaction
4

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Table 4
Scope of the three-component reaction catalyzed by USY zeolite.
Entrya
Aldehyde (R1)
Yield (%)b with dimedone
Yield (%)b with ethyl acetoacetate
1
C6H5
4a, 96
4b, 95
4c, 83
4d, 83
4e, traces
4f, 87
4k, 90
4l, 83
2
4-CH3OC6H4
3-BrC6H4
4-NCC6H4
4-NO2C6H4
C6H11
3
4m, 75
4n, 78
4o, traces
4p, 62
4q, 64
4r, 60
4s, 88
4t, 85
4
5
6
7
(CH2)6CH3
(CH2)8CH3
C4H4S
4g, 72
4h, 80
4i, 88
8
9
10
NC5H4
4j, 85
a
All reactions were performed using aldehyde (0.5 mmol), diketone (1.0 mmol), ammonium acetate (1.25 mmol), USY
zeolite (50 mg) and EtOH (0.5 mL) under MW irradiation (110°C, 300 W) for 20 min.
b
Isolated yield after column chromatography.
Scheme 2. Synthesis of acridinedione 5.
3. Conclusion
of the zeolites were determined by scanning electron microscopy
with energy-dispersive X-ray spectroscopy (SEM-EDX) using a FEI
Magellan 400L electronic microscope.
In conclusion we report herein the promising application of an
USY zeolite as a green catalyst in the synthesis of a series of 1,4-
dihydropyridines under microwave irradiation. After simple recov-
ery, the USY zeolite could be reused up to the 4th cycle still fur-
nishing excellent isolated yield (> 90%) of compound 4a. The USY
zeolite was fully characterized in order to better understanding its
catalytic stability and its role of as heterogeneous catalyst. The best
catalytic behavior of the USY zeolite was attributed to its microp-
orous structure and their textural and acidic properties. Using such
USY zeolite and optimized reaction conditions, 21 compounds were
prepared in 64-96% isolated yields.
Analyses of in-situ FTIR of adsorbed pyridine were used to in-
vestigate the nature of the acid sites (Brønsted and Lewis) of the
fresh and spent USY zeolites [43]. The measurements were per-
formed using a high-temperature cell (Harrick) and a Bruker Ver-
tex 70 spectrometer equipped with a mercury cadmium telluride
detector. Prior to the measurement, the analyzed sample was pre-
treated at 350°C for 1 h under an argon flow (60 mL min−1
)
and then cooled to 150°C. Afterward, the sample was saturated
by pulses of pyridine vapor. The excess and the weakly adsorbed
pyridine on the zeolite surface were purged with an argon flow
(60 mL min−1) for 2 h. Finally, the sample was analyzed in the re-
gion from 1700 to 1400 cm−1 with a nominal resolution of 4 cm−1
and accumulation of 180 scans. All the spectra of adsorbed pyri-
dine were collected at 150°C and removed from the spectrum of
the zeolite before adsorption. A reference spectrum was acquired
for dried KBr, under the same conditions. The concentration of
Brønsted and Lewis acid sites was estimated using the equations
CBrønsted = AB/(ɛB∗α) and CLewis = AL/(ɛL∗α), where AB and AL
are the areas of the bands at around 1545 cm−1 (pyridinium ions
bonded to Brønsted acid sites) and 1450 cm−1 (pyridine coordi-
nated to Lewis acid sites), respectively; ɛL (1.73 cm μmol−1) and
ɛB (1.23 cm μmol−1) are the extinction coefficients related to the
Lewis and Brønsted acid sites [39], respectively; and α is the ratio
of the sample mass to the pellet area.
4. Experimental section
4.1. Zeolites characterization
The zeolites used in this study were prepared as reported in
previous works [32], and only one batch of each catalyst has been
used. The X-ray diffractograms of the used zeolites were collected
between 5 and 50° (2θ) with a step-rate of 10° (2θ) min−1, us-
ing a Rigaku Miniflex diffractometer operated with Cu Kα radia-
˚
tion (λ = 1.5418 A) at 40 kV and 30 mA. The specific surface area
(BET) of the USY zeolite was obtained from N2 physisorption data
at -196°C using a Micromeritics ASAP-2020 apparatus. Prior to the
analysis, the zeolite was degassed for 5 h at 300°C under a vac-
uum of 20 μmHg. The micropores volume and the external specific
surface area were estimated using the t-plot method, assuming the
Harkins–Jura thickness equation [41]. Taking into consideration the
criteria recommended by IUPAC [42], values of the apparent BET
surface area at P/P0=0.95 of the fresh and spent USY zeolite were
determined. The morphological characteristics and the Si/Al ratio
4.2. Synthesis of 1,4-dihydropyridines
The commercially available reagents were purchased from
Sigma-Aldrich or Alfa Aesar and, when necessary, treated accord-
ing to the procedures described in the literature. The purification
5

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Light yellow solid (0.154g, 87%), m.p. 249-251°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 6.95 (bs, 1H), 4.05 (s, 1H), 2.42-2.20 (m,
9H), 1.62 (t, J = 14.8 Hz, 5H), 1.40-1.19 (m, 3H), 1.14 (s, 6H), 1.09
(s, 6H), 0.91-0.81 (m, 2H).
of the products was performed by a flash chromatographic column,
using silica gel 60, 230-400 mesh ASTM Merck and silica gel 60
A, 70-230 mesh AldrichCo. The thin layer chromatography anal-
yses were carried out on silica gel 60 F254 plates supported on
aluminum sheets and developed under ultraviolet light and / or
stained in an acid vanillin. The solvent excess was evaporated in
Buchi Rotavapor R-114 with BuchiWatherbath B-490 bath. The Nu-
clear Magnetic Resonance spectra (1H and 13C NMR) were recorded
on the Bruker ARX 400 MHz spectrometers. The chemical shifts (δ)
are expressed in ppm and the coupling constants (J) in Hertz (Hz).
To indicate the multiplicity of signs, the following abbreviation
was used: s (singlet), d (doublet), dd (double doublet), t (triplet),
m (multiplet). Mass Spectra were recorded on a Shimadzu GCMS-
QP5000. The reactions using microwaves were performed using a
CEM Discovery equipment making use of the equipment’s cooling
system in all reactions.
3,3,6,6-tetramethyl-9-heptyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4g) [8]:
Yellow solid (0.133g, 72%), m.p. 109-111°C. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.63 (s, 1H), 4.06 (t, J = 4.9 Hz, 1H), 2.42-2.19 (m,
8H), 1.44-1.14 (m, 12H), 1.10 (s, 6H), 1.09 (s, 6H), 0.82 (t, J = 6.8
Hz, 3H).
3,3,6,6-tetramethyl-9-nonyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4h):
Yellow solid (0.159g, 80%), m.p. 134-137°C. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.06 (bs, 1H), 4.07 (t, J = 4.8 Hz, 1H), 2.37-2.23 (m,
8H), 1.44-1.16 (m, 16H), 1.10 (s, 6H), 1.09 (s, 6H), 0.87 (t, J = 6.8 Hz,
3H). 13C NMR (101 MHz; CDCl3) δ 196.1, 149.8, 112.7, 51.0, 41.1, 35.1,
32.5, 31.9, 30.0, 29.7, 29.7, 29.6, 29.3, 27.2, 27.1, 25.4, 22.7, 14.1. GC-
MS (70 eV) m/z (%): 434.4 (100), 406.3, 398.3, 339.1, 325.1, 311.2.
3,3,6,6-tetramethyl-9-(thiophen-2-yl)-3,4,6,7,9,10-
4.2.1. General procedure
In a sealed tube, a mixture of diketone or β-ketoester (1.0 mol),
aldehyde (0.5 mol) and ammonium acetate or p-toluidine (1.25
mol) was carried out with the zeolite catalyst USY (50 mg) at 0.5
mL of ethanol, heated to 110°C (300 W) in an oil bath or under
microwave irradiation (300 W) for the time required for product
formation. The progress of the synthesis was verified by TLC. Af-
ter completing the time proposed in the optimization of the reac-
tion, the reaction mixture was diluted with ethanol (5-6 mL) and
the catalyst was separated by centrifugation, along 3 processes fol-
lowed by washing of the mixture composed of the desired product
diluted in ethanol and the heterogeneous catalyst, this solvent be-
ing eliminated by vacuum, resulting in a solid that was purified by
column chromatography using hexane / ethyl acetate as eluent.
For the catalyst recycling study, the zeolite was separated from
the reaction mixture and washed 4-5 times with ethanol followed
by centrifugations for 5 min at 5000 W. At the end of each wash-
ing process, the zeolite was placed in the kiln to remove the re-
maining ethanol and then weighed to be reused. In all cycles the
catalyst was practically fully recovered, that is, in all syntheses it
was possible to use approximately 50 mg of USY zeolite.
hexahydroacridine-1,8 (2H,5H)-dione (4i) [9]:
Light orange solid (0.155g, 80%); m.p. 284-286°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 6.98 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 3.1
Hz, 1H), 6.83-6.80 (m, 1H), 6.12 (bs, 1H), 5.40 (s, 1H), 2.37-2.25 (m,
8H), 1.10 (s, 6H), 1.04 (s, 6H).
3,3,6,6-tetramethyl-9-(pyridin-2-yl)-3,4,6,7,9,10-
hexahydroacridine-1,8 (2H,5H)-dione (4j) [9]:
Light orange solid (0.148g, 85%), m.p. 299-301°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 8.81 (d, J = 4.6 Hz, 1H), 7.61 (d, J = 7.7
Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.01-6.96 (m, 1H), 6.55 (bs, 1H),
5.20 (s, 1H), 2.35-2.15 (m, 8H), 1.07 (s, 6H), 0.98 (s, 6H).
Diethyl-2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate (4k) [44]:
Light yellow solid (0.168g, 90%), m.p. 155-157°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.24 (d, J = 1.9 Hz, 2H), 7.17 (t, J = 7.4 Hz,
2H), 7.09 (t, J = 7.2 Hz, 1H), 5.58 (bs, 1H), 4.96 (s, 1H), 4.10-4.01
(m, 4H), 2.30 (s, 6H), 1.19 (t, J = 7.1 Hz, 6H).
Diethyl-4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (4l) [21]:
Light yellow solid (0.148g, 83%); m.p. 164-166°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.19 (d, J = 8.0 Hz, 2H), 6.74 (d, J = 8.1
Hz, 2H), 5.70 (bs, 1H), 4.92 (s, 1H), 4.13-4.04 (m, 4H), 3.74 (s, 3H),
2.31 (s, 6H), 1.22 (t, J = 7.1 Hz, 6H).
4.2.2. Compounds characterization
3,3,6,6-tetramethyl-9-phenyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4a) [8]:
Light yellow solid (0.167g, 96%), m.p.190-192°C. 1H NMR (CDCl3,
400 MHz, ppm) δ 8.00 (bs, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.18 (t,
J = 7.4 Hz, 2H), 7.06 (t, J = 7.2 Hz, 1H), 5.08 (s, 1H), 2.32-2.10 (m,
8H), 1.05 (s, 6H), 0.94 (s, 6H).
Diethyl-4-(3-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4m) [44]:
Yellow solid (0.153g, 75%), m.p. 112-114°C. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.45 (bs, 1H), 7.35-7.29 (m, 2H), 7.07 (t, J = 7.8 Hz,
1H), 5.98 (s,1H), 4.94 (s, 1H), 4.12-4.05 (m, 4H), 2.31 (s, 6H), 1.21
(t, J = 6.8 Hz, 6H).
9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione (4b) [10b]:
Light yellow solid (0.180g, 95%), m.p. 270-272°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.96 (bs, 1H), 7.22-7.26 (m, 2H), 6.71 (d,
J = 8.4 Hz, 2H), 5.03 (s, 1H), 3.66 (s, 3H), 2.11-2.27 (m, 8H), 1.05
(s, 6H), 0.94 (s, 6H).
Diethyl-4-(4-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (4n) [21]:
Brown solid (0.138g, 78%); m.p. 192-194°C. 1H NMR (CDCl3, 400
MHz, ppm) δ 7.50 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 5.80
(bs, 1H), 5.03 (s, 1H), 4.12-4.04 (m, 4H), 2.34 (s, 6H), 1.20 (t, J = 7.1
Hz, 6H).
9-(3-bromophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-
hexahydroacridine-1,8 (2H,5H)-dione (4c) [8]:
Light yellow solid (0.170g, 83%), m.p. 286-288°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.44 (bs, 1H), 7.35 (bs, 1H), 7.25 (d,
J = 7.6 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H),
4.98 (s, 1H), 2.28-2.18 (m, 4H), 2.18–2.06 (m, 4H), 1.01 (s, 6H), 0.91
(s, 6H).
Diethyl-4-cyclohexyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4p) [44]:
Orange solid (0.100g, 60%); m.p. 112-114°C. 1H NMR (CDCl3, 400
MHz, ppm) δ 5.61(bs,1H), 4.23–4.12 (m, 4H), 3.91 (d, J=5.4 Hz, 1H);
2.29 (s, 6H), 1.54 (d, J = 12.0 Hz, 4H), 1.29 (t, J =7.1 Hz, 9H), 1.06
(d, J =7.2 Hz, 4H).
4-(3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-
decahydroacridin-9-yl) benzonitrile (4d) [14]:
Diethyl-4-heptyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4q) [45]:
Light yellow solid (0.155g, 83%), m.p. 298-300°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.47 (dd, J = 18.6, 8.0 Hz, 4H), 6.00 (bs,
1H), 5.03 (s, 1H), 2.40-2.16 (m, 8H), 1.03 (s, 6H), 0.89 (s, 6H).
9-cyclohexyl-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-
1,8(2H,5H)-dione (4f) [12]:
Orange oil (0.112g, 64%). 1H NMR (CDCl3, 400 MHz, ppm) δ 5.62
(bs, 1H), 4.23-4.11 (m, 4H), 3.91 (t, J = 5.8 Hz, 1H), 2.27 (s, 6H),
1.35-1.25 (m, 12H), 1.20 (bs, 6H), 0.85 (t, J = 7.0 Hz, 3H).
6

ARTICLE IN PRESS
JID: MOLSTR
[m5G;October 15, 2020;13:31]
L.H.R. Alponti, M. Picinini, E.A. Urquieta-Gonzalez et al.
Journal of Molecular Structure xxx (xxxx) xxx
Diethyl-2,6-dimethyl-4-nonyl-1,4-dihydropyridine-3,5-
dicarboxylate (4r) [46]:
[9] C.A. Navarro, C.A. Sierra, C. Ochoa-Puentes, RSC Adv. 6 (2016) 65355–65365.
[10] (a) M.A. Zolfigol, M. Safaiee, Synlett
G.-W. Wang, Arkivoc 16 (2008) 1–8.
5 (2004) 827–828; (b) Y.-S. Bing,
Orange oil (0.113g, 60%). 1H NMR (CDCl3, 400 MHz, ppm) δ
5.85-5.75 (m, 1H), 4.20-4.09 (m, 4H), 3.89 (t, J = 5.7 Hz, 1H), 2.25
(s, 6H), 1.30-1.22 (m, 12H), 1.21 (bs, 10H), 0.85 (t, J = 5.6 Hz, 3H).
Diethyl-2,6-dimethyl-4-(thiophen-2-yl)-1,4-dihydropyridine-3,5-
dicarboxylate (4s) [21]:
[11] R. Osnaya, G.A. Arroyo, L. Parada, F. Delgado, J. Trujillo, M. Salmón, R. Miranda,
Arkivoc 11 (2003) 112–117.
[12] C.M. Kormos, R.M. Hull, N.E. Leadbeater, Aust. J. Chem. 62 (2009) 51–57.
[13] (a) L. Ohberg, J. Westman, Synlett
8 (2001) 1296–1298; (b) S.K. Singh,
K.N. Singh, J. Heterocycl. Chem. 48 (2010) 69–73; (c) J.C. Legay, E.J.J. Vanden,
J.P. Bazureau, Tetrahedron 61 (2005) 12386–12397.
Light yellow solid (0.147g, 88%); m.p. 170-172°C. 1H NMR
(CDCl3, 400 MHz, ppm) δ 7.04 (d, J = 5.0 Hz, 1H), 6.84 (t, J = 4.2
Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H), 5.88 (bs, 1H), 5.34 (s, 1H), 4.25-
4.08 (m, 4H), 2.33 (s, 6H), 1.27 (t, J = 7.0 Hz, 6H).
Diethyl-2,6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-
dicarboxylate (4t) [22]:
[14] M. Patil, S. Karhale, A. Kudale, A. Kumbhar, S. More, V. Helavi, Curr. Sci. 6
(2019) 936–942.
[15] R.A. Sheldon, J. R. Soc. Interface 13 (2016) 20160087.
[16] J. Cejka, H. van Bekkum, A. Corma, F. Schüth, Introduction to Zeolite Science
and Practice (Studies in Surface Science and Catalysis), 168, 3rd ed, Elsevier
Science, 2007.
[17] C.G.S. Lima, N.M. Moreira, M.W. Paixão, A.G. Corrêa, Curr. Opin. Green Sustain.
Chem. 15 (2019) 7–12.
Brown solid (0.140g, 85%); m.p. 194-196°C. 1H NMR (CDCl3, 400
MHz, ppm) δ 9.03 (d, J = 13.3 Hz, 1H), 8.47 (d, J = 4.8 Hz, 1H),
7.58 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.16-7.11 (m, 1H),
5.18 (s, 1H), 4.04 (q, J = 7.0 Hz, 4H), 2.22 (s, 6H), 1.18 (t, J = 7.1 Hz,
6H).
[18] S.S. Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan, J. Taibah. Univ. Sci. 8 (2014)
265–275.
[19] M.A. Chari, K. Syamasundar, Catal. Commun. 6 (2005) 624–626.
[20] D. Angeles-Beltrán, L. Lomas-Romero, V.H. Lara-Corona, E. González-Zamora,
G. Negrón-Silva, Molecules 11 (2006) 731–738.
[21] A. Teimouri, L. Ghorbanian, A. Moatari, Bull. Chem. Soc. Ethiopia 27 (2013)
427–438.
[22] M. Jagadale, D. Kale, R. Salunkhe, M. Rajmane, G. Rashinkar, J. Molec. Liq. 265
(2018) 525–535.
3,3,6,6-tetramethyl-9-phenyl-10-(p-tolyl)-3,4,6,7,9,10-
hexahydroacridine-1,8(2H,5H)-dione (5) [18]:
Orange solid (0.140g, 64%); m.p.265-267 °C. 1H NMR (CDCl3,
400 MHz, ppm) δ 7.28 (d, J = 4.2 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H),
7.10 (t, J = 7.2 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.71 (d, J = 8.0 Hz,
2H), 5.26 (s, 1H), 2.47 – 2.18 (m, 11H), 1.11 (s, 6H), 1.01 (s, 6H).
[23] T. Momeni, M.M. Heravi, T. Hosseinnejad, M. Mirzaei, V. Zadsirjan, J. Mol.
Struct. 1199 (2020) 127011.
[24] T. Ennaert, J. Van Aelst, J. Dijkmans, R. De Clercq, W. Schutyser, M. Dusselier,
D. Verboekend, B.F. Sels, Chem. Soc. Rev. 45 (2016) 584–611.
[25] F.-S. Xiao, X. Meng, Zeolites in Sustainable Chemistry, 1st ed, Springer, Heidel-
berg, 2016.
[26] R. Srivastava, Catal. Today 309 (2018) 172–188.
Declaration of Competing Interest
There are no conflicts to declare.
[27] M. Nikpassand, M. Mamaghani, K. Tabatabaeian, Molecules 14 (2009)
1468–1474.
[28] (a) E. Jorge, T.M. Lima, C.G.S. Lima, L. Marchini, W.N. Castelblanco, D.G. Rivera,
E.A. Urquieta-González, R.S. Varma, M.W. Paixão, Green Chem. 19 (2017)
3856–3868; (b) T.M. Lima, C.G.S. Lima, A.K. Rathi, M.B. Gawande, J. Tuce,
E.A. Urquieta-González, R. Zborˇil, M.W. Paixão, R.S. Varma, Green Chem. 18
(2016) 5586–5593.
CRediT authorship contribution statement
[29] G. Busca, Micropor. Mesopor. Mat. 254 (2017) 3–16.
[30] (a) M.G. Dekamin, E. Kazemi, Z. Karimi, M. Mohammadalipoor, M.R. Naimi-Ja-
mal, Int. J. Biol. Macromol. 93 (2016) 767–774; (b) K.K. Pasunooti, C.N. Jensen,
H. Chai, M.L. Leow, D.W. Zhang, X.W. Liu, J. Comb. Chem. 12 (2010) 577–581.
[31] C.H. Baerlocher, L.B. McCusker, D.H. Olson, Atlas of Zeolite Framework Types,
6th edition, Elsevier, Amsterdam, 2007.
Leonardo H.R. Alponti: Conceptualization, Methodology.
Monize Picinini: Investigation, Formal analysis. Ernesto A.
Urquieta-Gonzalez: Supervision, Writing - original draft. Arlene G.
Corrêa: Supervision, Writing - review & editing.
[32] (a) D.S. Ferracine, E. D., K.T.G. Carvalho, D.S.A. Silva, E.A. Urquieta-Gonzalez,
Catal. Lett. (2020), doi:10.1007/s10562-020-03262-4; (b) K.T.G. Carvalho,
D.S. Araújo Silva, E.A. Urquieta-Gonzalez, Ind. Eng. Chem. Res. 58 (2019) 7044–
7051, doi:10.1007/s10562-020-03262-4.
Acknowledgements
The authors gratefully acknowledge FAPESP (grants 2013/07600-
3, 2014/50249-8 and 2018/12367-0), GlaxoSmithKline, CAPES
(Finance Code 001), and CNPq (grant 429748/2018-3 and
302140/2019-0) for funding and fellowships.
[33] M.M.J. Treacy, J.B. Higgins, Collection of Simulated XRD Powder Patterns for
Zeolites, 5th edition, Elsevier, Amsterdam, 2007.
[34] S. Mintova, V. Valtchev, T. Onfroy, C. Marichal, H. Knözinger, T. Bein, Micropor.
Mesopor. Mat. 90 (2006) 237–245.
[35] A. Corma, M. Moliner, Á. Cantín, M.J. Díaz-Cabañas, J.L. Jordá, D. Zhang, X. Zou,
Chem. Mater. 20 (2008) 3218–3223.
[36] (a) D.S.A. Silva, W.N. Castelblanco, D.H. Piva, V. de Macedo, K.T.G. Carvalho,
E.A. Urquieta-González, Mol. Catal. 492 (2020) 11026; (b) F. Jin, Y. Li, Catal.
Today. 145 (2009) 101–107.
Supplementary materials
[37] K.Y. Nandiwale, P. Gogoi, V.V. Bokade, Chem. Eng. Res. Des. 98 (2015) 212–219.
[38] J. Liu, N. Ding, X. Hong, S. Zhou, X. Zhou, J.A. Wang, L. Chen, Catal. Lett. 150
(2020) 2996–3006.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129430.
[39] P. Schneider, P. Hudec, O. Solcova, Micropor. Mesopor. Mater. 115 (2008)
491–496.
References
[40] M.M.J. Treacy, J.B. Higgins, Collection of Simulated XRD Powder Patterns for
Zeolites, 5th ed., Elsevier, Amsterdam, 2007.
[1] R.A. Sheldon, Green Chem. 19 (2017) 18–43.
[2] D. Das, Chemistry Select 1 (2016) 1959–1980.
[41] B.C. Lippens, J.H. de Boer, J. Catal. 4 (1965) 319–323.
[42] M. Thommes, K. Kaneko, A.V. Neimark, J.P. Olivier, F. Rodriguez-Reinoso, J. Rou-
querol, K.S.W. Sing, Pure Appl. Chem. 87 (2015) 1051–1069.
[43] M. Tamura, K.-I. Shimizu, A. Satsuma, Appl. Catal. A: General 433-434 (2012)
135–145.
[3] (a) A. Saini, S. Kumar, J.S. Sandhu, J. Sci. Ind. Res. 67 (2008) 95–111; (b)
F. Bossert, H. Meyer, E. Wehinger, Angew. Chem. Int. Ed. 20 (1981) 762–769.
[4] S. Sepehri, H.P. Sanchez, A. Fassihi, J. Pharm. Pharmac. Sci. 18 (2015) 1–52.
[5] P.-Z. Wang, J.-R. Chen, W.-J. Xiao, Org. Biomol. Chem. 17 (2019) 6936–6951.
[6] H.G.O. Alvim, E.N. da Silva Júnior, B.A.D. Neto, RSC Adv. 4 (2014) 54282–54299.
[7] (a) S. Farooq, M.A. Munawar, Z. Ngani, Curr. Org. Chem. 22 (2018) 2671–2680;
(b) L.L. Lu, H. Xu, P. Zhou, F.C. Yu, Chin. J. Org. Chem. 36 (2016) 2858–2879; (c)
D.M. Stout, A.I. Meyers, Chem. Rev. 82 (1982) 223–243.
[44] C.-C. Chang, S. Cao, S. Kang, L. Kai, X. Tian, P. Pandey, R.B. Silverman, Bioorg.
Med. Chem. 18 (2010) 3147–3158.
[45] D. Zhang, M. Sha, J. Chem. Res. 42 (2018) 141–144.
[46] K. Nakajima, Y. Zhang, Y. Nishibayashi, Org. Lett. 21 (2019) 4642–4645.
[8] K.N. Tiwari, M.R. Uttam, P. Kumari, P. Vatsa, S.M. Prabhakaran, Synth. Commun.
47 (2017) 1013–1019.
7