An efficient, one-pot synthesis of polyfunctionalised dihydropyridines catalysed by AgI nanoparticles

Article abstract of DOI:10.3184/174751914X13976454726953

Polyfunctionalised dihydropyridines were synthesised in high yields and in short reaction times by a four-component reaction of araldehydes, dimedone, ethyl acetoacetate and ammonium acetate in the presence of AgI nanoparticles in aqueous ethanol media un

Full text of DOI:10.3184/174751914X13976454726953

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MAY, 313–316
RESEARCH PAPER 313
An efficient, one-pot synthesis of polyfunctionalised dihydropyridines
catalysed by AgI nanoparticles
Mohammad Ali Ghasemzadeh* and Javad Safaei-Ghomi
Department of Chemistry, Qom Branch, Islamic Azad University, Qom, Iran
Polyfunctionalised dihydropyridines were synthesised in high yields and in short reaction times by a four-component reaction
of araldehydes, dimedone, ethyl acetoacetate and ammonium acetate in the presence of AgI nanoparticles in aqueous ethanol
media under reflux conditions. The catalyst was easily prepared and was recyclable.
Keywords: AgI nanoparticles, hexahydroquinoline, aqueous media, multi-component reaction
Multi-component reactions (MCRs) are special types of
synthetically useful organic reactions in which three or more
various substrates react to give a final product in a one-pot
procedure.1 Clearly, for multi-step synthetic pathways the
number of reaction and purification steps is among the most
important criteria for the efficiency and ability of the process
and should be as low as possible.2 Recently, the research and
discovery of new MCRs, have gained tremendous importance.
In addition the formation of carbon–carbon and carbon–
heteroatom bonds by MCRs is known in multitudinous
compounds that are of pharmaceutical, biological and material
interest.3
selectivity, different from those obtained in conventional
organic solvents.19 The significant enhancement in the rate of
reaction has been attributed to hydrophobic packing, solvent
polarity, hydration, and hydrogen bonding.20
The last decade has witnessed enormous developments in the
field of nanoscience and nanotechnology. Several reports show
an amazing level of performance of nanoparticles as catalysts in
terms of selectivity, reactivity and improved yields of products.
In addition, the high surface-to-volume ratio of nanoparticles
provides a larger number of active sites per unit area compared
to their heterogeneous counter parts.21,22Among different
metal nanoparticles, silver nanoparticles have received great
attention because of their significant properties and potential
applications in various reaction types.23 Silver nanoparticles,
generally require only mild reaction conditions to produce high
yields of products in short reaction times in comparison with
traditional catalysts and can be recycled.24
Nitrogen-containing
heterocyclic
compounds
are
widespread in nature and their applications as biologically
active pharmaceuticals, agrochemicals and functional
materials are becoming more and more important.4 Therefore,
the development of new efficient methods for synthesis of
N-heterocycles is a major interest of modern synthetic organic
chemistry.5 The four-component Hantzsch dihydropyridine
synthesis is a versatile procedure to achieve a class of
pharmaceutically important dihydropyridines including
polyhydroquinoline derivatives.
Recently, much attention has been paid to the synthesis
of polyhydroquinolines because these compounds possess
important pharmaceutical, antifungal, antitumor and other
biological properties,6–8 and have found wide usage as
drugs including nifedipine, nicardipine and amlodipine.9
Consequently, much attention has been paid to the development
of new methodologies for the preparation of polyhydroquinoline
derivatives.
Indeed, the syntheses of polyhydroquinolines have recently
been reported via the four-component coupling of aldehydes,
dimedone, ethyl acetoacetate and ammonium acetate in the
presence of diverse catalysts such as, Yb(OTf)3,10 molecular
iodine,11 Baker’s yeast,12 ZrCl4,13 p‑TSA,14 HClO4–SiO2,15
L-proline,16 BF3.SiO2,17 and Ni nanoparticles.18
Organic reactions in aqueous media have attracted much
attention in organic chemistry, not only because water is one
of the most abundant, cheapest, and environmentally friendly
solvents but also because it exhibits unique reactivity and
Recently, silver nanoparticles have been used as a robust
catalyst in many organic reactions including synthesis of
β-enaminones,25 oxidation reactions,26 three-component
couplings
of
aldehyde–amine–alkyne,27
Diels−Alder
cycloadditions of 2′‑hydroxychalcones,28 dehydrogenation
reactions29 and carbon–carbon coupling reactions.30
In continuation of our previous studies on the applications
of heterogeneous nanoparticles in MCRs,31–36 we report here
a highly efficient one-pot synthesis of polyhydroquinolines
via multi-component coupling in the presence of silver iodide
nanoparticles as a recyclable catalyst in aqueous ethanol media
(Scheme 1).
Results and discussion
The XRD pattern of AgI nanoparticles is shown in Fig. 1A.
All the reflection peaks in Fig. 1A can be readily indexed to
pure cubic phase of AgI with F-43m space group (JCDPS No.
78-0641). The crystallite size of AgI was 18 nm.
Figure 1B shows the FT-IR spectrum of AgI nanoparticles.
The broad peaks at 3436 cm–1 and 1628 cm–1 can be attributed
to ν (OH) stretching and bending vibrations, respectively, so
that, these peaks indicate the presence of physisorbed water on
the nanoparticles.
O
Ar
O
O
O
O
O
AgI NPs
OEt
CH3
+
+
+
NH
4OAc
H
3C
OEt
Reflux, H2O/ EtOH
Ar
H
O
N
H
1
2
4
5
3
Scheme 1
* Correspondent. E-mail: ghasemzadeh@qom-iau.ac.ir

314 JOURNAL OF CHEMICAL RESEARCH 2014
Fig. 1 The XRD pattern (A) and FT-IR spectrum (B) of silver iodide nanoparticles.
The size and morphology of silver iodide nanoparticles
were analysed by scanning (SEM) and transmission electron
microscopy (TEM). The SEM results (Fig. 2A) show that these
catalysts are nanostructures, and that a single phase primary
particle is spherical in shape with the average diameter between
40 and 50 nm. The TEM results (Fig. 2B) show that these
nanocatalysts consist of spherical particles with the crystallite
size between 15 and 20 nm, confirming the results calculated
from Scherrer’s equation based on the XRD pattern.
Reaction conditions were optimised on the basis of the
catalyst, solvent and reactants for carbon–carbon and carbon–
heteroatom bonds formation. To test the efficiency of catalytic
activity, we focussed our initial studies on a cyclisation model
reaction in the presence of different nanocatalysts such as
L-proline, Mn3O4, MgO, p-TSA, and AgI. We selected as
the model reaction a four-component MCR consisting of
During optimisation of the reaction conditions, we ran the
model reaction using AgI nanoparticles in various solvents and
under solvent-free conditions. The results (Table 2) show that a
mixture of water/ethanol is the most effective solvent for this
multi-component reaction. This is not surprising in view of
the fact that the hydrogen bonding between water/ethanol and
substrate can prompt the nucleophilic attack of the reactants.
In order to optimise the ratio of reactants, the model reaction
was carried out several times using AgI nanoparticles. The best
results were obtained when 4-nitrobenzaldehyde, dimedone,
ethyl acetoacetate and ammonium acetate were used as
substrates in a 1:1:1:1.5 mol ratio. To study the scope of this
procedure, next we used a variety of aldehydes in the four-
component reaction under the optimum conditions (Scheme 1,
Table3). ThedataofTable3showthataraldehydeswithelectron-
withdrawing groups such as NO2, Cl and Br (entries 6–9) reacted
4-nitrobenzaldehyde
1 (Ar=4-nitrophenyl), dimedone 2,
ammonium acetate 3 and ethyl acetoacetate 4 the yields of
which were determined using 20 mol% of various catalysts in
aqueous EtOH at reflux (Scheme 1).
Table 1 Yields of hexahydroquinoline 5g from reaction between
4-nitrobenzaldehyde 1 (Ar=4-nitrophenyl), dimedone 2, ammonium acetate
3 and ethyl acetoacetate 4 using 20 mol% of various catalysts in aqueous
EtOH at reflux (Scheme 1)
The results showed that AgI is the most effective catalyst
for this annulation reaction (Table 1, entries 1–5), so we were
encouraged to perform the model reaction in the presence of
silver iodide nanoparticles. As shown in Table 1 (entry 6), nano
AgI afforded an excellent yield in a shorter reaction time in
comparison with bulk AgI. Subsequently, we found the use of
10 mol% of this catalyst was sufficient, since an increase in the
amount of the catalyst did not change the yield or shorten the
reaction time.
Entry
Catalyst
Time/h
Yield/%a
1
2
3
4
5
6
L-proline
Mn3O4
MgO
p-TSA
AgI
2.5
3
4
2
1.5
0.75
65
45
50
70
75
92
AgI NPs
aIsolated yield.
Fig. 2 SEM (A) and TEM (B) images of AgI nanoparticles.

JOURNAL OF CHEMICAL RESEARCH 2014 315
Table 2 Yields of hexahydroquinoline 5g from reaction between
4-nitrobenzaldehyde 1 (Ar=4-nitrophenyl), dimedone 2, ammonium acetate
3 and ethyl acetoacetate 4 using 10 mol% AgI NPs as catalyst in various
solvents at reflux and under solvent-free conditions (Scheme 1)
400 MHz spectrometer (1H NMR at 400 Hz, 13C NMR at 100 Hz) in
CDCl3 using TMS as internal standard. Chemical shifts (δ) were given
in ppm and coupling constants (J) in Hz.
FT-IR spectra were recorded on
a Magna-IR, 550 Nicolet
Entry
Solvent
Time/h
Yield/%a
spectrometer in KBr pellets. The elemental analyses were obtained
from a Carlo ERBA Model EA 1108 analyser. Powder X-ray diffraction
(XRD) was carried out on a Philips diffractometer of X’pert Company
with mono chromatised Cu Kα radiation (λ=1.5406 Å). Microscopic
morphology of products was visualised by SEM (LEO 1455VP).
Transmission electron microscopy (TEM) was performed with a Jeol
JEM-2100UHR, operated at 200 kV.
1
2
3
4
5
6
Noneb
EtOH
DMF
Toluene
H2O
2
2
3.5
5
2.5
0.75
50
70
55
30
65
92
H2O/EtOH
aIsolated yield.
Synthesis of AgI nanoparticles
bSolvent-free 120 °C.
A solution of 0.415 g KI (25×10–4 mol) in distilled water (25 mL)
was added dropwise to a solution of AgNO3 [0.425 g, 25×10–4 mol
in distilled water (25 mL)] under ultrasound power in the presence
of 0.2 g SDS as surfactant. The yellow as-synthesised precipitate
was separated by centrifugation and washed with distilled water and
ethanol to remove impurities for several times and then dried.
Table 3 Yields of hexahydroquinolines 5a–n using 10 mol% AgI NPs as
catalysta
Araldehyde
(RCHO)
Entry
Product Time/min Yield/%b M.p./oC (lit. /oC)
201–203
1
2
C6H5
5a
5b
5c
5d
5e
5f
55
60
60
75
65
50
45
48
45
50
50
70
60
65
90
86
88
80
85
90
92
90
94
90
90
80
85
88
(202–204)17
212–214c
Synthesis of polyhydroquinolines (5a–n); general procedure
A mixture of aldehyde (1 mmol), dimedone (1 mmol), ammonium
acetate (1.5 mmol), ethyl acetoacetate (1 mmol) and AgI NPs (0.02 g,
0.1 mmol, 10 mol%) in (1:1) EtOH:H2O (5 mL) was refluxed in an oil
bath for appropriate times. The progress of the reaction was monitored
by TLC. After the reaction was complete, the mixture was cooled to
room temperature and then centrifuged to separate the catalyst. Then,
the solvent was evaporated and the solid obtained recrystallised from
ethanol to afford the pure polyhydroquinolines. All of the products
were characterised by m.p., 1H NMR, 13C NMR and FT-IR techniques.
Ethyl 2,7,7‑trimethyl‑5‑oxo‑4‑(m‑tolyl)‑1,4,5,6,7,8‑hexahydro‑
quinoline‑3‑carboxylate (5b): Yellow solid, m.p. 212–214 °C (EtOH);
FT-IR (cm–1): 3322 (NH), 3056, 1694 (C=O), 1612 (C=O), 1548, 1481
(C=C), 1363, 1212 (C–O); 1H NMR: δ 0.98 (6H, s, 2×CH3), 1.28 (3H, t,
J=7.1 Hz, OCH2CH3), 2.22 (3H, s, CH3¬), 2.25–2.29 (4H, m, 2×CH2),
2.33 (3H, s, Ar–CH3), 4.21 (2H, q, J=7.1 Hz, OCH2CH3), 4.91 (1H, s,
3-CH3C6H4
4-CH3C6H4
2-OMeC6H4
4-OMeC6H4
3-NO2C6H4
4-NO2C6H4
4-BrC6H4
262–263
3
(261–263)17
4
206–208c
254–256
5
(255–257)17
173–175
6
(174–176)17
245–247
7
5g
5h
5i
(244–246)17
252–253
8
(252–253)17
245–246
9
4-ClC6H4
(245–247)17
184–185
CH), 6.11 (1H, s, NH), 7.08 (1H, s, ArH), 7.22–8.43 (3H, m, ArH); 13
C
10
11
12
13
14
4-FC6H4
5j
(185–186)15
NMR: 14.2, 19.2, 23.1, 27.2, 32.8, 40.3, 44.2, 47.2, 56.1, 102.1, 111.6,
123.8, 125.9, 135.1, 142.2, 145.1, 148.7, 167.2, 191.1. Anal. calcd for
C22H27NO3 (Mr =353.20): C, 74.76; H, 7.70; N, 3.96; found: C, 74.61; H,
7.78; N, 4.06%.
4-CHOC6H4
3-OHC6H4
4-OHC6H4
4-N(CH3)2C6H4
5k
5l
196–197c
217–219
(218–220)17
Ethyl‑4‑(2‑methoxyphenyl)‑2,7,7‑trimethyl‑5‑oxo‑1,4,5,6,7,8‑
hexahydroquinoline‑3carboxylate (5d): Yellow solid, m.p. 206–208°C
(EtOH); FT-IR (cm–1): 3311(NH), 3076, 1691 (C=O), 1614 (C=O), 1526,
1485 (C=C), 1379, 1226 (C–O); 1H NMR: δ 0.96 (6H, s, 2×CH3), 1.22
(3H, t, J=7.1 Hz, OCH2CH3), 2.12 (3H, s, CH3), 2.22–2.25 (4H, m,
2×CH2), 3.92 (3H, s, OCH3), 4.12 (2H, q, J=7.1 Hz, OCH2CH3), 5.11
(1H, s, CH), 6.16 (1H, s, NH), 6.95–7.13 (4H, m, ArH); 13C NMR: 14.1,
19.2, 27.3, 32.5, 40.8, 44.1, 47.5, 55.8, 59.8, 106.1, 126.6, 127.3, 128.5,
136.9, 145.2, 145.1, 149.2, 167.1, 195.4. Anal. calcd for C22H27NO4
(Mr =369.19): C, 71.52; H, 7.37; N, 3.79; found: C, 71.64; H, 7.28; N,
3.71%.
Ethyl‑4‑(4‑formylphenyl)‑2,7,7‑trimethyl‑5‑oxo‑1,4,5,6,7,8‑
hexahydroquinoline‑3‑carboxylate (5k): Yellow solid (recrystallised
from ethanol), m.p. 196–197 °C (EtOH); FT-IR (cm–1): 3291(NH),
3078, 2873, 1692 (C=O), 1616 (C=O), 1523, 1481 (C=C), 1391, 1282
(C–O); 1H NMR: δ 0.81 (6H, s, 2×CH3), 0.98 (3H, t, J=7.1 Hz,
OCH2CH3), 2.14 (3H, s, CH3), 2.42–2.48 (4H, m, 2×CH2), 4.10 (2H,
q, J=7.1 Hz, OCH2CH3), 4.82 (1H, s, CH), 6.11(1H, s, NH), 7.13–7.15
(2H, d, J=7.9 Hz, ArH), 7.22–7.24 (2H, d, J=7.9 Hz, ArH), 9.82 (1H,
s, CHO); 13C NMR: 14.2, 19.2, 27.1, 32.3, 40.7, 44.1, 47.1, 60.1, 105.9,
126.1, 126.9, 127.8, 135.1, 144.1, 145.1, 149.5, 167.1, 195.1, 201.3. Anal.
calcd for C22H25NO4 (Mr =367.18): C, 71.91; H, 6.86; N, 3.81; found: C,
71.99; H, 6.78; N, 3.73%.
231–233
5m
5n
(231–233)17
231–233
(230–232)17
aReaction conditions: araldehyde 1 (1 mmol), dimedone 2 (1 mmol),
ammonium acetate 3 (1.5 mmol), ethyl acetoacetate 4 (1 mmol), in H2O/
EtOH (1:1) at reflux (Scheme 1).
bIsolated yield.
cNew compounds.
very smoothly to produce polyhydroquinoline derivatives in
relatively short reaction times. However, a sterically hindered
aldehyde (entry 4) reacted more slowly in comparison with
unhindered aldehydes.
In summary an efficient and mild method for the synthesis
of hexahydroquinolines has been developed which uses silver
iodide nanoparticles as a highly effective, recyclable catalyst in
aqueous ethanol media. The products were obtained in excellent
yields and the reaction times were significantly reduced in
comparison with use of bulk silver iodide.
Experimental
Chemicals were purchased from the Sigma-Aldrich and Merck
and were used without further purification. All melting points are
uncorrected and were determined in capillary tubes on a Boetius
melting point microscope. NMR spectra were obtained on a Bruker
Recycling and reuse of the catalyst: The recovered catalyst could be
reused five times with only a gradual decrease in the yield from 92 to
91, 89, 88, 86 and 84%.

316 JOURNAL OF CHEMICAL RESEARCH 2014
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The authors gratefully acknowledge the financial support of
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Received 13 February 2014; accepted 17 March 2014
Paper 1402467 doi: 10.3184/174751914X13976454726953
Published online: 6 May 2014
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