Introduction of a novel nanosized N-sulfonated Br?nsted acidic catalyst for the promotion of the synthesis of polyhydroquinoline derivatives via Hantzsch condensation under solvent-free conditions

Article abstract of DOI:10.1039/c6ra04148e

In this research 4,4′-(butane-1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium)tetrachloride (NS-C₄(DABCO-SO₃H)₂)·4Cl) as a new nano sized N-sulfonic acid was prepared and characterized using different types of methods including FT-IR, ¹H NMR, ¹³C NMR, mass, XRD, TGA, SEM and AFM analysis. After the characterization of this reagent, it was efficiently used for the promotion of the one-pot synthesis of hexahydroquinolines via one-pot four-component condensation of aryl aldehydes, 1,3-cyclohexadione derivatives, β-ketoesters and ammonium acetate under solvent-free conditions. The procedure gave the products in excellent yields in short reaction times and good to high yields. Also this catalyst can be reused several times without loss of its catalytic activity.

Full text of DOI:10.1039/c6ra04148e

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Introduction of a novel nanosized N-sulfonated
Bronsted acidic catalyst for the promotion of the
¨
Cite this: RSC Adv., 2016, 6, 26026
synthesis of polyhydroquinoline derivatives via
Hantzsch condensation under solvent-free
conditions†
*
Omid Goli-Jolodar, Farhad Shirini and Mohadeseh Seddighi
In this research 4,40-(butane-1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium)tetrachloride
(NS-C4(DABCO-SO3H)2)$4Cl) as a new nano sized N-sulfonic acid was prepared and characterized using
different types of methods including FT-IR, 1H NMR, 13C NMR, mass, XRD, TGA, SEM and AFM analysis.
After the characterization of this reagent, it was efficiently used for the promotion of the one-pot
synthesis of hexahydroquinolines via one-pot four-component condensation of aryl aldehydes,
1,3-cyclohexadione derivatives, b-ketoesters and ammonium acetate under solvent-free conditions. The
procedure gave the products in excellent yields in short reaction times and good to high yields. Also this
catalyst can be reused several times without loss of its catalytic activity.
Received 15th February 2016
Accepted 1st March 2016
DOI: 10.1039/c6ra04148e
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diseases) and hypertension (nifedipine, nicardipine, amlodi-
pine, and felodipine).7
Introduction
Hexahydroquinolines (HHQs) are one series of DHP deriva-
tives with an improved structural scaffold and many pharmaco-
logical properties such as antihypertensive, anti-inammatory,
antimalarial, antiasthmatic and tyrosine kinase inhibitory activ-
ities. These derivatives of DHP can be synthesized according to
Hantzsch synthesis using aryl aldehydes, 1,3-cyclohexanedione
derivatives, b-ketoesters, and ammonium acetate via one-pot
four-component condensation reaction.
Nanocatalysis is a rapidly growing eld which involves the use of
nanomaterials for a variety of homogeneous and heterogeneous
catalysis applications. This is because the nanoparticles have
a large surface-to-volume ratio compared to bulk materials, which
make them attractive candidates for the requested purposes.1
¨
The use of Bronsted-acidic catalysts has become one of the
remarkable and important branches in catalyst science because
of their unique properties such as ease of handling, storability,
In view of the biological, industrial and synthetic importance
of 1,4-dihydropyridines and polyhydroquinolines, a variety of
catalysts such as Bi(NO3)3$5H2O,8 MgO nanoparticles,9 P(4-
VPH)HSO4,10 Mn(III) complex,11 HClO4–SiO2,12 Al2(SO4)3,13
GuHCl,14 Hf(NPf2)4,15 Sc(OTf)3,16 K7[PW11CoO40],17 Yb(OTf)3,18
ceric ammonium nitrate (CAN),19 nickel nanoparticle,20 palla-
dium (0) nanoparticles,21 and alumina sulfuric acid (ASA),22
have been used to facilitate these reactions.
Although these procedures provide an improvement, they
suffer from disadvantages such as long reaction times, expen-
sive reagents, harsh reaction conditions, low-product yields and
the use of large quantity of volatile organic solvents. Further-
more, the main disadvantage of almost all existing methods is
that the catalysts are destroyed in the work-up procedure and
cannot be recovered or reused. Therefore, introduction of
simple, efficient and mild procedures with easily separable and
reusable catalysts to overcome these problems for the synthesis
of 1,4-DHP derivatives is still in demand.
stability to oxygen and water, ease of design and synthesis, and
2
¨
tunability. Among the different kinds of Bronsted-acidic cata-
lysts, N-sulfonated ones have designed to replace solid acids
and traditional mineral liquid acids like sulfuric acid and
hydrochloric acid. Furthermore, their polar nature makes them
useful for use under solvent-free conditions.3
Heterocyclic compounds are widely distributed in nature
and are essential to life. 1,4-Dihydropyridine (1,4-DHPs) deriv-
atives are an important class of heterocyclic compounds that
have a broad scope of pharmacological and biological activities
such as antidiabetic, antitumor, vasodilator, bronchodilator,
geroprotective and anti-atherosclerotic properties as well as
antiischemics exploration and treatment of Alzheimer's
disease.4–6 Particularly these derivatives are well known as Ca2+
channel blockers (drugs for the treatment of cardiovascular
Department of Chemistry, College of Sciences, University of Guilan, Iran. E-mail:
shirini@guilan.ac.ir
More recently, we have introduced some N-sulfonic acidic
catalysts which in them a SO3H group has bonded with
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra04148e
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a positive nitrogen (N+) in organic compound or/and porous
system, and they were successfully applied as catalysts and
regents in organic transformations.23–37 In continuation of these
studies, we have designed and synthesized nano sized 4,40-
(butane-1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-
diium)tetrachloride (NS-C4(DABCO-SO3H)2)$4Cl) as a novel
¨
nano sized Bronsted acidic catalyst. NS-C4(DABCO-SO3H)2)$
4Cl showed high efficiency in the synthesis of poly-
hydroquinolines derivatives probably due to nano size and
high polarity of this reagent which led to the large surface-to-
volume ratio compared to bulk catalyst.
Experimental
Material
Chemicals were purchased from Fluka, Merck, Aldrich and
Southern Clay Products Chemical Companies. Yields refer to
isolated products. Products were characterized by their physical
constants, comparison with authentic samples and IR and NMR
spectroscopy. The purity determination of the substrate and
reaction monitoring were accomplished by TLC on silica-gel
polygram SILG/UV 254 plates.
Fig.
1
Potentiometric titration and its first derivative curves of
[C4(DABCO)2]$2Cl with AgNO3.
General procedure for the synthesis of nano sized 4,40-
(butane-1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-
diium) chloride ([NS-C4(DABCO-SO3H)2]$4Cl)
Chlorosulfonic acid (0.66 mL, 10 mmol) was added drop wise to
a solution of C4(DABCO)2$2Cl (1.4 g, 5 mmol) in dry CH2Cl2
(25 mL) over a period of 30 min in an ice bath. Aer completion
of the addition, the reaction mixture was stirred for 12 h at room
temperature. The residue was washed with dry diethyl ether (3 ꢂ
5 mL) and dried under vacuum to give nano sized 4,40-(butane-
1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium)
chloride ([NS-C4(DABCO-SO3H)2)]$4Cl) as a white puffy solid in
98.7% yield (4.42 g).
Instrumentation
The FT-IR spectra were run on a VERTEX 70 Brucker company
(Germany). Thermogravimetric analyses (TGA) were performed
on TG/DTA6300 Sll-Nanotechnology Company (Japan). Samples
were heated from 25 to 700 C at ramp 10 C min under N2
atmosphere. Scanning election microphotographs (SEM) were
obtained on a SEM-Philips XL30. Wide-angle X-ray diffraction
(XRD) measurements were performed at room temperature on
ꢁ1
ꢀ
ꢀ
a
Siemens D-500 X-ray diffractometer (Germany), using
Ni-ltered Co-Ka radiation (l ¼ 0.15418 nm). The 1H NMR
(400 MHz) and 13C NMR (100 MHz) were run on a Bruker
AVANCEIII-400 spectrometer in DMSO using TMS as an internal
reference (d in ppm). The surface morphologies were charac-
terized by atomic force microscope (AFM, Ara nanoscope, Iran).
General procedure for the synthesis of polyhydroquinolines
In a round-bottomed ask a mixture of aldehyde (1 mmol), 1,3-
cyclohexanedione and/or dimedone (1 mmol), ammonium
acetate (1.5 mmol), a b-ketoester derivative (1 mmol) and [NS-
C4(DABCO-SO3H)2)]$4Cl (0.010 g, 5 mol%) was stirred and
heated in an oil-bath at 100 ꢀC for an appropriate period of time.
Aer completion of the reaction, as monitored by TLC (eluent:
EtOAc : n-hexane), water was added to separate the catalyst and
the crude product was separated and recrystallized by EtOH.
General procedure for the synthesis of 1,10-(butane-1,4-diyl)
bis(1,4-diazabicyclo[2.2.2]octan-1-ium)chloride
([C4(DABCO)2]$2Cl)
1,4-Dichlorobutane (0.547 mL, 5.0 mmol) was added to the
mixture of DABCO (1.121 g, 10.0 mmol) in dry CH3CN (50 mL)
and stirred for 4 h under reux conditions. Aer completion of
the reaction the solvent was removed under vacuum, and the
obtained solid was washed with diethyl ether. Aer drying at
50 ꢀC 1,10-(butane-1,4-diyl)bis(1,4-diazabicyclo[2.2.2]octan-1-
ium)chloride ([C4(DABCO)2]$2Cl) was obtained as a white
1
The obtained products were characterized by FT-IR, H NMR,
13C NMR and by comparison of their melting points with the
reported ones.
Results and discussions
solid in 98.7% yield (1.39 g). The amount of chloride in [C4- The structure of NS-C4(DABCO-SO3H)2]$4Cl as a novel nano
(DABCO)2]$2Cl was determined by potentiometric titration catalyst was identied by FT-IR, 1H NMR, 13C NMR, mass, TGA,
method. For this purpose, 10 mL of 0.05 M [C4(DABCO)2]$2Cl in DTG, XRD and SEM analysis.
water was titrated with 0.55 M AgNO3. As shown in Fig. 1, the
The corresponding FT-IR spectra of DABCO, [C4(DABCO)2]$
change was happened at 17.5 mL of consumed AgNO3. On the 2Cl and nano sized [C4(DABCO-SO3H)2]$4Cl are presented in
basis of these studies it can be concluded that [C4(DABCO)2]$ Fig. 2. Some of the stretching and bending vibrations in
2Cl has 2 equivalent of Clꢁ per one mol of this reagent.
[C4(DABCO)2]$2Cl reduced or eliminated compared with
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Fig. 2 FT-IR spectra of DABCO (a), [C4(DABCO)2]$2Cl (b) and NS-[C4(DABCO-SO3H)2]$4Cl (c).
DABCO spectrum, probably due to the limitation of vibrations weight percent for the TGA curve and the differential weight for
of the rings. the DTGA curve. As shown in these gures DABCO has
In the case of NS-[C4(DABCO-SO3H)2]$4Cl, the broad band decomposed before 150 ꢀC, while [C4(DABCO)2]$2Cl and NS-
between 3250 and 3750 cmꢁ1 that centered at 3422.53 cmꢁ1 can
be attributed to the OH stretching of the SO3H group.
NS-[C4(DABCO-SO3H)2]$4Cl exhibited other characteristic
absorption bands at 1221.27, 1056.74 and 590 cmꢁ1 which are
assigned to the S]O asymmetric and symmetric stretching,
S–OH bending and symmetric S–O stretching vibrations,
respectively. Furthermore, the bands at 1399.60, 885.08 and
883.01 cmꢁ1 in the NS-[C4(DABCO-SO3H)2]$4Cl can be related to
the N–SO2 vibrations.32
The mass spectra of NS-[C4(DABCO-SO3H)2]$4Cl ionic liquid is
presented in Fig. 3. The important peaks of MS spectrum of the
ionic liquid were related to the [M+] ¼ 584 and [M+ ꢁ SO3H] ¼
524.39
In order to gain insight into the thermal changes of [C4-
(DABCO)2]$2Cl and NS-[C4(DABCO-SO3H)2]$4Cl, the thermal
stability was probed with thermo gravimetric analysis. Fig. 4
and 5 display a typical TGA and DTGA spectra for DABCO,
[C4(DABCO)2]$2Cl and NS-[C4(DABCO-SO3H)2]$4Cl, using
Fig. 3 Mass data of nano sized NS-[C4(DABCO-SO3H)2]$4Cl.
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Fig. 6 1H NMR spectra of [C4(DABCO)2]$2Cl.
Fig. 4 TGA curves (up) curves (down) for DABCO, [C4(DABCO)2]$2Cl
and NS-[C4(DABCO-SO3H)2]$4Cl.
decomposition by dealkylation of the cation via SN2 reaction of
the easiest accessible alkyl group (Scheme 1),40 and 286–420 ꢀC
(Tmax ¼ 377) for the complete decomposition of the compound.
In the case of NS-[C4(DABCO-SO3H)2]$4Cl, the rst weight loss
appeared at <120 ꢀC attributed to the loss of the moisture
contents. The second weight loss which started from 210 ꢀC
(Tmax ¼ 262 ꢀC) can be a result of the thermal decomposition of
the pendant sulfonic groups. This sulfonated reagent moiety
undergoes intermolecular bonding interactions in the solid
state, leading to the formation of a rigid network structure
which requires higher temperature for decomposition. This is
conrmed by the third and fourth (356–556 ꢀC) decomposition
stages. The DTGA-TGA data show that the NS-[C4(DABCO-
[C4(DABCO-SO3H)2]$4Cl have higher thermal stability. This
increase can be caused by hydrogen bonding sites and nearby
the positive and negative sides.
[C4(DABCO)2]$2Cl shows
a thermal decomposition at
<120 ꢀC which is corresponding to the loss of the moisture. The
large proportion of it underwent degradation in the range of
244–286 ꢀC (Tmax ¼ 277) that can be related to the thermal
ꢀ
SO3H)2]$4Cl catalyst is stable to 210 C.
1H NMR spectra of [C4(DABCO)2]$2Cl and NS-[C4(DABCO-
SO3H)2]$4Cl are presented in Fig. 6 and 7. The spectrum of
[C4(DABCO)2]$2Cl displayed two broad singlet peaks at 1.73 and
3.41 ppm which can be attributed to the chain hydrogens, and
two triplet peaks at 3.04 and 3.34 are related to cyclic hydrogens.
Aer modication of [C4(DABCO)2]$2Cl with chlorosulfonic
acid and under the inuence of the SO3H groups, the peaks of
Fig.
5 TGA curves (up) and DTGA curves (down) for DABCO,
[C4(DABCO)2]$2Cl and NS-[C4(DABCO-SO3H)2]$4Cl.
Scheme 1 Thermally decomposing by dealkylation of the cation via
SN2 reaction.
Fig. 7 1H NMR spectra of NS-[C4(DABCO-SO3H)2]$4Cl.
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The samples of DABCO, [C4(DABCO)2]$2Cl and nano sized
[C4(DABCO-SO3H)2]$4Cl were also analyzed by scanning elec-
tron microscopy (SEM) for determination of the particle shape,
surface morphology and size distribution (Fig. 9). In DABCO
surface morphology picture, the sample has tatter and irregular
shape with tiny holes (a), aer reaction with 1,4-dichlor-
obutaneand they join together so the surface convert to smooth
(b), nally aer the reaction of [C4(DABCO)2]$2Cl with chlor-
osulfonic acid the morphology of [C4(DABCO)2]$2Cl was
completely changed and the particles size reduced to the nano
scale (c). Both size reductions and bumpy surface resulted in
increase in the surface area of the catalyst which led to the
increase in the catalytic activity of the catalyst in reaction.32,39
Fig. 10 shows the two-dimensionally (2D) and three-
dimensionally (3D) AFM images of at [C4(DABCO)2]$2Cl
surface (a) and nano NS-[C4(DABCO-SO3H)2]$4Cl surface (b)
which were obtained using AFM with a conventional rectan-
gular cantilever. It is clear that the at surface was smooth and
uniform (Fig. 10a), while the nano NS-[C4(DABCO-SO3H)2]$4Cl
surface possessed uniform rough structures (Fig. 10b).
Fig. 8 13C NMR spectra of NS-[C4(DABCO-SO3H)2]$4Cl.
cyclic hydrogens were shied to the upper ppm. Furthermore,
the peak of the acidic hydrogens of NS-[C4(DABCO-SO3H)2]$4Cl
was appeared at 6.39 ppm. Also the 13C NMR of NS-[C4(DABCO-
SO3H)2]$4Cl showed 4 peaks which demonstrated its structure.
The peaks which related to corresponding carbons are specied
in Fig. 8.38
XRD patterns of DABCO, [C4(DABCO)2]$2Cl and nano sized
[C4(DABCO-SO3H)2]$4Cl were investigated in comparison with
each other in a domain of 10–70ꢀ (Fig. 11). As shown in this
gure, the XRD patterns of DABCO were revealed at 2q ¼ 16.7ꢀ,
Fig. 9 SEM micrographs of DABCO (a), [C4(DABCO)2]$2Cl (b) and NS-[C4(DABCO-SO3H)2]$4Cl (c).
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Fig. 10 Atomic force microscopy (AFM) images in two- and three dimensions for [C4(DABCO)2]$2Cl (a) and [C4(DABCO-SO3H)2]$4Cl (b).
Table
1 XRD data of DABCO (1), [C4(DABCO)2]$2Cl (2) and
NS-[C4(DABCO-SO3H)2]$4Cl (3)
Peak width [FWHM]
Entry
2q
(degree)
Size [nm]
1
2
3
19.39
22.08
19.4
0.157
0.393
1.152
51.37
20.52
7
nally, the XRD pattern of NS-[C4(DABCO-SO3H)2]$4Cl showed
a broad maximum that assigned to amorphous peak at 2q ¼
19.4ꢀ. Furthermore, size of particles were measured in the
highest diffraction line via the Scherrer equation [D ¼
Kl/(b cos q)], (l: Cu radiation (0.154178 nm) (Table 1). As it can
be realized in Table 1, the size of the particles were reduced to
nano-size that can be caused by addition of ionic component,
hydrogen bonding sites and nearby the positive and negative
sites. There is a good accordance between crystallite sizes ob-
tained from XRD and SEM data (Fig. 12).41
Fig. 11 XRD patterns of DABCO (a), [C4(DABCO)2]$2Cl (b) and NS-
[C4(DABCO-SO3H)2]$4Cl (c).
For pH analysis of catalyst, a solution of nano sized
[C4(DABCO-SO3H)2]$4Cl was titrated with NaOH. The titration
curve for the reaction of 15 mL of 0.1 M ionic liquid with
0.050 M NaOH is given in Fig. 13. This gure clearly shows that
17.2ꢀ, 18.5ꢀ, 19.4ꢀ, 30.2ꢀ, 30.9ꢀ, 33.15ꢀ, 35.46ꢀ, 41.96ꢀ and
45.24ꢀ, in the XRD pattern of [C4(DABCO)2]$2Cl the reections
appeared at 2q ¼ 15.23ꢀ, 19.43ꢀ, 22.08ꢀ, 27.4ꢀ and 30.16ꢀ and
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Fig. 12 Particle size of NS-[C4(DABCO-SO3H)2]$4Cl obtained from
SEM analysis.
Scheme 2 Synthesis of the NS-[C4(DABCO-SO3H)2]$4Cl.
Fig. 13 Titration and its first derivative curves of NS-[C4(DABCO-
SO3H)2]$4Cl by NaOH.
when 63 mL of the basic solution is added, all the acidic protons
are neutralized. On the other hand, eqn (1) shows that for the
neutralization of each of the acidic protons 30 mL of the basic
solution is needed. On the basis of these studies it can be
concluded that this ionic liquid has two protic protons with
almost the same acidic power.
Fig. 14 The optimized geometry of NS-[C4(DABCO-SO3H)2]$4Cl (a)
and [C4(DABCO)2]$2Cl (b).
MðacidÞ ꢂ VðacidÞ ¼ MðbaseÞ ꢂ VðbaseÞ
0:1ðmolarÞ ꢂ 15ðmLÞ ¼ 0:05ðmolarÞ ꢂ VðbaseÞ
VðbaseÞ ¼ 30 mL
(1)
bound structure is a reasonable surrogate for the transition
state or the protraction complex, from which we obtained
information on key nonbonding interactions. For intermolec-
ular interactions, density functional theory were employed to
investigate interaction energy (IE) of the catalyst between
cationic pice and four Clꢁ anions by using Gaussian 03
program. The structure of catalyst were fully optimized at M06–
On the basis of the above mentioned studies, the structure
which is shown in Scheme 2 is selected for the prepared IL.
The nature of the intermolecular forces in all materials
mainly controls their physical properties. Therefore, it is vital to
be able to study the fundamental interaction being possible in
NS-[C4(DABCO-SO3H)2]$4Cl. We guessed that the covalently
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Scheme 3 Synthesis of hexahydroquinolines catalyzed by NS-[C4(DABCO-SO3H)2]$4Cl.
Table 2 Synthesis of polyhydroquinoline derivatives from dimedone, aryl aldehydes, b-ketoesters and ammonium acetate catalyzed by NS-
[C4(DABCO-SO3H)2]$4Cl at 100 ꢀC under solvent-free condition
Mp (ꢀC)
Entry
Aldehyde
R0
R00
Product
Time (min)
Yielda (%)
Found
Reported (ref.)
1
2
3
4
5
6
7
8
C6H5–
2-Cl–C6H4–
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
a
b
c
d
e
f
g
h
i
j
k
8
10
7
25
4
98
95
98
87
98
97
97
90
92
97
95
87
98
98
90
90
88
85
95
98
98
98
98
95
88
89
98
98
98
93
80
80
87
87
220–222
202–204
248–250
200–202
210–212
229–231
198–200
170–172
241–243
248–252
254–256
238–240
227–229
259–261
140–142
239–241
231–233
179–181
250–252
243–246
254–255
244–246
194–195
251–254
204–206
220–221
248–252
219–221
267–269
258–259
147–149
160–162
207–209
246–248
224–226 (ref. 42)
207–209 (ref. 42)
257–259 (ref. 42)
204–206 (ref. 42)
—
2-OCH3–C6H4–
2-NO2–C6H4–
2-CH3–C6H4 –
3-Br–C6H4–
3-CH3O–C6H4–
3-NO2–C6H4–
4-Cl–C6H4–
7
8
230–232 (ref. 43)
201–203 (ref. 42)
173–175 (ref. 42)
245–246 (ref. 42)
255–256 (ref. 43)
258–260 (ref. 42)
242–244 (ref. 42)
228–230 (ref. 42)
256–258 (ref. 42)
140–142 (ref. 42)
240–242 (ref. 44)
233–235 (ref. 42)
182–184 (ref. 42)
240–242 (ref. 45)
234–236 (ref. 45)
253–254 (ref. 45)
222–224 (ref. 45)
192–193 (ref. 17)
241–243 (ref. 45)
—
220–221 (ref. 46)
249–251 (ref. 46)
220–222 (ref. 46)
274–276 (ref. 46)
257–258 (ref. 12)
147–149 (ref. 42)
161–163 (ref. 42)
210–212 (ref. 19)
245–247 (ref. 42)
22
18
10
15
27
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
4-Br–C6H4–
4-CH3O–C6H4–
4-NO2–C6H4–
4-OH–C6H4–
4-CH3–C6H4–
4-CN–C6H4–
4-CH3S–C6H4–
4-(CH3)2N–C6H4–
4-Isopro-C6H4–
C6H5–
l
m
n
o
p
q
r
s
t
u
v
w
x
2
15
15
50
40
10
5
5
3
5
12
50
20
5
5
3
40
45
40
5
4-Cl–C6H4–
4-Br–C6H4–
4-OH–C6H4–
4-CH3O–C6H4–
4-CH3–C6H4–
4-(CH3)2N–C6H4–
4-Cl–C6H4–
y
z
4-CH3O–C6H4–
4-CN–C6H4–
aa
bb
cc
dd
ff
gg
hh
ii
4-CH3–C6H4–
4-(CH3)2N–C6H4–
Butyraldehyde
Isobutyraldehyde
Furan-2-carbaldehyde
Furan-2-carbaldehyde
CH3
4
35
36
CH3
OEt
ll
15
100
281–282
—
H
OEt
OEt
mm
nn
5
7
85
98
293–294
305–307
—
37
CH3
294–296 (ref. 43)
a
Isolated yields.
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Scheme 4 The proposed mechanism for the synthesis polyhydroquinoline derivatives in the presence of NS-[C4(DABCO-SO3H)2]$4Cl.
2X/6-311++G(d,p) level of theory level in gas phase. As can be examined its catalytic activity to promote the synthesis of
seen in Fig. 14, Clꢁ anions can be located in four regions in the hexahydroquinolines (HHQs). For this purpose, a mixture of
vicinity of the cation, and Clꢁ anions can interact with nitrogens dimedone (2 mmol), 4-chlorobenzaldehyde (2 mmol), ethyl
of cation.
acetoacetate (2 mmol) and ammonium acetate (2.4 mmol) was
The interaction energy of the studied catalyst has been reacted in the presence of different amounts of NS-[C4(DABCO-
computed as a difference between the total energy of the catalyst SO3H)2]$4Cl at a range of 25 to 100 ꢀC in the absence of solvent.
and the energies of the isolated ions. The interaction energy for The results showed that 5 mol% of NS-[C4(DABCO-SO3H)2]$4Cl
studied catalyst is (ꢁ801.56 kcal molꢁ1) in gas phase. Structure, was sufficient to catalyze the reaction efficiently at 100 C.
ꢀ
composition and intermolecular forces determine the melting
To illustrate the efficiency of NS-[C4(DABCO-SO3H)2]$4Cl, the
point and the thermal stability of catalyst. The great IE obtained synthesis of ethyl 2,7,7-trimethyl-4-(4-chlorophenyl)-5-oxo-
for catalyst is in good agreement with reported melting point. 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was also carried
The molecular volumes of NS-[C4(DABCO-SO3H)2]$4Cl and out using DABCO and [C4(DABCO)2]$2Cl as the catalysts and
[C4(DABCO)2]$2Cl were calculated using COSMO-RS model at also in the absence of catalyst under the optimized conditions.
BVP86/TZVP level of theory using M06/6-311++G(d, p) optimized The obtained results showed that these reactions were not
geometry in gas phase. As can be seen, the calculated Vm of NS- completed even aer prolonged reaction times. These results
[C4(DABCO-SO3H)2]$4Cl and [C4(DABCO)2]$2Cl are 0.57 and demonstrated that the NS-[C4(DABCO-SO3H)2]$4Cl is necessary
0.35 nm3 moleculeꢁ1
Aer the characterization of NS-[C4(DABCO-SO3H)2]$4Cl and
.
to produce the products.
Aer optimization of the reaction conditions and in order to
on the basis of the obtained information from these studies, we establish the effectiveness and the acceptability of the method,
26034 | RSC Adv., 2016, 6, 26026–26037
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HHQs. This result may be due to the strong electron donation of
dimethylamino group which decreases the reactivity of the
aldehydic carbonyl group.
The proposed mechanism for the synthesis of poly-
hydroquinoline derivatives in the presence of NS-[C4(DABCO-
SO3H)2]$4Cl is shown in Scheme 4. On the basis of this mech-
anism, the synthesis of polyhydroquinoline derivatives could be
achieved via two ways. In these ways NS-[C4(DABCO-SO3H)2]$
4Cl can catalyze the Knoevenagel condensation type coupling of
aldehydes with one of the compounds having active methylene
group (dimedone or ethyl acetoacetate). On the other hand,
another activated methylene compound and ammonia (resulted
from ammonium acetate) produces enamine. Aerward, the
enol (Knoevenagel condensation product) and enamine react
with together to afford intermediate I and/or II. Intermediate I
and/or II affords desired product by intramolecular nucleo-
philic attack of the NH2 group to the activated carbonyl group
and then removes one molecule of H2O. It is important to note
that any change to the substrates concentrations cause to
produce some unidentied by products. The mechanism is
conrmed by the literature.9,42,45,49–51
To check the reusability of the catalyst, the reaction of
4-chloro benzaldehyde, dimedone, ethyl acetoacetate and
ammonium acetate under the optimized reaction conditions
was studied again. When the reaction completed, ethanol was
added and the catalyst was separated by ltration. The recov-
ered catalyst was washed with ethyl acetate, dried and reused for
the same reaction. This process was carried out over ve runs
and all reactions led to the desired products without signicant
changes in terms of the reaction time and yield which clearly
demonstrates practical recyclability of this catalyst (Fig. 15).
To highlight the merits of our newly developed procedures,
we have compared our results for the synthesis of ethyl 2,7,7-
trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate using NS-[C4(DABCO-SO3H)2]$4Cl as catalyst with
other results reported in the literature and also N-sulfonated
DABCO ([DABCO](SO3H)2(Cl)2).52 As it showed in Table 3, the
newly developed method avoids some of the disadvantages
Fig. 15 Reusability of the NS-[C4(DABCO-SO3H)2]$4Cl.
a variety of substrates were submitted to the optimum reaction
conditions and the desired products were obtained in good to
excellent yields (Scheme 3).
As can be seen in Table 2, aromatic aldehydes containing
both electron-withdrawing and electron-donating groups as
well as heterocyclic systems reacted pretty good with the
selected
1,3-diketone
(dimedone
and/or
1,3-cyclo-
hexanediones), b-ketoesters (methyl and/or ethyl acetoacetate)
and ammonium acetate under the optimized reaction condi-
tions. The reactions were completed in 2–50 min and high
yields of polyhydroquinolines were obtained. Aliphatic alde-
hydes were also converted to their corresponding HHQs using
this method (Table 2, entries 31–32). Also this method was
found to be useful for the usage of dialdehydes (Table 2, entry
35–37). Under the selected conditions, isophthaldealdehyde
and terephthaldialdehyde as dialdehydes proceeded well to give
the corresponding HHQs with high yields and short times.
Using 4-dimethylamino benzaldehyde (Table 2, entry 17, 25 and
30) longer time was needed for the production of the requested
Table 3 Comparison of the results obtained from the synthesis of ethyl 2,7,7-trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate in the presence of NS-[C4(DABCO-SO3H)2]$4Cl with those obtained using other procedure
Entry
Catalyst (loading)
Reaction condition
EtOH/80 ꢀ
H2O/reux
EtOH/reux
EtOH/reux
C10F18/60 ꢀC
EtOH/r.t.
Time (min)
Yield (%)
Ref.
8a,c
10b
1
2
3
4
5
6
7
8
Bi(NO3)3$5H2O (5 mol%)
P(4-VPH)HSO4 (0.03 g)
(bzacen)MnCl (10 mg)
Al2(SO4)3 (10 mol%)
Hf(Npf)4 (1 mol%)
Sc(OTf)3 (10 mol%)
Yb(OTf)3 (5 mol%)
Pd nanoparticle (4 mol%)
La2O3 (10 mol%)
Ce(SO4)2$4H2O (5 mol%)
Gd(OTf)3 (5 mol%)
[DABCO](SO3H)2(Cl)2
NS-[C4(DABCO-SO3H)2]$4Cl (5 mol%)
C
4 h
15
20
4 h
3 h
4 h
5 h
4 h
60
92
96
90
92
95
93
90
89
90
92
89
87
98
11b
13a,b,c
15a
16a
18a
EtOH/r.t.
THF/reux
TFE/r.t.
21a,b
44b c
,
47b,c
9
10
11
12
13
EtOH : H2O/reux
EtOH/r.t.
15
5 h
45
48a
Solvent-free/100 ꢀ
Solvent-free/100 ꢀ
C
C
52d
This work
8
a
c
Long reaction time. b Reux conditions. High catalyst loading. d Instability of catalyst in the present of moisture.
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associated with the other procedures such as long reaction 17 M. M. Heravi, K. Bakhtiari, N. M. Javadi, F. F. Bamoharramb,
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bad conditions for catalyst preparation.
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In summary, we have introduced a novel nano N-sulfonic
¨
Bronsted acidic catalyst formulated as C4(DABCO-SO3H)2$4Cl
as a high-performance catalyst for the synthesis of poly-
hydroquinoline derivatives. The most important advantages of
this catalyst that can be representing are (1) nano-size and high
polarity of catalyst, (2) simplicity in the preparation procedure,
(3) not is harmful for environment, (4) availability of the starting
material and, (5) ease to use C4(DABCO-SO3H)2$4Cl (because
C4(DABCO-SO3H)2$4Cl is a solid but chlorosulfonic acid is one
of the strong corrosive liquid acids that its handling can be
dangerous). Also, simplicity and easy work-up, high reaction
rates, excellent yields and eco-friendly procedure are the
advantages of the present method used for the preparation of
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