Solvent-free synthesis of polyhydroquinoline derivatives employing mesoporous vanadium ion doped titania nanoparticles as a robust heterogeneous catalyst via the Hantzsch reaction

Article abstract of DOI:10.1039/c6ra26664a

Mesoporous vanadium ion doped titania nanoparticles (V-TiO₂) were used as a reusable and robust heterogeneous catalyst for one-pot four component synthesis of polyhydroquinoline derivatives via the esteemed Hantzsch reaction using arylaldehyde,

Full text of DOI:10.1039/c6ra26664a

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Solvent-free synthesis of polyhydroquinoline
derivatives employing mesoporous vanadium ion
doped titania nanoparticles as a robust
Cite this: RSC Adv., 2017, 7, 3611
heterogeneous catalyst via the Hantzsch reaction†
ab
b
a
*
*
S. Nagakalyan and G. K. Prasad
G. B. Dharma Rao,
Mesoporous vanadium ion doped titania nanoparticles (V–TiO2) were used as a reusable and robust
heterogeneous catalyst for one-pot four component synthesis of polyhydroquinoline derivatives via the
esteemed Hantzsch reaction using arylaldehyde, b-ketoester, dimedone and ammonium acetate at
80 ꢀC under solvent-free conditions as a multi-component synthesis. On the other hand, the catalytic
activity of V–TiO2 was compared with undoped commercial titania nanocatalyst. This protocol was
successfully pertinent to a wide range of structurally diverse arylaldehydes with b-ketoester, dimedone
and ammonium acetate to afford the corresponding polyhydroquinoline derivatives. Operational
simplicity, short reaction time and satisfactory yields are the key features of this protocol. The catalyst
could easily be recycled and reused without observable decrease in catalytic activity.
Received 11th November 2016
Accepted 5th December 2016
DOI: 10.1039/c6ra26664a
www.rsc.org/advances
Bearing in mind the considerable applications in the elds
of medicinal, bioorganic and synthetic organic chemistry, there
1. Introduction
has been incredible attention in developing procient methods
for the synthesis of PHQ. Such a medicinally signicant 1,4-
DHPs was initially established by Arthur Hantzsch in 1882 via
the reaction of aldehydes with ethyl acetoacetate and ammonia
in acetic acid or by reuxing in alcohols more than a century
ago.12 Though, the yields of the desired products were modest.
In addition, a notable number of citations13 for the synthesis of
PHQ are currently addressed to advances the reaction condi-
tions as maximize the product yield and minimize the reaction
time along with deviation in precursors to acquire the poly-
functionalized PHQ. Practically all new advanced technologies
have also been contributed in synthesis of 1,4-DHPs such as,
microwave-mediated synthesis,14 the support of solar thermal
energy,15 ultrasound irradiation,16 infrared irradiation,17 ionic
liquids,18 grinding19 and metal halides or triates.20 Even
supposing most of these processes place ahead individual
advantages and some are associated with more than a few of
shortcomings such as extend reaction times, expensive/toxic
reagents, deadly reaction circumstances, modest-product
yields and the use of volatile organic solvents.
1,4-Dihydropyridines (1,4-DHPs) and polyhydroquinoline (PHQ)
derivatives has become
a noticeable class of privileged
N-heterocyclic compounds and were widely investigated in past
decades due to their promising pharmacological and biological
activities.1 Some of them have antitubercular properties,2 anti-
cancer,3 neurotropic,4 neuropeptide YY1 receptor antagonists,5
neuroprotective,6 platelet anti-aggregation,7 bronchodilating8
and antidiabetic activities.9 The 1,4-DHPs and PHQ derivatives
which are commercially accessible, as analogues of nicotinamide
adenine dinucleotide (NADH) coenzymes are extensively used as
calcium channel blockers for the treatment of cardiovascular
disorder including hypertension, angina and cardiac arrhyth-
mias.10 Besides this, the focus on the synthesis of 1,4-DHPs with
respect to multidrug resistance (MDR) reversal in tumor cells
provided a new aspect to their applications.11 By the evidence of
the above pharmacological and biological activities, the 1,4-DHPs
and PHQ core units have occupied a governing position in
medicinal chemistry, which evidently expresses the extraordinary
potential of new 1,4-DHP and PHQ analogues as a source of
precious drug candidates.
The improvement in nanotechnology has lead to an
increasing insist for multifunctional materials. Highly ordered
mesoporous materials occupied as stupendous catalysts owing
to their high surface area and surface functionalities. The
physical and chemical properties of mesoporous V–TiO2 mate-
rials depend on their particle size as well as percentage of
vanadium ion doped in TiO2 lattice. Smaller sized particles are
expected to expose enhanced chemical reactivity because of
aDefence Research & Development Establishment, Jhansi Road, Gwalior 474 002, M.P.,
India. E-mail: gbdharmarao@gmail.com; gkprasad2001@yahoo.com
bDepartment of Chemistry, Kommuri Pratap Reddy Institute of Technology, Hyderabad
– 501 301, TS, India
† Electronic supplementary information (ESI) available: General experimental
information, spectral characterization data and copies of ESI-MS and GC-MS
spectra of the products. See DOI: 10.1039/c6ra26664a
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Scheme
1 Poly-functionalized hydroquinoline derivatives via
Hantzsch hetero annulations.
their huge surface area to volume ratio, augmented number of
surface defect sites. Particle size excessively plays imperative
responsibility in dynamics of electron/hole recombination
process and inuences its catalytic properties.
Fig. 1 XRD patterns of (a) TiO2 (b) 0.1 V–TiO2 (c) 0.25 V–TiO2 (d) 0.55
V–TiO2 (e) 2.0 V–TiO2 nanocatalysts.
The data also illustrated peak broadening in XRD pattern
indicating the formation of crystallites with very small size. The
crystallite sizes of V–TiO2 catalysts were calculated by Scherrer
equation and they were found to be 6.12, 6.45, 5.85, 6.76 nm
respectively for 0.1 V–TiO2, 0.25 V–TiO2, 0.55 V–TiO2 and 2 V–
TiO2 respectively. The crystallite size of bare TiO2 nanoparticles
(TiO2 NPs) was found to be 11 nm.
TEM was used to determine the crystallite sizes of TiO2
particles synthesized by modied sol–gel method followed by
hydrothermal treatment. TEM images of both doped (0.1 V–
TiO2) and bare (TiO2 NPs) samples are shown in Fig. 2(a) and
(b). No noteworthy differences are observed when the images of
V–TiO2 and TiO2 NPs samples are compared. TEM images
visibly indicate that particles have homogeneity and quite small
size. It can be seen from the images that particles are estab-
lished to be embedded in the agglomerates with crystallite sizes
around 6 to 11 nm which are found to be comparable to average
crystallite sizes determined from XRD data.
Hence keeping these particulars in observation, in this
communication, we were concerned in attaining the solvent-free
synthesis of polyhydroquinoline derivatives using catalytic
amount of V–TiO2 nanoparticles. Our exploration started with an
optimization study for the union between dimedone (1), p-
methoxybenzaldehyde (2c), ethyl acetoacetate (3) and ammonium
acetate (4) (Table 4, entry 3) in the presence of a catalytic amount
of various size V–TiO2 NPs as well as commercial TiO2 NPs.
The best result was observed when dimedone (1), p-methox-
ybenzaldehyde (2c), ethyl acetoacetate (3) and ammonium acetate
Moreover, the noxious and volatile nature of many organic
solvents used in organic synthesis has posed a grave menace to
the environment. Accordingly, protocols that effectively mini-
mize their use are currently the subject of substantial awareness
for synthetic chemists.21 Furthermore, it is imperative to note
that the amalgamation of heterogeneous catalysis with the use
of solvent-free conditions stand for an appropriate way in the
direction of the so-called ideal synthesis. Nanoparticle TiO2
powerfully catalyzes the conjugate 1,4-addition of indoles to
a,b-unsaturated ketones and 1,2-addition of Me3SiCN to
carbonyl compounds.22 They conrmed the efficiency of TiO2
NPs and attributed it to the enhanced acidic sites and surface
area. In this regards and the advantage of enhanced catalytic
activity of TiO2 NPs herein, we describe an expeditious, practical
and one-pot four component solvent-free synthesis of poly-
hydroquinoline derivatives via esteemed Hantzsch reaction
promoted by V–TiO2 NPs.
Above and beyond, TiO2 is more steady, copious, non
hazardous and inexpensive. For this motive, we have synthe-
sized mesoporous V–TiO2 materials of nano-size by sol–gel
method and characterized them by XRD, TEM, EDX, XPS and
FT-IR techniques. In prolongation of our work on new synthetic
approaches23 and to determine the catalytic application of V–
TiO2 (ref. 24) in this communication, we explanation the
percentage of vanadium ion doped in TiO2 size dependant
application of V–TiO2 nanoparticles of dissimilar sizes
(6.12 nm, 6.45 nm, 5.85 nm, 6.76 nm, and 11 nm) as reusable
robust heterogeneous catalysts for the synthesis of poly-
functionalized hydroquinoline analogues 5a–u (Scheme 1) via
Hantzsch hetero-annulation under solvent-free conditions.
2. Results and discussion
2.1. Characterization of V–TiO2 NPs
XRD patterns of the synthesized V–TiO2 catalysts are depicted in
Fig. 1. Data depicts peaks at 2q values 25.2ꢀ, 37.8ꢀ, 48.0ꢀ, 53.8ꢀ,
and 62.7ꢀ. These peaks can be recognized to the presence of (1 0
1), (0 0 4), (2 0 0), (1 0 5), and (2 1 5) indices. This XRD pattern
demonstrates 2q values and relative intensities that match with
(JCPDS 21-1272) data of anatase phase of TiO2. No peaks cor-
responding to oxides of vanadium (V2O5 or VxOy) are observed
even for samples doped with 2 at% vanadium. This observation
indicates the incorporation of vanadium ion into TiO2 lattice. Fig. 2 TEM images of (a) TiO2 NPs (b) 0.1 V–TiO2 NPs.
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Table 1 Effect of catalytic concentration for the solvent-free synthesis
of polyhydroquinoline using V–TiO2 NPs
(4) were used in the mole ratio 1 : 1 : 1 : 2 employed by the cata-
lytic amount of V–TiO2 NPs of 5.85 nm size at 80 ꢀC under solvent-
free conditions, to afford the resulting ethyl 4-(4-methoxyphenyl)-
2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
(5c) (Table 4, entry 3) in 90% yield without any other bi-products.
This four component union reaction proceeded efficiently at
temperature (80 ꢀC) with high yield under solvent-free reaction
condition and shown in Fig. 3.
From the above considerations, we examine the different
catalytic concentrations for the solvent-free synthesis of poly-
hydroquinoline derivatives using V–TiO2 NPs with 5.85 nm
particle size as heterogeneous catalyst at 80 ꢀC. To study the
feasibility of the different catalytic concentrations, the reaction
of dimedone (1), p-methoxybenzaldehyde (2c), ethyl acetoace-
tate (3) and ammonium acetate (4) was selected as model
reactants for the synthesis of corresponding polyhydroquino-
line (Table 4, entry 3) and xed the reaction time to 12 min.
However, among all the catalytic concentrations, it was
observed that, 2.0 mol% of V–TiO2 NPs of 5.85 nm size was
found to be the most effective for the reaction of four compo-
nent Hantzsch reaction with respect to yield as tabulated in
Table 1.
During exploratory reactions, we studied the four-
component condensation reaction of model reactants dime-
done (1), p-methoxybenzaldehyde (2), ethyl acetoacetate (3) and
ammonium acetate (4) in the mole ratio ¼ 1 : 1 : 1 : 2 under
different addressed catalytic conditions for 12 min as reaction
time. However, V–TiO2 powerfully catalyzed the reaction and
afford high yield of the corresponding PHQ product (Table 2,
entry 4).
The possibility of optimized reaction conditions was further
extended to the synthesis of more functionalized poly-
hydroquinoline derivatives and experiments were performed by
making use of wide range of arylaldehyde bearing variety of
functional groups. As shown in the Table 2, the desired ring
closure annulations of polyhydroquinoline (PHQ) ring was ob-
tained with mono, di (Table 4, entries 6, 12 and 16) and even tri-
substituted (Table 4, entries 8 and 19) arylaldehydes in good to
excellent yields (70–92%). Furthermore, hetero arylaldehydes
such as furfural and pyridine-3-carboxyaldehyde (Table 4,
entries 14 and 15) also afforded the target products in good
yields (62–78%) under the same reaction conditions. In all these
Catalytic conc.
(mol%)
Reaction time
(min)
Entry
% yield
1
2
3
4
5
0.5
1.0
1.5
2.0
2.5
12
12
12
12
12
45
62
76
90
81
Table 2 Effect of addressed catalysts for the solvent-free synthesis of
PHQa
S. no.
Catalystref.
% yield
1
2
3
4
5
p-TSA13b
I2 (ref. 13c)
TiO2 (ref. 13a)
V–TiO2
72
35
42
90
NR
None
a
Reaction conditions: the mixture of 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0
mmol) and 4 (2.0 mmol) at 80 ꢀC using reported catalysts under solvent-
free condition for 12 min. NR ¼ no result.
cases, the reactions were clean and the products were obtained
with simple work-up in good to excellent yields. Compared to
reports which were addressed in the literature, this method has
numerous advantages, which include operational simplicity,
short reaction time and satisfactory yields, does not require
chromatographic separation and wider substrate scope are the
key features of this protocol. The catalyst could easily be recy-
cled and reused without observable decrease in catalytic
activity.
2.2. Reusability of the catalyst
In order to explore the recyclability of catalyst, it was ltered off
at the end of the reaction from the reaction mixture and washed
with mixture of hot ethanol and water, dried and activated at
300 ꢀC for 2 h. Catalyst was and reused as such for subsequent
experiments (up to four cycles) under the similar reaction
conditions and the change in their catalytic activity was studied
w.r.t time and % yield. The recyclability of catalyst was veried
Table 3 Recyclability of the V–TiO2 NPs for the synthesis of poly-
hydroquinoline (Table 4, 5c)a
Entry
Cycle
% yieldb
1
2
3
4
Cycle 1
Cycle 2
Cycle 3
Cycle 4
90
86
80
72
a
Reaction conditions: the mixture of 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0
mmol) and 4 (2.0 mmol) at 80 ꢀC using V–TiO2 NPs of 5.85 nm size
under solvent-free condition for 12 min. Yields aer consecutive
b
Fig. 3 Effect of V–TiO2 NPs size for the solvent-free synthesis of
cycles.
polyhydroquinoline derivatives.
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Table 4 V–TiO2 NPs of 5.85 nm size promoted synthesis of polyhydroquinoline derivativesa
Entry
R
R1
R2
Time (min)
Product
Yieldb (%)
Mp (ꢀC)
Reported mp (ꢀC)
1
2
3
4
5
6
7
8
H-
4-CH3-
4-CH3O-
4-Cl-
4-NO2-
2,4-Cl2-
2-Cl-
3,4,5-(OCH3)3-
2-NO2-
3-NO2-
4-F-
3,4-(OCH3)2-
4-N(CH3)2-
2-Furyl
3-Pyridyl
4-OH-3-CH3O-
4-OH-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OEt
10
12
12
14
15
12
15
20
15
14
10
20
15
12
18
14
18
12
20
12
16
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
85
90
90
82
80
74
76
76
70
82
94
88
90
65
74
78
82
90
72
78
82
203–204
261–262
256–257
245–246
243–244
242–243
207–208
199–200
206–207
178–179
185–186
196–198
262–263
247–248
66–68
202–204
260–261
257–259
245–246
242–244
241–243
208–210
198–199
206–208
177–178
184–186
198–199
263–264
246–248
66–67
9
10
11
12
13
14
15
16
17
18
19
20
21
211–212
230–231
252–253
220–221
257–258
230–232
210–212
232–234
253–255
220–224
258–260
234–236
4-Br-
3,4,5-(OCH3)3-
4-N(CH3)2-
3-Br-
5s
5t
5u
a
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol) and 4 (2.0 mmol) at 80 ꢀC using V–TiO2 NPs of 5.85 nm size under solvent-free
condition. b Isolated yield.
on the reaction of dimedone (1), p-methoxybenzaldehyde (2c), Bronsted acid sites in addition to basic surface sites. Surface of
ethyl acetoacetate (3) and ammonium acetate (4) (Table 4, entry V–TiO2 nanoparticles was found to be basic in nature. Further
3) was selected as model reactants and xed the reaction time to incorporation of vanadium transition metal into TiO2 lattice
12 min to afford the corresponding polyhydroquinoline in 90, would increase the number of Lewis acid sites, Bronsted acid
86, 80 and 72% yields over four cycles (Table 3). It was noticed sites and other defects which play main role in increasing the
that yields of the product remained comparable in these reactivity of metal oxides as heterogeneous catalyst. The inter-
experiments, and thereby pointing the reusability of the catalyst action between arylaldehyde with the acidic sites of V–TiO2 NPs
without any signicant loss in catalytic activity.
catalyst surface generated the more electrophilic carbon center
On the basis of the above explanations and the literature followed by the nucleophilic attack of b-ketoester followed by
precedents, the possible mechanistic path for the synthesis of dimedone to give reactive adduct intermediate. The resulting
polyhydroquinoline (PHQ) derivatives is given in Scheme 2. The intermediate undergoes a intramolecular cyclization in pres-
used metal oxides species contains Lewis acid sites and ence of NH4OAc affording the corresponding desired poly-
hydroquinoline followed by the elimination of water molecule.
3. Experimental details
3.1. Materials
Vanadyl acetylacetonate, titanium tetraisopropoxide (TTIP)
were procured from Acros organics, UK. Dichloromethane,
ethanol and acetonitrile were obtained from E. Merck India Ltd.
Arylaldehydes, methyl/ethyl b-ketoester, dimedone and ammo-
nium acetate were purchased from Sigma-Aldrich, India.
Chemicals purchased from Across, Sigma-Aldrich and Merck
(India) were used without further purication.
3.2. Preparation of vanadium ion doped TiO2 nanoparticles
(V–TiO2 NPs)
V–TiO2 NPs of various dimensions were synthesized in our
laboratory by modied sol–gel hydrolysis of titanium(IV) iso-
Scheme
2 Proposed mechanism for the synthesis of poly-
hydroquinoline derivatives.
propoxide (TTIP) subsequently hydrothermal treatment
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procedure as follows: initially, the mixture of deionized water
and ethanol were placed at room temperature with constant
vigorous stirring. To this mixture add TTIP drop wise which is
dissolved in anhydrous ethanol. As the observed gel was relo-
4. Conclusion
In conclusion, a simple, efficient and environmentally benign
procedure has been developed using mesoporous vanadium ion
doped titania nanoparticles (V–TiO2) as robust heterogeneous
nanocatalyst for the synthesis of polyhydroquinoline derivatives
via esteemed Hantzsch reaction of arylaldehyde, b-ketoester,
ꢀ
cated into Teon lined autoclave and heated at 80 C for 24 h.
The accomplished solid was dried at room temperature and
nally tagged as bare TiO2 nanoparticles (TiO2 NPs). At last, the
obtained TiO2 NPs were washed with excess of ethanol to
eradicate organic moieties.25 In the same way, metal ion
dopants were incorporated through adding appropriate
amounts of vanadyl acetylacetonate into distilled water fore-
going to the hydrolysis of TTIP. By varying concentration of
vanadyl acetylacetonate, diverse nanoparticles were synthe-
sized. The nanoparticles were tagged as 0.1 V–TiO2 (0.1 at% V in
TiO2), 0.25 V–TiO2 (0.25 at% V in TiO2), 0.55 V–TiO2 (0.55 at% V
in TiO2) and 2.0 V–TiO2 (2.0 at% V in TiO2).
ꢀ
dimedone and ammonium acetate at 80 C under solvent-free
conditions as multi-component synthesis. This protocol was
successfully pertinent to a wide range of structurally diverse
arylaldehydes with b-ketoester, dimedone and ammonium
acetate to afford the corresponding polyhydroquinoline deriv-
atives. The advantages of performing the Hantzsch reaction in
the presence of V–TiO2 NPs as catalyst can be summarized as
follows: (1) use of a safe, non-volatile, non-corrosive and easily
handled V–TiO2 NPs; (2) recovery of V–TiO2 NPs at the end of the
reactions by simple ltration and washing; (3) desired products
are obtained in admirable yields under mild reaction condi-
tions; and (4) the reactions are carried out under solvent-free
conditions with economic benets. Excellent reusability of the
catalyst and ease of isolation of product are the other added
advantages that make this approach an attractive alternative for
the synthesis of these polyhydroquinoline derivatives.
3.3. Catalyst characterization techniques
Powder X-ray diffraction (XRD) patterns of the synthesized
samples were recorded on X'Pert Pro Diffractometer of M/s
Panalytical, Netherlands make using Cu Ka radiation. Trans-
mission electron microscopy (TEM) measurements were done
on Tecnai transmission electron microscope of FEI make.
Samples were suspended in 30 mL of acetone, and the
suspension was sonicated for 30 min. Aer that, suspension
was placed on carbon coated copper grids of 3 mm dia and
dried at room temperature prior to the analysis. Nitrogen
adsorption measurements were done on ASAP 2020 surface area
analyzer of Micrometrics, USA. FT-IR measurements were done
as KBr pellets on Perkin Elmer, USA instrument. X-ray photo-
electron spectroscopy (XPS) data was recorded on KRATOS AXIS
165 instrument. TiO2, V–TiO2 nanoparticles are conrmed by
Energy-Dispersive X-ray spectroscopy (EDX) spectrum that
reveals the presence of Ti, V and O elements. Au and C signals
could be due to gold coating and carbon lm supporting the
specimen during SEM observation.
Acknowledgements
Authors express deep sense of gratitude to Ravi K. Gujjula,
Principal, KPRIT, Hyderabad and also special thanks to IISER,
Bhopal.
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