Nano-TiO2 as an Efficient Catalyst for Tandem Knoevenagel-Michael-Cyclocondensation Reaction of Dimedone with Aromatic Aldehydes and Ammonium Acetate or Aromatic Amines under Solvent-free Conditions

Article abstract of DOI:10.1002/jccs.201500384

TiO₂ nanoparticles in anatase and rutile forms was characterized and studied by several techniques including X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM) and successfully applied as an efficient and heterogeneous catalyst in the synthesis of 1,8-dioxo-decahydroacridines via the one-pot multi-component condensation reaction of dimedone with aromatic aldehydes and ammonium acetate or aromatic amines under mild and solvent-free conditions.

Full text of DOI:10.1002/jccs.201500384

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Nano-TiO2 as an Efficient Catalyst for Tandem Knoevenagel–Michael-Cyclocondensation
Reaction of Dimedone with Aromatic Aldehydes and Ammonium Acetate or Aromatic
Amines under Solvent-free Conditions
Ardeshir Khazaei,a* Ahmad Reza Moosavi-Zare,b* Zahra Mohammadi,a Vahid Khakyzadeha and
Javad Afsara
aFaculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran
bDepartment of Chemistry, Sayyed Jamaleddin Asadabadi University, Asadabad, 6541835583, Iran
(Received: Sep. 17, 2015; Accepted: Nov. 11, 2015; Published Online: Dec. 21, 2015; DOI: 10.1002/jccs.201500384)
TiO2 nanoparticles in anatase and rutile forms was characterized and studied by several techniques in-
cluding X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron micros-
copy (TEM) and successfully applied as an efficient and heterogeneous catalyst in the synthesis of
1,8-dioxo-decahydroacridines via the one-pot multi-component condensation reaction of dimedone
with aromatic aldehydes and ammonium acetate or aromatic amines under mild and solvent-free condi-
tions.
Keywords: Nano-TiO2; Tandem reaction; 1,8-Dioxo-decahydroacridine; Heterogeneous; Catalyst.
INTRODUCTION
Tandem reaction, as a modern strategy in organic syn-
hydroacridine derivatives.22-27 However, some of them suf-
fer from the drawbacks such as the use of toxic metals, the
use of volatile organic solvents, high cost and low yields.
Solvent-free reactions have been demonstrated to be as an
efficient technique for various organic transformations in-
stead of using harmful organic solvents. Solvent-free con-
ditions mostly lead to a considerable decrease in reaction
times, increased yields, easier workup, matches with green
chemistry protocols, and may enhance the regioselectivity
and stereoselectivity of reactions.28-33
thesis, is a reaction in which several bonds are formed in
some sequences without isolating of any intermediates,
changing reaction conditions and adding reagents. The
main advantages of this reaction are that the reaction is of-
ten fast because of its intramolecular nature, clean reaction
condition, high atomic economy and much complexity in
effectively one step.1-5
TiO2 nanoparticles have been applied as an efficient
catalyst in some organic transformations,6 such as catalyst
support for proton exchange membrane fuel cells,7 cata-
lytic activity for esterification,8 co-catalyst to improve win-
kle-resistance of cotton fabric,9 sonocatalytic degradation
of methyl parathion,10 photodecomposition of methylene-
blue by highly dispersed on Ag,11 catalyst for rhodamine B
degradation,12 photocatalytic degradation of styrene,13
crosslinking of cotton cellulose with succinic acid under
UV14 and synthesis of quinoxalines.15 The synthesis of
1,4-Dihydropyridines (1,4-DHPs) is important due to their
wide range of pharmaceutical and biological properties, in-
cluding anti-tubercular, antibacterial, antihypertensive,
anticancer, and anti-inflammatory effects.16-20 1,8-dioxo-
decahydroacridines are poly-functionalized 1,4-dihydro-
pyridine derivatives which have received less attention
than other 1,4-DHP derivatives.21 Several methods have
been introduced for the preparation of 1,8-dioxo-deca-
Herein, we report the solvent-free preparation of
1,8-dioxo-decahydroacridine derivatives using TiO2 nano-
particles as an efficient, heterogeneous and recyclable cata-
lyst. This work has none of the above mentioned draw-
backs at all (Scheme 1).
The synthesis of 1,8-dioxo-decahydroacri-
dines
Scheme 1
* Corresponding author. Email: Khazaei_1326@yahoo.com or moosavizare@yahoo.com
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500384
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Khazaei et al.
RESULTS AND DISCUSSION
decahydroacridines was investigated. For this purpose, as a
model reaction, a mixture of dimedone (2 mmol) with
3-bromobenzaldehyde (1 mmol) and ammonium acetate (1
mmol), was stirred in the presence of different amounts of
nano-TiO2 in rutile form at range of 60 to 110 °C under sol-
vent-free conditions. The results are summarized in Table
1. As it can be seen in Table 1, 10 mol% of nano-TiO2 was
suitable to catalyze the reaction at 75 °C. In this reaction
condition, the expected 1,8-dioxo-decahydroacridine was
efficiently synthesized in 90% yield within 15 min (Table
1, entry 3). The model reaction was studied in the presence
Initially, nano-TiO2 in anatase and rutile forms was
prepared according the previous literature. Then, the cry-
stallinity and the crystallite size were investigated by XRD.
The XRD pattern of TiO2 was obtained in the range of 2q =
0-90°. All the peaks in the XRD patterns could be indexed
as rutile phases of TiO2 (Figure 1) and anatase phases (Fig-
ure 2). All peaks were in good agreement with the standard
spectrum (JCPDS no.: 88-1175 and 84-1286). Crystallite
size was obtained by Debye-Scherrer’s formula given by
equation: D = Kl/(bcosq). The crystallite size obtained us-
ing this formula, was at about 9.6 nm for rutile phases and
13.1 nm for anatase phases.
In another investigation, the SEM micrographs of the
catalyst showed that the particles have not agglomerated.
Also, particles of the catalyst were observed in nano size
(Figures 3 and 4).
To further prove the nanostructure of nano-TiO2 in
anatase and rutile forms, Transmission electron micro-
graphs (TEM) measurements were performed as shown in
Figures 5 and 6. TEM micrographs confirm the presence of
more or less spherical nanoparticles with a mean diameter
of 25 nm.
In the next step, catalytic activity of nano-TiO2 in
anatase and rutile forms on the synthesis of 1,8-dioxo-
Fig. 3. SEM micrograph of TiO2 nanoparticles in rutile
form.
Fig. 1. XRD pattern of TiO2 nanoparticles in rutile
form.
Fig. 2. XRD pattern of TiO2 nanoparticles in anatase
form.
Fig. 4. SEM micrograph of TiO2 nanoparticles in ana-
tase form.
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Synthesis of 1,8-Dioxo-decahydroacridines
Table 1. Effect of different amounts of the catalyst and
temperature on the reaction of dimedone with 3-
bromobenzaldehyde in the absence of solvent
Catalyst
Temp. Time Yielda
Entry
Catalyst
amount
(mol%)
(°C) (min) (%)
1
2
3
4
5
6
7
8
9
Nano-TiO2 (R)b
Nano-TiO2 (R)
Nano-TiO2 (R)
Nano-TiO2 (R)
Nano-TiO2 (R)
Nano-TiO2 (R)
Nano-TiO2 (R)
Nano-TiO2 (R)
Nano-TiO2 (A)c
10
10
10
10
-
60
90
75
110
75
75
75
75
75
60
60
15
15
70
85
90
90
300 trace
5
90
55
15
15
68
81
90
90
7
12
10
a Isolated yield; b Catalyst was used in rutile (R) form; c Catalyst
was used in anatase (A) form.
Fig. 5. Transmission electron micrographs (TEM) TiO2
nanoparticles in rutile form.
In a plausible mechanism, at first, aldehyde is acti-
vated by nano-TiO2 to give I. Then, dimedone attacks to the
carbonyl group of the activated aldehyde and affords inter-
mediate II. Next, by removing H2O from II, III is prepared
as a michael acceptor. Nano-TiO2 activates intermediate
III again. Afterward, Michael addition of dimedone with
intermediate III affords IV. Ammonia, which is resulted
from ammonium acetate, attacks to the activated carbonyl
group of IV and then by removing one molecule of H2O,
Intermediates V and VI is prepared respectively. VI is con-
verted to VII by tautomerization, and then by the cyclo-
condensation reaction of NH2 group with activated car-
bonyl group of VII and removing one molecule H2O, the
desired product is prepared (Scheme 2).
Fig. 6. Transmission electron micrographs (TEM) TiO2
nanoparticles in anatase form.
In another investigation, recyclability of the catalyst
was studied upon the reaction of dimedone with 3-bromo-
benzaldehyde and ammonium acetate. The reaction mixture
was extracted by hot EtOH and separated from the catalyst.
Then, the recycled catalyst was dried and used for next run.
We observed that the catalytic activity of the catalyst was re-
stored within the limits of the experimental errors for 8 suc-
cessive runs without any noticeable decline in the yields.
To compare the efficiency of our catalyst with the re-
ported catalysts for the synthesis of 1,8-dioxo-decahydro-
acridines, we have tabulated the results of these catalysts to
perform the reaction of dimedone with 3-bromobenzal-
dehyde and ammonium acetate, in Table 3. As Table 3 indi-
cates, nano-TiO2 has remarkably improved the synthesis of
1,8-dioxo-decahydroacridines; the reaction times were
shorter, and the yields were higher when our catalyst was
utilized.
of nano-TiO2 in anatase form. The catalytic application for
rutile and anatase forms in this reaction condition was same
(Table 1, entry 9). The solvent-free condensation was also
tested at 75 °C without catalyst in which the reaction was
not progressed even after long reaction time.
To investigate the efficacy and the generality of the
catalyst, dimedone was reacted with various aromatic alde-
hydes (aromatic as well as aliphatic containing electron-
withdrawing groups, electron-donating groups and halo-
gens) and ammomium acetate under the optimized reaction
conditions; the results are displayed in Table 2. As it is
shown in Table 2, all reactions proceeded efficiently to ob-
tain the expected 1,8-dioxo-decahydroacridine derivatives
in high yields and in short reaction times.
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Khazaei et al.
EXPERIMENTAL
General: All chemicals were purchased from Merck or
Fluka Chemical Companies. All known compounds were identi-
fied by comparison of their melting points and spectral data with
those reported in the literature. Nano-TiO2 was prepared accord-
ing to the reported procedure.36 Progress of the reactions was
monitored by thin layer chromatography (TLC) using silica gel
SIL G/UV 254 plates. The melting points were recorded on a
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Synthesis of 1,8-Dioxo-decahydroacridines
The plausible mechanism for the synthesis
Table 3. Comparison of the results of the condensation reaction
of dimedone with 3-bromobenzaldehyde and
Scheme 2
of 1,8-dioxo-decahydroacridines in the pre-
sence of nano-TiO2
ammonium acetate catalyzed by nano-TiO2 with those
obtained by the recently reported catalysts
Catalyst
loading
Time Yielda TOFb
(min) (%) (min-1)
Reaction condition
Ref.
L-Proline, H2O,
reflux
35 mol%
120
82
84
0.0195 [34]
0.0070 [34]
0.0110 [34]
Zn(OAc)2.2H2O,
H2O, reflux
100 mol% 120
NH4Cl, H2O, reflux 65 mol%
120
180
86
90
HY-zeolite, EtOH,
reflux
0.1 g
-
[35]
c
-
Nano-TiO2 (R),
solvent-free, 75 °C
10 mol%
20
80
0.4000
a Isolated yield; b Turn over frequency; c Our work.
test tube was firstly stirred magnetically. After completion the re-
action monitored by TLC, the mixture was cooled to room tem-
perature and warm EtOH (30 mL) was added to it. Then the reac-
tion mixture was concentrated to 10 mL and centrifuged for 20
min to separate the nano-TiO2. After evaporation of the solvent
from the supernatant, the resulting solid was recrystallized from
EtOH (95%) to give the pure product. EtOAc (10 mL) was added
to the recycled nano-TiO2 and centrifuged (two times). Finally,
the nano-TiO2 was dried and reused for the next run.
CONCLUSIONS
In summary, we have introduced nano-TiO2 as a reus-
able, stable, general and heterogeneous catalyst for the sol-
vent-free synthesis of 1,8-dioxo-decahydroacridines. The
promising points for the presented method are efficiency,
generality, high yields of the products, short reaction times,
simplicity, cleaner reaction profile, low cost, ease prepara-
tion and reusability of the catalyst.
ACKNOWLEDGEMENTS
The authors acknowledge to Bu-Ali Sina University
Research Councils, Center of Excellence in Development
of Chemistry Methods (CEDCM) and National Foundation
of elites (BMN) of Sayyed Jamaleddin Asadabadi Univer-
sity, for support of this work.
Büchi B-545 apparatus in open capillary tubes. The 1H NMR (90
or 400 MHz) and 13C NMR (100) were run on a Bruker Avance
DPX, FT-NMR spectrometers, d in ppm. Mass spectra were ob-
tained with Shimadzu GC-MS-QP 1100 EX model.
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