Palladium(0) nanoparticles: An efficient catalyst for the one-pot synthesis of polyhydroquinolines

Article abstract of DOI:10.1016/j.tetlet.2011.07.031

A mild, concise, and efficient protocol for the synthesis of polyhydroquinoline via four component reaction of aromatic aldehydes, dimedone, ethyl acetoacetate or ethyl cyanoacetate, and ammonium acetate using Pd-nanoparticles is described. The same phenomenon was observed in the case of arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones), ethyl acetoacetate, ammonium acetate, and Pd-nanoparticles in one-pot. The present method also allows us to synthesize highly functionalized title compounds from simple and readily available inputs.

Full text of DOI:10.1016/j.tetlet.2011.07.031

Tetrahedron Letters 52 (2011) 4872–4877
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(0) nanoparticles: an efficient catalyst for the one-pot synthesis
of polyhydroquinolines
⇑
Mithu Saha, Amarta Kumar Pal
Department of Chemistry, North Eastern Hill University, NEHU Campus, Shillong 793022, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, concise, and efficient protocol for the synthesis of polyhydroquinoline via four component reac-
tion of aromatic aldehydes, dimedone, ethyl acetoacetate or ethyl cyanoacetate, and ammonium acetate
using Pd-nanoparticles is described. The same phenomenon was observed in the case of arylmethylene
bis(3-hydroxy-2-cyclohexene-1-ones), ethyl acetoacetate, ammonium acetate, and Pd-nanoparticles in
one-pot. The present method also allows us to synthesize highly functionalized title compounds from
simple and readily available inputs.
Received 12 May 2011
Revised 8 July 2011
Accepted 11 July 2011
Available online 23 July 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Palladium nanoparticles
Multicomponent reaction
Polyhydroquinolines
Dimedone
Knoevenagel condensation
Michael addition
Design of highly efficient chemical reaction sequence that
provides maximum structural complexity and diversity with a
minimum number of synthetic steps to assemble compounds with
increasing properties is a major challenge of modern drug discov-
ery.1 Recently, multicomponent reaction has emerged as a highly
valuable synthetic tool in the context of modern drug discovery.
The atom-economy and convergent character, the simplicity of
one-pot procedure, the possible structural variation, the accessible
complexion of the molecule, and the very large number of accessi-
ble compounds are among the described advantages of multicom-
ponent reaction.2 Thus, they are perfectly amenable to automation
for combinatorial synthesis.3
Polyhydroquinolines are an important group of nitrogen con-
taining heterocycles that have attracted much attention because
of their diverse therapeutic and pharmacological properties, such
as calcium channel blockers, vasodilator, hepatoprotective, anti-
atherosclerotic, bronchodilator, antitumor, geroprotective, antidia-
betic activity, etc.4,5 Furthermore, recent studies have revealed
several other medicinal applications that include neuroprotectant
and platelet anti-aggregatory activity, cerebral anti-ischemic activ-
ity in the treatment of Alzheimer’s disease, and as a chemosensitiz-
er in tumor therapy.6
flates,9 HClO4–SiO2,10 HY-zeolites,11 TMSCl-NaI,12 ceric ammonium
nitrate,13 grinding technique,14 ultrasound,15 montmorillonite K-
10,16 p-TSA,17 polymer,18,19 hetrapolyacid,20 organic catalyst,21
L-
proline,22 Bakers’ yeast,23 ZrCl4,
MCM-41,25 solar heat,26 Hf
24
(NPf2)4,27 Yb(OTf)3,28 Cu(OTf)2,29 triphenyl phosphine,30 and liquid
phase.31 Although most of these processes offer distinct advanta-
ges, they also suffer from certain drawbacks, such as longer reac-
tion time, unsatisfactory yields, high costs, harsh reaction
conditions, stoichiometric amounts of catalyst, and also environ-
mentally toxic catalysts. In recent time, interest in nanoparticles
catalysis has increased considerably because of its improved
efficiency (higher surface to volume ratio)32,33 under mild and
environmentally benign conditions in the context of green chemis-
try and palladium nanoparticles have been found to be active
species in various C–C bond formation reaction, namely Heck,
Sonogashira, and Suzuki, coupling reactions and thus showed great
promise for further applications.33
To the best of our knowledge, however, any palladium nanopar-
ticles promoted synthesis of polyhydroquinoline derivatives has
not been reported till date. In the present work, we report here a
novel, ligand-free protocol for the synthesis of polyhydroquino-
lines catalyzed by palladium(0) nanoparticles. The overall process
involves the Knoevenagel condensation of dimedone with aryl
aldehydes, followed by in situ Michael addition of ethyl acetoace-
tate in a single operation.
Therefore, several methods have been developed for the prepa-
ration of polyhydroquinoline derivatives by using various catalysts,
including molecular iodine,7 ionic liquid,8 rare earth metal tri-
In continuation of our research work in the development of
highly expedient methodologies for the synthesis of biologically
important heterocyclic compounds,34 we became interested in
⇑
Corresponding author. Tel.: +91 364 2307930x2636; fax: +91 364 2550076.
E-mail address: amartya_pal22@yahoo.com (A.K. Pal).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.031

M. Saha, A. K. Pal / Tetrahedron Letters 52 (2011) 4872–4877
4873
R
O
CHO
O
O
Y
O
i)
+
X
+
O
+
NH4 OAc
O
O
N
H
4
3
R
1
2a-p
5a-p
Y = CH3
Y = NH2
X = CH3CO
X = CN
Scheme 1. Synthesis of polyhydroquinoline derivatives 5a–p from dimedone. Reagents and conditions: (i)PdCl2, Na2CO3, TBAB, THF, refluxed 4–5 h.
100
80
60
40
20
0
1
2
3
No of cycle
Figure 1. TEM image of palladium nanoparticles.
Figure 2. Recyclability chart.
developing a methodology for the synthesis of polyhydroquino-
line derivatives using various aromatic aldehydes, ethyl acetoace-
tate or ethyl cyanoacetate, ammonium acetate, and dimedone
under Pd-nanoparticles mediated reaction condition. As a model
reaction, we selected 1 equiv of dimedone 1, 1 equiv of benzalde-
hyde 2a, 1 equiv of ethyl acetoacetate 3, 2 equiv of ammonium
acetate 4, 0.04 equiv of PdCl2, 1 equiv of TBAB, and 3 equiv of
Na2CO3 in THF under refluxing condition and obtained 5a in
89% yield (Scheme 1). The formation of Pd-(0) nanoparticles
in situ from this reagent system was detected from the analysis
of the reaction mixture by transmission electron microscope
(TEM) (Fig. 1) and X-ray diffraction (XRD) (Fig. 3). The morphol-
ogy and grain size of the palladium nanoparticles were
investigated by TEM. They had spherical with a narrow size dis-
tribution from 10 to 40 nm. The presence of some larger particles
should be attributed to aggregating or overlapping of smaller par-
ticles. The data were in good agreement with the previously re-
ported results.35 Encouraged by the initial success, we extended
the scope of the present protocol for the synthesis of polyhydro-
quinolines from aryl aldehydes (Scheme 1). As shown in the Table
1, aromatic aldehydes carrying either electron donating or
withdrawing substituent worked well, giving excellent yields of
products with high purity, but aliphatic aldehydes under similar
condition did not produce any polyhydroquinolines. Only starting
materials were recovered.
P d
P d
30
40
50
60
70
80
90
Figure 3. Powder XRD pattern with characteristic dihedral angels at 40.17° and
45.73° corresponding to Pd nanoparticles.
and water led to low yields (Table 2, entries 1–3) under refluxing
condition, but the best conversion was observed when the reaction
was carried out in tetrahydrofuran (Table 2, entry 4).
In transition metal catalyzed reactions, ligands play an impor-
tant role. Various phosphine and nonphosphine ligands for palla-
dium catalyzed coupling reactions are described in the literature.
Most of these ligands are air and moisture sensitive, difficult to
prepare, and expensive. Thus, catalysis by a ligand-free condition
is an area of high importance.36
The Knoevenagel condensation followed by Michael addition
reaction of dimedone with several aromatic aldehydes, ammonium
acetate, and ethyl acetoacetate in the presence of palladium nano-
particles was investigated using a range of different solvents. The
results of Table 2 indicate that solvents affected the efficiency of
the reaction. In general, solvent like dichloromethane, acetonitrile,
In evaluating the effect of catalyst concentration, the best yields
were obtained in the presence of just 0.04 mmol of palladium

4874
M. Saha, A. K. Pal / Tetrahedron Letters 52 (2011) 4872–4877
Table 1
Synthesis of polyhydroquinoline derivatives 5a–p
aIsolated yields

M. Saha, A. K. Pal / Tetrahedron Letters 52 (2011) 4872–4877
4875
nanoparticles. A higher amount of catalyst 0.06, 0.08, and 1.0 mmol
did not improve the yield of the desired product. On decreasing the
Pd concentration from 0.04 to 0.02 and 0.01 mmol, the yield of
polyhydroquinoline dropped even after 6 h. The reaction without
the catalyst has also been carried out but no polyhydroquinoline
derivatives were witnessed and only dimedone and aryl aldehyde
were recovered. Reusability is one of the important properties of
this catalyst. In this study, the catalyst was recovered and reused
in another run. The catalyst was recovered by a simple filtration
using centrifugation method and reused during three consecutive
runs without any apparent loss of activity for the same reaction
(Fig. 2).
Kumar et al.23 reported the conversion of arylmethylene bis(3-
hydroxy-2-cyclohexene-1-one) to polyhydroquinoline using
Bakers’ yeast as a catalyst. Encouraged by our initial results, we
extended the scope of our present protocol for the synthesis of
polyhydroquinoline from arylmethylene bis(3-hydroxy-2-cycloh-
exene-1-one) 6a–j and it afforded polyhydroquinoline (5a–j)
(Scheme 2) in good to excellent yields (Table 3). The mechanism
for the formation of polyhydroquinoline 5a–j from arylmethylene
bis(3-hydroxy-2-cyclohexene-1-one) 6a–j is still uncertain. All
the products were analytically pure and structures were deter-
mined by the spectral methods.
In summary, we have developed a novel, mild, and efficient
strategy for the synthesis of polyhydroquinoline from dimedone,
aryl aldehydes, and ammonium acetate and ethyl acetoacetate or
ethyl cyanoacetate via Knoevenagel condensation followed by Mi-
chael addition reaction using Pd-nanoparticles as catalyst. The
methodology is simple, rapid, and relatively inexpensive affording
good to excellent yields with operational simplicity.
Table 2
Optimization of solvent effect
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
DCM
CH3CN
Water
THF
Reflux
Reflux
Reflux
Reflux
Reflux
4
4
4
4
6
67
59
52
89
89
Acknowledgments
We thank Department of Chemistry (NEHU), UGC-SAP, and SAIF
(NEHU) and IACS (Kolkata) for analytical support. We are also
thankful to Professor R. K. Poddar and Dr. Rama Ranjan
Bhattacharya.
THF
R
R
O
O
O
O
O
O
i)
O
+
NH4OAc
+
O
N
4
3
OH OH
H
6 a-j
5 a-j
Scheme 2. Synthesis of polyhydroquinoline derivatives 5a–j from arylmethylene bis(3-hydroxy-2-cyclohexene-1-one). Reagents and conditions: (i) PdCl2, Na2CO3, TBAB,
THF, refluxed 4–5 h.
Table 3
Synthesis of polyhydroquinoline (5a–j) derivatives from arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones) 6a–j
Entry
Arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones) 6a-j
Product
Time (h)
Yields (%)a
O
O
1
5a
4.3
87
OH OH
6a
NO2
O
O
2
5b
4
91
OH OH
6b
(continued on next page)

4876
M. Saha, A. K. Pal / Tetrahedron Letters 52 (2011) 4872–4877
Table 3 (continued)
Entry
Arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones) 6a-j
Product
Time (h)
Yields (%)a
F
O
O
3
5c
4
88
OH OH
6c
Cl
O
O
4
5
6
5d
5e
5f
4
87
85
88
OH OH
6d
O
O
4.3
OH OH
6e
Br
O
O
O
O
O
O
4
OH OH
6f
O
7
5g
5
83
OH OH
6g
N
8
5h
5
81
OH OH
6h

M. Saha, A. K. Pal / Tetrahedron Letters 52 (2011) 4872–4877
4877
Table 3 (continued)
Entry
Arylmethylene bis(3-hydroxy-2-cyclohexene-1-ones) 6a-j
Product
Time (h)
Yields (%)a
F
O
O
9
5i
4.3
87
OH OH
6i
Cl
O
O
10
5j
4.3
89
OH OH
6j
a
Isolated yields
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