Nano crystalline ZnO: A competent and reusable catalyst for one pot synthesis of novel benzylamino coumarin derivatives in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2012.04.033

A green, efficient and facile protocol was developed for the synthesis of a series of benzylamino coumarin derivatives by the reaction of 4-hydroxycoumarin, cyclic secondary amine, and aromatic aldehyde in aqueous media in the presence of nano crystalline ZnO at room temperature. A wide range of functional groups were tolerated in the developed protocol. The target molecules were obtained in good to excellent yield applying the current method. The nano crystalline ZnO can be recycled five times with almost the same catalytic activity.

Full text of DOI:10.1016/j.tetlet.2012.04.033

Tetrahedron Letters 53 (2012) 3140–3143
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nano crystalline ZnO: a competent and reusable catalyst for one pot synthesis
of novel benzylamino coumarin derivatives in aqueous media
⇑
Partha Pratim Ghosh, Asish R. Das
Department of Chemistry, University of Calcutta, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A green, efficient and facile protocol was developed for the synthesis of a series of benzylamino coumarin
derivatives by the reaction of 4-hydroxycoumarin, cyclic secondary amine, and aromatic aldehyde in
aqueous media in the presence of nano crystalline ZnO at room temperature. A wide range of functional
groups were tolerated in the developed protocol. The target molecules were obtained in good to excellent
yield applying the current method. The nano crystalline ZnO can be recycled five times with almost the
same catalytic activity.
Received 1 March 2012
Revised 5 April 2012
Accepted 6 April 2012
Available online 14 April 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Multicomponent reaction
3-Benzyl substituted coumarin derivative
Nano crystalline ZnO
Green synthesis
Multicomponent reactions (MCRs) are a powerful tool for atom-
efficient, time, cost-advantageous and environmentally waste-free
synthesis of complex building blocks of bioactive heterocycles.1
From the perspective of green chemistry, organic synthesis in
water has received considerable attention because of its cost-effec-
tiveness, easy availability and safe character. We preferred water
as the reaction medium over potentially toxic organic solvents to
decrease chemical impurity, to allow easy work-up and because
of its ideal behavior.2
In recent years, much attention has been directed towards the
synthesis of 3-benzyl substituted 4-hydroxycoumarins owing to
their tremendous application in various research fields including
biological science and medicinal chemistry. 3-Benzyl substituted
4-hydroxycoumarin derivatives are components of numerous
O
OH
OH
OH
O
O
O
O
O
O
Coumatetralyl
Phenprocoumon
Warfarin
OH
N
O
O
O
O
O
O
O
Bromadialone
Carbochromen
Figure 1. Biologically active 3-substituted coumarins.
⇑
Corresponding author. Tel.: +91 3323501014; mobile: +91 9433120265; fax: +91 3323519754.
E-mail addresses: ardchem@caluniv.ac.in, ardas66@rediffmail.com (A.R. Das).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.033

P. P. Ghosh, A. R. Das / Tetrahedron Letters 53 (2012) 3140–3143
3141
OH
N
O
OH
O
O
nano ZnO
Ar
N
H
3
Ar
H
H2O ,r.t.
O
4
O
2
1
Scheme 1. Synthesis of benzylamino coumarin derivatives catalysed by nanocrystalline ZnO at room temperature (25 °C).
Table 2
Table 1
Influence of different catalysts on the synthesis of benzylamino coumarin
Solvent effects on the three-component coupling reaction for the synthesis of
derivative 4da
benzylamino coumarin derivative 4da
Yieldb (%)
Entry
Catalysts
Time (h)
Yieldb (%)
Entry
Solvent
1
2
3
Nano aluminium oxide (Al2O3)
Zeolites
8
7
6
26
32
43
1
2
3
4
5
6
7
Toluene
40
46
50
60
77
72
93
Tetrahydrofuran
Acetonitrile
DMSO
Ethanol
Methanol
H2O
L-proline
4
5
6
7
Alum
8
6
8
0.25
29
24
66
93
Tetrabutylammonium bromide
Commercial ZnO
Nano ZnO
a
a
The reaction was carried out using 4-hydroxycoumarin (1 mmol), piperi-
The reaction was carried out using 4-hydroxycoumarin (1 mmol), piperi-
dine(1 mmol) and m-nitrobenzaldehyde(1 mmol) in the presence nano crystalline
dine(1 mmol) and m-nitrobenzaldehyde(1 mmol) in presence of water at room
ZnO(10 mol %) at room temperature (25 °C).
temperature (25 °C).
b
b
Isolated yield of the pure product.
Isolated yield of the pure product.
natural products like warfarin, phenprocoumon, coumatetralyl,
carbochromen, bromadialone, (Fig. 1) etc. These compounds also
exhibit a wide band of biological activities including antibacterial,
anti-HIV,3 antiviral,4 anticoagulant,5 antioxidant6 and anticancer
activities.7 The vast biological importance of the amino derivatives
of 4-hydroxycoumarin inspired us to develop a novel protocol for
the efficient synthesis of new benzylamino coumarin derivatives.
A number of synthetic protocols have been applied for the syn-
thesis of nitrogen containing coumarin derivatives.8–11 Mannich
reaction12 is the best way to synthesize such type of compounds
by the condensation of 4-hydroxycoumarin with an aromatic alde-
hyde and a secondary amine. The methods reported previously for
the synthesis of benzylamino coumarin derivatives suffer from se-
vere disadvantages such as longer reaction time, inadequate yields
and use of expensive non-recoverable surfactant.9,10 Thus, the
development of environmentally benign, high-yielding, and clean
synthesis of benzylamino coumarin derivatives still remains a de-
sired goal in organic synthesis. Herein, we disclose a general, rapid,
high yielding and green synthetic protocol for a wide variety of ben-
zylamino coumarin derivatives starting from 4-hydroxycoumarin.
Recently, nano crystalline metal oxides have attracted consider-
able attention of synthetic and medicinal chemists because of their
high catalytic activity and reusability. There are a few reports
available in the literature for the use of nano crystalline ZnO in
MCRs. We recently demonstrated the high catalytic activity of
nano crystalline ZnO in multicomponent coupling reactions.13
Herein we wish to uncover another significant catalytic activity
of nano crystalline ZnO for the one pot three-component coupling
reaction of 4-hydroxycoumarin with an aromatic aldehyde and a
secondary amine (Scheme 1) in aqueous media.14
Table 3
Optimization of catalyst loading for the three component coupling reaction of
4-hydroxycoumarin, piperidine and m-nitrobenzaldehyde
Entry Catalysts
Yields
of 4b(%)
1
2
3
4
5
6
7
8
Nano-ZnO (3 mol %)
36
62
93
86
Nano-ZnO (7 mol %)
Nano-ZnO (10 mol %)
Nano-ZnO (15 mol %)
Nano-ZnO (10 mol %) + p-toluenesulphonic acid (10 mol %) 14
Nano-ZnO (10 mol %) + methanesulphonic acid (10 mol %)
Nano-ZnO (10 mol %) + boric acid (10 mol %)
Nano-ZnO (10 mol %) + tetrabutylammonium bromide
(10 mol %)
29
23
27
b
Isolated yield of the pure product.
polar protic solvents afforded better yield than other solvents
and the best catalytic activity of nano ZnO (10 mol %) was observed
(yield 93%) in aqueous medium (Table 1).
Then we focused on the systematic evaluation of different cat-
alysts for the model reaction in aqueous medium at room temper-
ature (25 °C). A wide variety of catalysts including nano aluminium
oxide (Al2O3), L-proline, alum, zeolites, tetrabutylammonium bro-
mide and commercial ZnO were employed to test their efficacy
for the specific synthesis of benzylamino coumarins (Table 2).
The results presented in Table 2 show that in presence of nano-
ZnO, the desired product was obtained in 93% yield within
15 min. Therefore, this catalyst appears to be superior to any of
the other catalysts tested which include commercial ZnO (66%,
Initially, m-nitrobenzaldehyde (1 mmol), 4-hydroxycoumarin
(1 mmol) and piperidine (1 mmol) were employed as reactants
for the model reaction to synthesize benzylamino coumarin deriv-
atives in the presence of catalytic amount of zinc oxide (10 mol %)
(Table 1). In our initial study for the optimization of the reaction
condition, a screening was performed with a variety of polar and
nonpolar solvents like DMSO, ethanol, methanol, toluene,
tetrahydrofuran and acetonitrile (Table 1). We noticed that the
8 h) and L-proline (43%, 6 h).
The quantity of the catalyst plays a vital role for the formation
of the desired product. The results summarized in Table 3 clearly
revealed that an enhancement in catalyst loading from 3 to
10 mol %, increased the yield of the desired product to a great ex-
tent (36–93%). Again it also revealed that no other additive combi-
nations like protic or Lewis acids are at all advantageous in this
method (Table 3).

3142
P. P. Ghosh, A. R. Das / Tetrahedron Letters 53 (2012) 3140–3143
Table 4
composite plays an important role for the rapid formation and sta-
bilization of the imine intermediate. The catalyst may induce 4-hy-
droxy coumarin to act as the Mannich donor for the very fast
formation of benzylamino coumarin derivatives. The rapid imine
generation and subsequent ‘C–C’ bond formation within a very
short time catalysed by amphoteric nano ZnO (forming colloidal
composite) (Scheme 2) are the attractive features of this protocol.
The reusability of the catalyst was studied through the conden-
sation of m-nitrobenzaldehyde, 4-hydroxycoumarin and piperi-
dine. The separated catalyst was collected, followed by washing
with acetone several times to remove all the organic substances.
It was then dried at room temperature and was recycled five con-
secutive times with almost unaltered catalytic activity (recovery
amount 92% and yield, 89% after 5th run). Furthermore, to take
advantage of the highly efficient green protocol, the reaction was
scaled up to 10 mmol scale,15 excellent results were obtained in
the stipulated time as mentioned in Table 4.
In conclusion, a highly efficient and environmentally green
methodology for the synthesis of benzylamino coumarin deriva-
tives via the one pot three-component reactions of 4-hydroxy-
coumarin, aldehyde and secondary amine has been developed.
The attractive features of this protocol are simple reaction proce-
dure, short reaction time, easy product separation, purification
and reusability of nano crystalline ZnO, and its high adaptability
for the synthesis of a broad spectrum of benzylamino coumarin
derivatives in good to excellent yields. To the best of our knowl-
edge, this is the first report about the synthesis of benzylamino
coumarin derivatives using nano crystalline metal oxide as a
catalyst.
Synthesis of benzylamino coumarins over nanocrystalline ZnO catalysta
Entry Ar
Amine
Product Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
C6H5
C6H5
C6H5
Piperidine
Morpholine
Pyrolidine
Piperidine
Morpholine
Pyrolidine
Pyrolidine
Pyrolidine
Piperidine
Morpholine
Pyrolidine
Piperidine
4a
4b
4c
4d
4e
4f
4g
4h
4i
15
25
25
15
20
25
20
20
20
25
25
25
25
20
20
25
25
25
25
35
30
35
30
25
30
92
90
93
93
90
91
92
95
93
90
91
87
89
87
92
93
92
90
90
91
91
91
90
93
91
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
4-Cl C6H4
4-F C6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
4-Pyridyl
4-Pyridyl
4-Pyridyl
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4j
4k
4l
Morpholine 4m
Pyrolidine
Piperidine
Morpholine
Pyrolidine
Piperidine
Morpholine
Pyrolidine
4n
4o
4p
4q
4r
4s
4t
4-MeO,3-OHC6H3 Piperidine
4-MeO,3-OHC6H3 Morpholine
2,3-DiMeOC6H3
2,3-DiMeOC6H3
2,3-DiMeOC6H3
4u
4v
4w
4x
4y
Piperidine
Morpholine
Pyrolidine
a
The reaction was carried out using 4-hydroxycoumarin (1 mmol), secondary
amine(1 mmol) and aromatic aldehyde(1 mmol) in the presence of nano crystalline
ZnO (10 mol %) at room temperature (25 °C) in water
b
Isolated yield of the pure compound.
These excellent preliminary results encouraged us to further ex-
plore the applicability of the catalyst for the synthesis of benzyl-
amino coumarin derivatives (Table 4). To study the scope and
limitations of this protocol, we have employed a wide range of aro-
matic and hetero-aromatic aldehydes. Piperidine, morpholine and
pyrolidine are the amine sources used to get the corresponding
benzylamino coumarins. As mentioned in Table 4 the reaction
proceeded smoothly with hetero-aromatic aldehydes, unsubstitut-
ed benzaldehyde, electron-withdrawing or electron-releasing
para-substituted benzaldehydes.
Acknowledgments
We gratefully acknowledge financial support from U.G.C. and
Calcutta University. P.P.G. thanks U.G.C, New Delhi, India for the
grant of Junior Research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
033.
In view of these results, we offer a mechanistic interpretation
for the high catalytic activity of nano crystalline ZnO specifically
in aqueous media. The nano ZnO catalyst-water colloidal
NO2
Nano ZnO
+
Nano ZnO
CHO
N
H
OH
NO2
OH
O
O
O2N
N
N
O
O
Scheme 2. Pictorial presentation for the formation of benzyl amino coumarin.

P. P. Ghosh, A. R. Das / Tetrahedron Letters 53 (2012) 3140–3143
3143
12. Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D. Green Chem. 2004, 6,
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(see time, Table 4). After completion of the reaction (TLC), the reaction mixture
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15. Rescaled procedure for the synthesis of benzylamino coumarin derivatives: A
mixture of 4-hydroxycoumarin (10 mmol), an aldehyde (10 mmol), and
a
secondary amine (10 mmol), was stirred at room temperature (25 °C) in water
(30 ml) in the presence of catalytic amount of nano crystalline ZnO (10 mol %)
(see time, Table 4). After completion of the reaction (TLC), the reaction mixture
was extracted with ethyl acetate (3 Â 50 ml). The extract was then filtered to
separate the nano ZnO catalyst. Upon concentrating the extract under reduced
pressure crude product was obtained which was finally purified by
recrystallisation from ethanol. The isolated compounds were characterized
by mp, IR, 1H NMR, 13C NMR and elemental analysis (C, H and N).