One-pot three-component synthesis of 3-(α-aminobenzyl)-4-hydroxycoumarin derivatives using nanocrystalline TiO2 as reusable catalyst

Article abstract of DOI:10.1134/S107042801501011X

An efficient nanocrystalline TiO₂-catalyzed one-pot synthesis of 3-[(piperidin-1-yl)phenylmethyl]- and 3-[(morpholin-4-yl)phenylmethyl]-4-hydroxycoumarins has been developed via three-component Mannich type condensation of 4-hydroxycoumarin wit

Full text of DOI:10.1134/S107042801501011X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 1, pp. 69–73. © Pleiades Publishing, Ltd., 2015.
One-Pot Three-Component Synthesis of 3-(α-Aminobenzyl)-
4-hydroxycoumarin Derivatives Using Nanocrystalline TiO2
as Reusable Catalyst*
J. N. Sangshetti, F. A. K. Khan, C. S. Kute, Z. Zaheer, and R. Z. Ahmed
Dr. Rafiq Zakaria Campus, Y.B. Chavan College of Pharmacy, Aurangabad, Maharashtra, 431001 India
e-mail: jnsangshetti@rediffmail.com
Received January 17, 2014
Abstract—An efficient nanocrystalline TiO2-catalyzed one-pot synthesis of 3-[(piperidin-1-yl)phenylmethyl]-
and 3-[(morpholin-4-yl)phenylmethyl]-4-hydroxycoumarins has been developed via three-component Mannich
type condensation of 4-hydroxycoumarin with aromatic aldehydes and secondary amines (piperidine or
morpholine) in ethanol at room temperature. The catalyst can be easily recovered and reused with almost the
same catalytic activity. The proposed method is advantageous due to its simplicity, short reaction time, catalyst
reusability, good to excellent yield, and clean and easy work-up.
DOI: 10.1134/S107042801501011X
Development of new multicomponent reactions
(MCRs) and improvement of known MCRs constitute
an area of considerable current interest. As opposed to
the classical way of synthesizing complex molecules
by sequential reactions, MCRs allow assembly of
complex molecules from simple starting materials in
one-pot mode and show a facile execution, high atom-
economy, and high selectivity [1–5]. Therefore, the
design of new protocol for MCRs has attracted great
attention of research groups working in medicinal
chemistry and drug discovery.
derivatives [12, 13]. The best way to synthesize such
compounds is the condensation of 4-hydroxycoumarin
with an aromatic aldehyde and a secondary amine, i.e.,
Mannich type reaction [14]. The known methods for
the synthesis of such compounds suffer from severe
disadvantages such as long reaction time, poor yield,
laborious work-up, and the use of expensive non-
recoverable catalysts [15–17]. Thus, the development
of high-yielding, short-time, easy-work-up, and clean
synthesis of α-aminobenzyl 4-hydroxycoumarin deriv-
atives still remains a desired goal in organic chemistry.
In recent years, there has been a tremendous
increase of interest in various chemical transformations
performed under heterogeneous catalysis. Among
heterogeneous catalysts, nanocrystalline metal oxides
have attracted considerable interest in synthetic
organic chemistry due to their high catalytic activity,
reusability and benign character in the context of green
chemistry. These materials possess numerous surface
sites with enhanced surface reactivity such as crystal
corners, edges, or ion vacancies [18–23].
4-Hydroxycoumarin and its derivatives belong to
an important class of heterocyclic compounds that
have got tremendous application in various research
fields, including biological science and medicinal
chemistry. These compounds exhibit a broad spectrum
of biological activity, in particular antiviral [6], anti-
coagulant [7], anti-HIV [8], antioxidant [9], and anti-
cancer [10]. Various compounds containing 4-hy-
droxycoumarin moiety like warfarin, acenocoumarol,
dicoumarol, phenprocoumon, coumatetralyl, carbo-
chromen, bromadialone, etc. are available clinically.
Among various derivatives of 4-hydroxycoumarins,
3-benzyl-substituted ones have found important
clinical applications [11].
Nanocrystalline titanium dioxide has attracted con-
siderable interest of synthetic and medicinal chemists
as an efficient, versatile, and reusable catalyst, but
there are still a few reports available in the literature on
the use of nanocrystalline TiO2 in MCRs [24–26].
Nanocrystalline TiO2 has been used as a solid acid
catalyst in organic reactions like chemoselective
trimethylsilylation of alcohols and phenols [27],
A number of synthetic protocols have been reported
for the synthesis of α-aminobenzyl 4-hydroxycoumarin
* The text was submitted by the authors in English.
69

SANGSHETTI et al.
70
Scheme 1.
X
N
O
H
OH
O
OH
O
X
Nano-TiO2, EtOH, 25°C
+
+
N
H
O
O
R
R
I
IIa–IIf
IIIa, IIIb
IVa–IVk
II, R = H (a), 4-MeO (b), 4-O2N (c), 4-Me (d), 3,4-(MeO)2 (e), 4-Cl (f); III, X = CH2 (a), O (b); IV, R = H (a, g), 4-MeO (b, h),
4-O2N (c, i), 4-Me (d, j), 3,4-(MeO)2 (e, k), 4-Cl (f).
deprotection of silyl ethers [28], Friedel–Crafts
alkylation of indoles with epoxides [29], synthesis of
bis(indolyl)methanes [30], Mannich synthesis of
β-amino carbonyl compounds, and esterification of
free fatty acids [31]. In view of the above stated in
continuation of our ongoing work on multicomponent
reactions [32, 33], we have developed a new protocol
for the efficient synthesis of α-aminobenzyl 4-hy-
droxycoumarin derivatives via one-pot three-compo-
nent Mannich type reaction. Herein we report signif-
icant catalytic activity of nanocrystalline TiO2 in the
one-pot three-component condensation of 4-hydroxy-
coumarin with an aromatic aldehyde and a secondary
amine (piperidine or morpholine) in ethanol at room
temperature (Scheme 1).
Table 1. Three-component condensation of 4-hydroxycou-
marin with benzaldehyde and piperidine in the presence of
different catalysts (30 mol %; EtOH, 25°C)
Catalyst
Boric acid
Time, min Yield of IVa,a %
Initially, 4-hydroxycoumarin (1.0 mmol), benzalde-
hyde (1.0 mmol), and piperidine (1.0 mmol) were used
as reactants for the model reaction to synthesize
4-hydroxycoumarin derivative IVa. For optimization
of the reaction conditions, we evaluated the effect of
different catalysts using ethanol as solvent at room
temperature (25°C). A wide variety of catalysts includ-
ing boric acid, oxalic acid, sulfamic acid, p-toluene-
sulfonic acid, AlCl3, FeCl3, ZnCl2, ZnO, TiO2, and
nanocrystalline TiO2 were tested in an amount of
30 mol % (Table 1). The best yield of IVa (97%) was
obtained in the presence of nanocrystalline TiO2 in
a shorter time (15 min) than with other catalysts.
300
240
180
240
300
360
270
150
120
015
56
63
72
53
48
45
64
70
82
97
Oxalic acid
Sulfamic acid
p-Toluenesulfonic acid
AlCl3
FeCl3
ZnCl2
ZnO
TiO2
Nanocrystalline TiO2
a
Hereinafter, isolated yield of pure product.
The effect of solvent was studied using nanocrys-
talline TiO2 (30 mol %) at room temperature (25°C).
Among a variety of solvents tested (toluene, dimethyl
sulfoxide, methanol, ethanol, tetrahydrofuran, methy-
lene chloride, acetonitrile), ethanol emerged as a sol-
vent of choice in terms of reaction rate (15 min) and
product yield (97%) (Table 2). Also, the use of ethanol
as solvent did not require any special efforts for the
isolation of products in good yield. The amount of
nanocrystalline TiO2 was optimized in the model reac-
tion in ethanol at room temperature. The catalyst was
added in amounts of 0, 5, 10, 15, 20, and 30 mol %.
The results shown in Table 3 indicate that increase in
the catalyst load from 0 to 15 mol % increases the
yield of IVa from 12 to 97%. However, further
Table 2. Three-component condensation of 4-hydroxycou-
marin with benzaldehyde and piperidine in the presence of
nanocrystalline titanium dioxide (30 mol %) in different
solvents at 25°C
Solvent
Toluene
Time, min
Yield of IVa, %
180
120
100
015
150
100
100
45
68
85
97
58
79
74
Dimethyl sulfoxide
Methanol
Ethanol
Tetrahydrofuran
Methylene chloride
Acetonitrile
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015

ONE-POT THREE-COMPONENT SYNTHESIS OF 3-(α-AMINOBENZYL)-...
71
Table 3. Three-component condensation of 4-hydroxycou-
marin with benzaldehyde and piperidine in the presence of
different amounts of nanocrystalline TiO2 in ethanol at 25°C
increase of the amount of nanocrystalline TiO2 to 20
and 30 mol % has almost no effect on the yield (97%).
Therefore, 15 mol % of the catalyst was assumed to
ensure the best yield.
Amount of nano-TiO2, mol %
Yield of IVa, %
Our results make the process under study more at-
tractive and interesting from the viewpoint of economy
and simplicity. Under the optimized conditions, we
extended the aromatic aldehyde and secondary amine
series and obtained 4-hydroxycoumarin derivatives
IVa–IVk. The reaction proceeded smoothly under
mild conditions with a wide range of aromatic
aldehydes bearing both electron-donating and electron-
withdrawing substituent along with piperidine and
morpholine (secondary amine). As shown in Table 4,
the isolated yield of IVa–IVk ranged from 92 to 97%,
and the time necessary for the reaction completion was
15–20 min. The work-up of these reactions was very
clean and required only filtration, and the desired
products were thus isolated with high purity. To the
best of our knowledge, the synthesis of 3-(α-amino-
benzyl)-4-hydroxycoumarin derivatives using nano-
crystalline TiO2 as catalyst has not been reported pre-
viously. The catalyst is not only efficient but also mild
and easy to handle.
00
05
10
15
20
30
12
45
86
97
97
97
marin derivatives IVa–IVk from 4-hydroxycoumarin,
aromatic aldehyde, and secondary amine (piperidine or
morpholine) in ethanol at room temperature using
nanocrystalline TiO2 as catalyst. Advantages of the
proposed procedure include mild reaction conditions,
simplicity, short reaction time, easy work-up, high
yield, and reusability of the catalyst. The method
overcomes the earlier disadvantages and therefore will
be of general use and interest to synthetic chemists.
EXPERIMENTAL
Reusability of catalyst is very important from the
industrial and economic points of view. The reusability
of nanocrystalline TiO2 was studied for the model
reaction in ethanol at room temperature. When the
reaction was complete, the catalyst was separated, re-
peatedly washed with acetone to remove organic sub-
stances, and dried at room temperature. The recycled
catalyst showed no appreciable loss in activity even
after the fifth cycle. Listed below are the cycle number
and yield of IVa (%): 1, 97; 2, 97; 3, 95; 4, 93; 5, 92.
Commercial 4-hydroxycoumarin, substituted aro-
matic aldehydes, and secondary amines (piperidine and
morpholine) were used without further purification.
The melting points were determined in open capillaries
and are uncorrected. The purity of the isolated com-
pounds was monitored by ascending TLC on alumi-
num plates coated with silica gel-G (Merck); spots
were visualized by treatment with iodine vapor. The IR
spectra (400–4000 cm−1) were recorded in KBr on
1
a JASCO FTIR (PS4000) instrument. The H NMR
spectra were recorded on a Varian Gemini spectrom-
eter at 400 MHz using TMS as internal standard. The
mass spectra were taken on a Waters Micromass-
QUATTRO-II mass spectrometer.
Scheme 2 illustrates a probable mechanism of
formation of 3-(α-aminobenzyl)-4-hydroxycoumarins
from 4-hydroxycoumarin, aromatic aldehyde, and
secondary amine in the presence of nanocrystalline
titanium dioxide.
General procedure for the synthesis of
3-(α-aminobenzyl)-4-hydroxycoumarin derivatives
IVa–IVk. A mixture of 4-hydroxycoumarin
(1.0 mmol), aromatic aldehyde (1.0 mmol), piperidine
In conclusion, we have developed a highly efficient
one-pot three-component method for the synthesis of
biologically significant α-aminobenzyl 4-hydroxycou-
Scheme 2.
OH
O
TiO2
O
H
OH
O
X
N
O
TiO2, EtOH
N
+
X
NH
–TiO2
X
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 1 2015

SANGSHETTI et al.
72
Table 4. α-Aminobenzyl 4-hydroxycoumarin derivatives IVa–IVk
Melting point, °C
observed reported
Aldehyde no.
Amine
Product no.
Yield, %
Time, min
IIa
IIb
IIc
IId
IIe
IIf
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
97
93
94
96
97
95
96
97
95
96
94
15
15
20
15
15
20
20
15
20
20
15
180–182
142–144
170–172
186–188
180–182
190–192
164–166
148–150
174–176
198–200
158–160
182 [17]
143 [17]
170 [17]
190 [17]
182 [17]
188–190 [16]
168 [17]
146 [17]
176 [17]
202 [17]
156 [17]
IIa
IIb
IIc
IId
IIe
IVj
IVk
or morpholine (1.0 mmol), and nanocrystalline TiO2
(15 mol %) in ethanol (15 mL) was stirred for 15–
20 min at room temperature (25°C). When the reaction
was complete (TLC), the mixture was filtered to
separate the catalyst which can be used in further runs.
The filtrate was concentrated, and the crude product
was finally purified by recrystallization from ethanol
(Table 4).
2.42 s (3H), 3.48 m (4H), 5.05 s (1H), 6.48 s (1H),
7.23–7.39 m (4H), 7.47–7.68 m (4H). Mass spectrum:
m/z 352.15 [M + H]+.
The authors thank Mrs. Fatima Rafiq Zakaria,
Chairman Maulana Azad Educational Trust, and Prin-
cipal, Y.B. Chavan College of Pharmacy, Dr. Rafiq
Zakaria Campus, Aurangabad, 431001 (M.S.) India,
for providing laboratory facilities.
4-Hydroxy-3-[phenyl(piperidin-1-yl)methyl]-2H-
chromen-2-one (IVa). IR spectrum, ν, cm–1: 3058,
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