Use of a highly efficient and recyclable solid-phase catalyst based on nanocrystalline titania for the pechmann condensation

Article abstract of DOI:10.1016/j.crci.2014.04.001

Nanocrystalline titania-based sulfonic acid was used as an efficient and reusable catalyst for the synthesis of coumarins. The clean, mild acidity condition, the quantitative yields of products, the short reaction time, and the low reaction temperature are attractive features of this method, making it suitable for heat- or acid-sensitive substrates, particularly in drug synthesis. In practice, this method affords an advantageous combination of satisfactory yields, easy product isolation and purification.

Full text of DOI:10.1016/j.crci.2014.04.001

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C. R. Chimie xxx (2014) xxx–xxx
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Preliminary communication/Communication
Use of a highly efficient and recyclable solid-phase catalyst
based on nanocrystalline titania for the Pechmann
condensation
Seyyed Vahid Atghia *, Somayyeh Sarvi Beigbaghlou
Young Researchers Club, Rasht Branch, Islamic Azad University, Rasht, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Nanocrystalline titania-based sulfonic acid was used as an efficient and reusable catalyst
for the synthesis of coumarins. The clean, mild acidity condition, the quantitative yields of
products, the short reaction time, and the low reaction temperature are attractive features
of this method, making it suitable for heat- or acid-sensitive substrates, particularly in
drug synthesis. In practice, this method affords an advantageous combination of
satisfactory yields, easy product isolation and purification.
Received 22 July 2013
Accepted after revision 3 April 2014
Available online xxx
Keywords:
Coumarins
ß 2014 Acad e´ mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
b-keto esters
Recyclable catalyst
Solvent-free conditions
1
. Introduction
Coumarins are one of the important classes of hetero-
the Pechmann condensation. In the conventional method,
concentrated sulfuric acid is used as the catalyst [15]. In
addition, several other acid catalysts, including Lewis
acids, such as InCl [16], BiCl [17], ZrCl [18], VCl [19],
and Sm(NO [20], are known to affect this
Á6H
cyclic compounds whose synthesis has been the focus of
attention from many organic and medicinal chemists.
Many products, which contain the subunit of coumarin,
exhibit useful and variant biological activities, such as
inhibition of platelet aggregation [1], antibacterial [2] and
3
3
4
3
3
)
3
2
O
condensation. Butyl methylimidazolium ionic liquids also
have been utilized as catalysts for this reaction [21–23],
but these methods also generated strongly acidic wastes
and highly expensive and non-recyclable reagents. To
solve these problems, a number of heterogeneous alter-
anticancer [3] properties, inhibition of steroid 5a-reduc-
tase [4] and of HIV-1 protease [5]. Coumarins also serve as
intermediates for the synthesis of fluorocoumarins,
chromenes, coumarones, and 2-acylresorcinols [6].
Many routes have been used for the synthesis of
coumarins, such as Baylis–Hillman [7], Knoevenagel [8–
3
natives, such as SBA-15-SO H [24], Amberlyst-15 [25],
montmorillonite clays [26–28], and other solid acids [29–
32] have been employed for this purpose in the Pechmann
condensation. Although these methods are improvements,
most of them suffer from disadvantages, such as harsh
reaction conditions, long reaction times, poor yields, poor
selectivity, use of toxic or expensive reagents, and use of
large amounts of catalyst. Thus, the searches for new
reagents and methods that utilize ecofriendly protocols are
still in demand.
1
[
0], Perkin [11], Reformatsky [12], and Wittig reactions
13], but, between these routes, the Pechmann method is a
much simple method for the synthesis of coumarins based
on a two-component (phenol and -ketoester) coupling
under acid catalysis [14]. In the past decades, more than
0 methodologies with different catalysts were used for
b
6
In recent years, there has been considerable growth of
interest in the catalysis of organic reactions by solid acid
catalysts. Solid acids provide numerous opportunities for
recovering and recycling from reaction environments;
*
Corresponding author.
E-mail address: atghia@yahoo.com (S.V. Atghia).
http://dx.doi.org/10.1016/j.crci.2014.04.001
631-0748/ß 2014 Acad e´ mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1
Please cite this article in press as: Atghia SV, Beigbaghlou SS. Use of a highly efficient and recyclable solid-phase
catalyst based on nanocrystalline titania for the Pechmann condensation. C. R. Chimie (2014), http://dx.doi.org/
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the yields refer to the isolated products. Identification of
the products was confirmed by comparison of their
physical constants with those of authentic samples. The
purity determination of the substrate and reaction
monitoring were accompanied by thin-layer chromato-
graphy (TLC) on silica gel POLYGRAM SILG-UV254 (Carl
Roth GmbH, Karlsruhe, Germany) plates.
Scheme 1. Preparation of nanocrystalline titania-based sulfonic acid
2.2. Catalyst preparation
2 3
(TiO –Pr–SO H).
2.2.1. Synthesis of 3-mercaptopropyltitania
To 20 g of TiO (anatase, from Sigma–Aldrich) in dry
toluene, 25 mL of (3-mercaptopropyl) trimethoxysilane
were added, and the reaction mixture was refluxed for
4 h. After this period, the mixture was filtered to obtain
-mercaptopropyltitania (MPT), which was washed with
acetone and dried.
2
also, they can lead to improved processing steps, better
process economics, and environmentally friendly indus-
trial manufacturing. Amongst solid acids, metal oxides
have been used extensively either as catalysts or as
supports in conjunction with other active components for
many industrial oxidation, reduction and acid–base-
2
3
2
catalyzed reactions. Among semiconducting oxides, TiO ,
2
.2.2. Oxidation of 3-mercaptopropyltitania
MPT was oxidized with 10 wt% H
20 mL) for 24 h at room temperature. The prepared
sample was then treated with 1 N H SO at ambient
temperature for complete protonation, and then, the
mixture was filtered and washed with H O and acetone
to obtain TiO –Pr–SO H catalyst (Scheme 1).
due to its low cost and long-term stability, has been widely
used as a solid acid catalyst in organic transformations,
such as Friedel–Crafts alkylation of indoles [33], synthesis
2 2
O in methanol
(
of bis(indolyl) methanes [34], Mannich synthesis of
aminocarbonyls [35], and esterification of free fatty acids
36]. But traditional TiO has many limitations in the
nature of its active sites, because TiO nanoparticles can
lonely catalyze the organic reactions by their weak Lewis
acidity, so with surface modification of TiO by acidic
b
-
2
4
[
2
2
2
3
2
2.3. Catalyst characterization
2
moieties, we can benefit from the dual acidity of titanium
and acidic groups. To solve this problem, for the first time,
we successfully prepared sulfonic acid-functionalized
The synthesized catalyst was characterized by Fourier
transform–infrared spectroscopy (FT–IR), X-ray diffraction
XRD), scanning electron microscopy (SEM), transmission
(
2 3
nanocrystalline titania (TiO –Pr–SO H) by modification
electron microscopy (TEM), and thermogravimetric ana-
lysis (TGA). Also, the acidic property of the synthesized
catalyst was evaluated by the calculation of the Hammett
acidity function [37,38].
of TiO with sulfonic acid moieties [37,38]. The preparation
2
strategy for the nanoreactor is shown in Scheme 1. In our
first report, we used this reagent as an efficient catalyst for
the preparation of quinoxaline derivatives [37], our
procedure provided better activity with high yields and
turnover compared to the previously reported hetero-
geneous ones. Also, we used this reagent for the promotion
of the N-Boc protection of amines successfully [38]. Herein
and in continuation of the above-mentioned studies, we
2.4. General procedure
A mixture of substrate (1 mmol), methyl or ethyl
2 3
acetoacetate (1 mmol) and TiO –Pr–SO H (8 mg) was
taken in a 25-mL round bottomed flask equipped with a
condenser. The mixture was heated in an oil bath at 90 8C
under stirring and the reaction was monitored by TLC.
After completion, the mixture was allowed to cool, ethyl
acetate (5 mL) was added and the catalyst was recovered
by filtration, washed with ethyl acetate (5 mL), dried and
reused according to the procedure mentioned above.
Evaporation of the solvent from the filtrate and recrys-
tallization of the solid residue from hot ethanol afforded
the requested coumarins in high yields. The results are
given in Table 2 and spectral data and melting points are in
good agreement with those reported in the literature [24–
29].
are reporting the promoting effect of TiO
new catalyst for the preparation of coumarin derivatives
Scheme 2).
2 3
–Pr–SO H as a
(
2
. Experimental
2.1. Materials
Chemicals were purchased from Merck (Darmstadt,
Germany) and Sigma–Aldrich (St. Louis, MO, USA). All of
OH
+
O
O
O
O
Cat.
R1
R1
H
3
C
OR2
Solvent-free
90 °C
3. Results and discussion
CH
3
In order to optimize the reaction conditions, we
conducted the preparation of 4,7-dimethylcoumarin from
the reaction of m-Cresol (1 mmol) and ethylacetoacetate
O
O
Si
3
SO H
O
Cat.
Scheme 2. Preparation of coumarins in the presence of TiO
(
1 mmol) in the presence of various amount of TiO
2
–Pr–
2
–Pr–SO
3
H.
SO H at different temperatures and in solventless media
3
Please cite this article in press as: Atghia SV, Beigbaghlou SS. Use of a highly efficient and recyclable solid-phase
catalyst based on nanocrystalline titania for the Pechmann condensation. C. R. Chimie (2014), http://dx.doi.org/
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3
Table 1
The Pechmann condensation reaction between m-Cresol and ethylacetoacetate in different conditions.
H C
3
OH
+
O
O
TiO2
So
H C
3
OEt
a
Entry
Catalyst
Catalyst (mg)
Temperature (8C)
Time (min)
Yield (%)
b
1
2
3
4
5
6
7
8
9
1
—
—
20
20
15
10
8
100
100
100
100
100
100
100
95
120
120
30
NR
TiO
TiO
TiO
TiO
TiO
TiO
TiO
2
2
2
2
2
2
2
trace
92
–Pr–SO
–Pr–SO
–Pr–SO
–Pr–SO
–Pr–SO
–Pr–SO
3
H
H
H
H
H
H
3
3
3
3
3
30
90
30
93
30
95
5
45
30
80
8
90
TiO
TiO
2
–Pr–SO
–Pr–SO
3
H
8
90
30
60
95
0
2
3
H
8
80
75
The bold elements in the table show the optimized conditions of the reaction.
a
Isolated yield.
b
No reaction.
(
Table 1). As shown in Table 1, the above-mentioned
14). Phenols that have more than two hydroxyl groups in
their structure are slightly more active compared to other
phenols because hydroxyl groups activate the aromatic
ring and their reaction is faster with higher yields (entries
4, 5, 11 and 12) [30]. It is noticeable that only one product
can be obtained by these phenols, because the new
produced ring deactivates other hydroxyl groups by
resonance and the reaction cannot continue farther.
The possible mechanism for the preparation of cou-
reaction in the absence of catalyst and in the presence of
2
1
SO
0 mg bare TiO
00 8C (entries 1, 2). However, using 20 mg of TiO
H at 100 8C yielded 92% of 4,7-dimethylcoumarin in
0 min (entry 3). Decreasing the amount of catalyst show
2
did not produce any product in 120 min at
2
–Pr–
3
3
better results in the yield of the product and also
decreasing the reaction temperature from 100 8C to
9
0 8C did not affect the duration of the reaction and the
product yield (entry 9).
2 3
marins in the presence of TiO –Pr–SO H as a promoter is
After optimization of the reaction conditions, the
reaction of other phenols with ethyl acetoacetate or
shown in Scheme 3. On the basis of this mechanism,
intermediate I is generated from the transesterification of
phenol with ethyl acetoacetate or methyl acetoacetate.
Then, Michael addition reaction generates a new ring to
afford species II. Rearomatization leads to the formation of
2 3
methyl acetoacetate in the presence of TiO –Pr–SO H is
carried out and the results are presented in Table 2. It can
easily be seen that the Pechmann condensation proceeded
smoothly under solvent-free conditions and gave good to
high yields ranging from 81% to 95%. Many phenols, such as
resorcinol, hydroquinone, pyrogallol, 3-methoxy phenol,
m-Cresol, orcinol and phloroglucinol could be converted
into the corresponding coumarins in high yields. As shown
in Table 2, the reaction of 2-naphthol is slower than with
other phenols and the yields of the products are fewer due
to steric hindrance around the reaction centre (entries 13,
the coumarin skeleton III. At last stage, TiO
2
–Pr–SO
3
H can
be regenerated by dehydration.
The recycling performance of TiO
2
–Pr–SO
3
H
was
investigated in the reaction of pyrogallol and ethyl
acetoacetate. After performing one reaction under the
conditions described in Table 1, the catalyst was recovered
by filtration, washed with ethyl acetate (5 mL), dried at
100 8C and reused for a consecutive run under the same
Table 2
Time (min)
0
89 88
Yield (%)
87
Pechmann synthesis of coumarins in the presence of TiO
2
–Pr–SO
3
H.
100
93 92 92 91
9
8
9
88
86 85
85 85
1
2
a
88
Entry
R
R
Time (min)
Yield (%)
8
6
4
0
0
0
1
2
3
4
5
6
7
8
9
3-OH
Et
32
45
30
28
33
24
38
30
60
26
22
23
75
90
93
85
92
91
95
86
92
95
90
93
93
90
83
81
3-OH
Me
Et
4-OH
2,3-(OH)
2,3-(OH)
3-OMe
3-OMe
3-Me
2
2
Et
Me
Et
2
7
28 28
5
25 25 25
2
6 27
22 22 23 24 24 24
2
Me
Et
20
0
3-Me
Me
Et
10
11
12
13
14
3-Me-5-OH
3,5-(OH)
3,5-(OH)
2
2
Et
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
Me
Et
Run
2-naphthol
2-naphthol
Me
Fig. 1. (Color online.) Reusability of the catalyst in the synthesis of 7,8-
a
Isolated yields.
dihydroxy-4-methylcoumarin.
Please cite this article in press as: Atghia SV, Beigbaghlou SS. Use of a highly efficient and recyclable solid-phase
catalyst based on nanocrystalline titania for the Pechmann condensation. C. R. Chimie (2014), http://dx.doi.org/
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OH
R1
2
O
O
R O
CH3
O
O
2
R OH R1
-
R1
O
O
H C
3
H
HHO CH3
O
H
O
O
(II)
(
I)
TiO2
SANM
R1
O
O
TiO
2
R1
O
H
H
O
H C
3
(
III)
-
H O
2
O
O
CH3
H
Scheme 3. Proposed mechanism for the Pechmann condensation using TiO
2 3
–Pr–SO H.
reaction conditions. Thus, after the first run, which gave
the corresponding coumarin with 91% yield, and after
recovery, the catalyst was subjected to a second reaction
affording the product obtained with 89% yield; the average
time for 15 consecutive runs was 25 min and 88.5% yield
To illustrate the efficiency of the present method, Table
3 compares our result in the synthesis of 7-hydroxy-4-
methylcoumarin with the same results reported by the
relevant reagents in the literature. By comparing with
different homogeneous Lewis acid catalysts [16–20], ionic
liquids [22,30] and other solid acids with different
supports such as montmorillonites [27], polymers [31]
2
for all (Fig. 1). Also, TEM and SEM images of TiO and of the
recycled catalyst demonstrated that the morphology of the
catalyst did not change after the fifth run (Figs. 2 and 3).
This reusability shows the high stability and turnover of
2 3
and silica [32], TiO –Pr–SO H give the 7-hydroxy-4-
methylcoumarin with using a lower amount of catalyst
and with an excellent yield. Also, our synthesized catalyst
can be reused 14 times without noticeable decrease in its
catalytic activity (Table 3, last column).
2 3
solid titania-based sulfonic acid (TiO –Pr–SO H) under the
conditions employed. It should be noted that the recycl-
ability test was stopped after 15 runs.
2 3 2 3
Fig. 2. TEM images of fresh TiO –Pr–SO H (a) and TiO –Pr–SO H after the first (b) and fourth (c) runs.
2 3 2 3
Fig. 3. SEM images of fresh TiO –Pr–SO H (a) and TiO –Pr–SO H after the fourth (b) run.
Please cite this article in press as: Atghia SV, Beigbaghlou SS. Use of a highly efficient and recyclable solid-phase
catalyst based on nanocrystalline titania for the Pechmann condensation. C. R. Chimie (2014), http://dx.doi.org/
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Table 3
Compared performance of various catalysts in the synthesis of 7-hydroxy-4-methylcoumarin.
a
Catalyst
TiO –Pr–SO
Catalyst loading (mg)
Reaction Temp. (8C)
Time (min)
Yield (%)
Time of runs
2
3
H (this work)
8
22.2
15.8
24
90
32
30
60
5
93
98
92
92
92
98
90
96
88
94
91
89
15
–
–
–
–
–
–
5
5
5
3
5
InCl
BiCl
3
[16]
[17]
[18]
[19]
Reflux in 65 8C under N
2
75
3
ZrCl
VCl
4
RT
3
15.8
24
50–55
120
20
35
240
300
25
10
15
Sm(NO
3
)
3
Á6H
2
O [20]
Reflux in 80 8C
Chloroaluminate [22]
Mont-K10 [27]
265
72
130
150
150
40
Mont-KSF [27]
72
b
[
Msim]HSO
4
[30]
25
c
PEG-SO
3
H
[31]
11
80
Silica-bonded S-sulfonic acid [32]
100
80
All procedures were carried out without use of solvent.
a
For one reaction.
b
Msim = 3-methyl-1-sulfonic acid imidazolium.
c
With methylacetoacetate as
b-keto ester.
[
12] I. Yavari, R. Hekmat-Shoar, A. Zonouzi, Tetrahedron Lett. 39 (1998)
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. Conclusion
2
[
In conclusion, in this article, we have reported the
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coumarins via the Pechmann condensation of phenols
with methyl or ethyl acetoacetate in the absence of
solvent. Our methodology has several advantages: it is
green by avoiding toxic catalysts and traditional solvents,
the catalyst is very cheap, it proceeds with high reaction
rates, affording excellent yields, there is no side reaction,
the catalyst is easy to prepare and to handle, it can be
effectively recovered and reused with a high turnover rate,
it needs only a lower loading and a simple experimental
procedure. Further work to explore this novel catalyst in
other organic transformations is in progress.
9
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[
Please cite this article in press as: Atghia SV, Beigbaghlou SS. Use of a highly efficient and recyclable solid-phase
catalyst based on nanocrystalline titania for the Pechmann condensation. C. R. Chimie (2014), http://dx.doi.org/
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0.1016/j.crci.2014.04.001