Melamine-formaldehyde resin supported H+ a mild and inexpensive reagent for synthesis of coumarins under mild conditions

Article abstract of DOI:10.1016/j.cclet.2011.06.009

Melamine-formaldehyde resin supported H⁺ is used as an efficient catalyst in the Pechmann condensation reaction of phenols with β-ketoesters, in solvent-free media leading to the formation of coumarin derivatives using conventional heating and

Full text of DOI:10.1016/j.cclet.2011.06.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1313–1316
www.elsevier.com/locate/cclet
Melamine–formaldehyde resin supported H+ a mild and inexpensive
reagent for synthesis of coumarins under mild conditions
a
a
b
Ramin Rezaei a, , Leila Dorosty , Maryam Rajabzadeh , Reza Khalifeh
*
a Department of Chemistry, Firoozabad Branch, Islamic Azad University, P.O. Box 74715-117 Firoozabad, Iran
b Department of Chemistry, Faculty of Basic Sciences, Shiraz University of Technology, Shiraz 71555-313, Iran
Received 13 April 2011
Available online 30 July 2011
Abstract
Melamine–formaldehyde resin supported H+ is used as an efficient catalyst in the Pechmann condensation reaction of phenols
with b-ketoesters, in solvent-free media leading to the formation of coumarin derivatives using conventional heating and microwave
irradiation in excellent yields with good purity.
# 2011 Ramin Rezaei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Coumarins; Phenols; b-Ketoesters; Melamine–formaldehyde resin; Pechmann condensation; Solvent-free
Coumarins and their derivatives form an elite class of compounds, occupying an important place in the realm of
natural products and synthetic organic chemistry. Their applications range from additives in food, perfumes,
cosmetics, pharmaceuticals and in the preparation of insecticides [1], optical brighteners [2] and dispersed fluorescent
and tunable laser dyes [3]. Also, coumarins have varied bioactivities, for example, inhibition of platelet aggregation
[4], anticancer [5] and inhibition of steroid 5a-reductase [6]. These properties have made coumarins into interesting
targets for organic chemists. The last decade witnessed a series of publications on the development of synthetic
protocols for this important heterocyclic scaffold. Thus, it is clearly evident that the need for the development of new
and flexible protocols is required, especially when they accommodate important functionalities. Coumarins have been
synthesized by several routes including Pechmann [7], Perkin [8], Knoevenagel [9], Reformatsky [10] and Wittig
reactions [11] and by flash vacuum pyrolysis [12]. Among these, the Pechmann reaction is the most widely used
method, as the reaction involves the use of simple starting materials, that is, phenols and b-ketoesters, in the presence
of a variety of acidic agents. The use of various reagents such as H2SO4, P2O5, FeCl3, ZnCl2, POCl3, AlCl3, PPA, HCl,
phosphoric acid, trifluoroacetic acid, montmorillonite and other clays are all well documented in the literature [13].
Most of these methods suffer from severe drawbacks including the use of a large amount of catalysts, sometimes long
reaction times and very often temperatures to the extent of 150 8C. Some of the recent achievements in the efficient
construction of this nucleus include the development of cation exchange resins [14], several solid acid catalysts [15a–
c] and metal nitrates [15d] supported polyaniline catalysts [16], the use of microwave irradiation [17] and recently, the
use of ionic liquids as efficient catalysts [18].
* Corresponding author.
E-mail address: rezaieramin@yahoo.com (R. Rezaei).
1001-8417/$ – see front matter # 2011 Ramin Rezaei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.06.009

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R. Rezaei et al. / Chinese Chemical Letters 22 (2011) 1313–1316
OH
CH
3
O
O
MFRH
+
OR
x
o
O
O
80 C, Solvent-free
x
R= Et or Me
Scheme 1. Pechmann condensation using melamine–formaldehyde resin supported H+ (MFRH).
Herein, we report an efficient method for the preparation of coumarins using melamine–formaldehyde resin
supported H+ (MFRH) as a catalyst in the pechmann reaction through a mixture of a phenol and a b-ketoester under
solvent-free conditions (Scheme 1).
In a typical experimental procedure involves the condensation of phenol with ethyl acetoacetate. The reactants were
heated together in the presence of a catalytic amount of MFRH (0.05 g/mmol) at 80 8C in a preheated oil-bath for a
short period of time as required to complete the reaction (monitored by TLC). In order to study substituent effects on
the reactivity of the phenol, the reactions were performed on a wide range of structurally diverse phenols and ethyl
acetoacetate as well as with methyl acetoacetate. The reaction proceeds and the results are summarized in Table 1. The
use of just 0.05 g/mmol of MFRH is sufficient to push the reaction forward. Higher amounts of MFRH did not improve
the result to any extent. The yields are, in general, high regardless of the structural variations in phenols. Another
important aspect of this procedure is survival of a variety of functional groups such as CH3, OH, OCH3 under the
reaction conditions. Phenol (entry 1) required a higher reaction temperature and longer reaction duration, as no
electron-donating group is present. m-Methoxyphenol (entry 5) showed no detectable demethylation under the
reaction conditions. Similarly, 1-naphthol (entry 10) requires a slightly higher temperature and longer reaction time.
Both the acetoacetic esters (ethyl and methyl) reacted almost similarly to produce coumarins. Similarly, resorcinol was
treated with a variety of b-ketoesters viz., ethyl 4-chloroacetoacetae, ethyl benzoylacetate and ethyl furoacetate (Table
2, entries 1–3) to furnish corresponding coumarins.
The catalyst was recovered, activated and reused for four consecutive times with only slight variation in the yields
of the products. All the products were identified by comparison of analytical data (IR, NMR, and MS) of those reported
for authentic samples [13–18].
In conclusion this procedure described provides a useful, clean and fast method for the preparation of 4-substituted
coumarins. For most of the substrates, the reaction time is reduced in contrast to classical methods. In conclusion other
green advantages of the procedure are the low formation of wastes, no requiring for the use of adsorbents; and
principally, the replacement of corrosive mineral acids.
1. Experimental
All chemicals and analytical grade solvents were purchased from Merck or Fluka chemical company. Melting
points of all coumarins were determined in open glass capillaries on Mettler FP51 melting point apparatus. 1H NMR
spectra were recorded on an Bruker AVANCE DRX 500 spectrometer. A stars SYNTH microwave oven was used
with power output of 450 W for all the experiments. The reaction was monitored by TLC using pre-coated plates
(Merck).
Preparation of melamine–formaldehyde resin supported H+ (MFRH): HCl (3.0 g, as a 36.5% aq. solution) was
added to a suspension of melamine–formaldehyde resin (5 g) in Et2O (70.0 mL). The mixture was concentrated and
the residue was heated at 100 8C for 72 h under vacuum to furnish MFRH as a free flowing powder.
1.1. Conventional method (method A)
A mixture of a phenol (1 mmol), ethyl acetoacetate or methyl acetoacetate (1.1 mmol) and MFRH (0.05 g) was
added and the reaction mixture was stirred at 80 8C in a pre-heated oil-bath. The reaction was monitored by TLC. After
completion of the reaction, warm ethanol (10 mL) was added and filtered, and the remaining was washed with warm
ethanol (2 Â 10 mL) in order to separate catalyst. Ethanol was evaporated and crude product was recrystallized from
EtOH. Products were characterized by comparison of their physical and spectral data with those of authentic samples
[13–18].

R. Rezaei et al. / Chinese Chemical Letters 22 (2011) 1313–1316
1315
Table 1
Synthesis of coumarins using MFRH under solvent-free conditions.
Entry
Substrate
Product
Method A
Method B
Mp (8C)
Time
(min)
Yield
(%)
Time
(min)
Yield (%)
Found
Reported
83–84
65a
90a
80a
62b
90b
77b
3
1
2
70a
90a
80a
70b
80–82
O
O
1
2
3
50
15
20
OH
90b
78b
180–182
180–182
183–185
184–186
HO
HO
HO
HO
O
O
OH
O
O
OH
85a
88a
92a
82b
83b
90b
2
2
1
88a
90a
94a
85b
87b
94b
160–162
157–159
279–281
164–166
160–161
280–282
O
O
4
5
6
25
20
15
OH
MeO
MeO
MeO
MeO
O
O
OH
OH
HO
HO
O
O
HO
HO
OH
OH
80a
80b
2
85a
83b
241–243
243–244
OH
7
25
HO
HO
O
O
OH
OH
85a
70a
83b
67b
2
2
85a
80a
80b
80b
245–247
136–137
246–248
137–139
HO
O
O
8
9
20
30
H C
3
CH
3
CH
HO
CH
3
3
HO
O
O
OH
10
20
75a
73b
2
75a
72b
150–152
153–155
OH
O
O
a
Ethyl acetoacetate is used as a reactant.
b
Methyl acetoacetate is used as a reactant.
1.2. Microwave method (method B)
To a mixture of the phenolic compound (1 mmol) and ethyl acetoacetate or methyl acetoacetate (1.1 mmol), MFRH
(0.05 g) was added and the mixture was placed in a microwave oven and heated at 450 W for the appropriate time
(TLC). After completion of the reaction, warm ethanol (10 mL) was added and filtered, and the remaining was washed
with warm ethanol (2 Â 10 mL) in order to separate catalyst. Ethanol was evaporated and crude product was
recrystallized from EtOH. Products were characterized by comparison of their physical and spectral data with those of
corresponding samples [13–18].

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Table 2
Pechmann condensation of resorcinol with b-ketoesters for the synthesis of corresponding 4-substituted coumarins.
HO
O
O
O
O
HO
OH
+
.
O
R
R
No.
R
Method A
Method B
Mp (8C)
Time (min)
Yield (%)
Time (min)
Yield (%)
Found
Reported
1
2
3
R
R
R
CH2Cl
Ph
15
20
20
85
80
78
2
2
2
80
77
70
177–179
253–255
206–207
180–181
256–257
210–212
Furyl
Spectral data for selected products: Compound 6: IR (Neat) (cmÀ1) 3473, 3199, 1660, 1618, 1533, 1416, 1160, 815;
1H NMR (CDCl3, 500 MHz): d 9.90 (brs, 1H), 9.70 (brs, 1H), 6.23 (d, 1H, J = 7.0 Hz), 6.17 (d, 1H, J = 7.0 Hz), 5.70 (s,
1H), 2.11 (s, 3H); EIMS (m/z) 192 (M+); Anal. Calcd. for C10H8O4: C, 62.5; H, 4.16%. Found: C, 62.2; H, 4.20%.
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