MoO3/Al2O3: An efficient and reusable heterogeneous catalyst for solvent-free synthesis of coumarins via pechmann condensation

Article abstract of DOI:10.3987/COM-07-11288

16 wt % alumina supported MoO₃ has been found to be an efficient catalyst for the synthesis of various substituted coumarins via Pechmann condensation. This method offers several advantages like high yields, facile recovery and reusability of the catalyst without loss in activity, nearly neutral and solvent free condition.

Full text of DOI:10.3987/COM-07-11288

HETEROCYCLES, Vol. 75, No. 5, 2008
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HETEROCYCLES, Vol. 75, No. 5, 2008, pp. 1205 - 1211. © The Japan Institute of Heterocyclic Chemistry
Received, 4th December, 2007 Accepted, 22nd January, 2008, Published online, 25th January, 2008. COM-07-11288
MoO3/Al2O3: AN EFFICIENT AND REUSABLE HETEROGENEOUS
CATALYST FOR SOLVENT-FREE SYNTHESIS OF COUMARINS VIA
PECHMANN CONDENSATION
Sweety Singhal, Suman L. Jain, and Bir Sain*
Chemical and Biotechnology Division, Indian Institute of Petroleum, Dehradun-
248005, India
E-mail: birsain@hotmail.com
Abstract – 16 wt % alumina supported MoO3 has been found to be an efficient
catalyst for the synthesis of various substituted coumarins via Pechmann
condensation. This method offers several advantages like high yields, facile
recovery and reusability of the catalyst without loss in activity, nearly neutral and
solvent free condition.
INTRODUCTION
In the recent years, development of greener and more sustainable technologies in chemical industry has
become a pressing need due to the stringent environmental and economical regulations. In this context,
use of heterogeneous catalyst under solvent free condition is gaining ever-increasing interest due to the
facile recovery and reusability of the expensive catalyst. Further solvent-less synthetic methods are
valuable not only for green chemistry reason but also for simplicity in procedure and high yields of the
products.1 Coumarin and its derivatives represent an important class of compounds due to their
widespread application as additives in food, perfumes, cosmetics, pharmaceuticals, insecticides, optical
brightening agents and laser dyes.2 These compounds are well known to have diverse biological activities
including anti-HIV, antiviral, antitumour, antibiotic, anti-inflammatory and antioxidant. Therefore,
synthesis of coumarin and its derivatives has become an area of tremendous importance in recent years.
Among the various approaches known, Pechmann condensation,3 which involves the reaction of a phenol
with β-ketoester in presence of acid, is particularly useful as it proceeds with simple substrates and
affords good yields of the products. However one of the major limitations of this method is the use of
strong acid like H2SO4, which is difficult to handle and causes environmental hazards.
Consequently, several alternative methods using polyphosphoric acid, trifluroacetic acid,4 solid
superacid,5 ZnCl2, POCl3, AlCl3,6 P2O5,7 ion exchange resins,8 zeolite H-BEA, Nafion-H,9

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Montmorillonite-K,10 silica sulfuric acid,11 alumina supported MeSO3H12 as catalysts have been explored
for synthesis of coumarins via Pechmann condensation. The Pechmann condensation has also been
attempted using microwave irradiation13 and in ionic liquids14 as alternatives to conventional methods.
However limitations associated with most of these methods such as requirement of stoichiometric amount
of catalyst, tedious purification process, expensive reagents, toxic/volatile organic solvents, longer
reaction times and low selectivity leave scope for further development of an efficient, facile and versatile
catalytic system for Pechmann condensation. Use of supported reagents helps in meeting the requirement
of green synthesis due to their several inherent properties such as improved activity and selectivity of a
reagent dispersed on support, high thermal and mechanical stability, non-corrosive nature, easy separation
of catalyst from the reaction mixture and reusability. In view of this, herein we reveal the first time use of
16 wt % MoO3 supported on alumina15 as a recyclable catalytic system for the synthesis of coumarins via
Pechmann condensation under solvent free conditions. (Scheme 1).
OH
R1
O
O
MoO3/Al2O3
+
150 oC, solvent-free
R1
R2
O
O
R
R
R1= Me, Ph
R2= OMe, OEt, OPh
2
1
3
Scheme 1
RESULTS AND DISCUSSION
16 wt % MoO3/Al2O3 catalyst was prepared on γ-Al2O3 support by incipient wet impregnation method
o
using ammonium heptamolybdate [(NH4)6Mo7O24 4H2O] salt. The catalyst was dried at 110 C
(overnight) and finally calcined at 550 oC for 6 h.16
Mo content of the prepared catalyst was estimated by ICP-AES (Inductively Coupled Plasma Atomic
Emission Spectroscopy) analysis and was found to be 16 %. X-Ray diffraction pattern of the catalyst
showed the amorphous nature and did not show any characteristic peak of MoO3 indicating that MoO3 is
finely dispersed over Al2O3 surface. BET surface area of the catalyst was determined by N2 adsorption-
desorption isotherm at liquid nitrogen temperature (-195 oC) and found to be SBET 248.9 m2/g and total
pore volume 0.394 mL/g, with pore size distribution <10 (15.14 %), 10-20 Å (8.04 %), 20-100 Å
(48.85 %), 100-200 Å (25.71 %), 200-500 Å (1.49 %), > 500 Å (0.77 %).
Initially, we carried out the cyclocondensation of resorcinol and ethyl acetoacetate in presence of catalytic
amount of 16 % MoO3 supported on alumina (5 mol %) at 150 oC under solvent free reaction conditions.
The reaction mixture got solidified within 30 min. The resulting solid mixture was diluted with ethyl
acetate and catalyst was separated by filtration. The filtrate obtained was washed with water, dried over

HETEROCYCLES, Vol. 75, No. 5, 2008
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anhydrous MgSO4 and concentrated under reduced pressure to yield crude product, which was further
purified by recrystallization with EtOH to yield pure 7-hydroxy-4-methylcoumarin in 97% yield.
Similarly resorcinol was reacted with methyl acetoacetate, phenyl acetoacetate and ethyl benzoylacetate
to afford corresponding coumarin under similar reaction condition. These results are presented in Table 1
(entries 1-3). A variety of substituted phenols were efficiently reacted with β-ketoesters to afford
corresponding coumarins in high yields using catalytic amounts of 16 % MoO3 supported on alumina (5
mol %) under similar reaction conditions. These results are summarized in Table 1. Polyhydric alcohols
such as resorcinol, pyrogallol and phloroglucinol were found to be more reactive. Phenol reacted
sluggishly and yielded coumarin in moderate yield (Table 1, entry 7). 1-Naphthol afforded corresponding
coumarin in good yield but requires longer reaction time (Table 1, entry 8). Condensation of 3-
methoxyphenol with ethyl acetoacetate under described reaction conditions yielded coumarin selectively
without any evidence for the formation of demethylated product as mentioned in various conventional
methods14 (Table 1, entry 9). In a controlled blank experiment, Pechmann condensation of resorcinol and
ethyl acetoacetate did not proceed in the absence of catalyst, establishing the MoO3 supported on alumina
to be the main promoter for this reaction. Similarly no reaction between resorcinol and ethyl acetoacetate
was observed in the presence of pure thermally treated alumina under similar reaction conditions. Further
we studied the condensation of resorcinol and ethyl acetoacetate in presence of pure thermally treated
MoO3 (Aldrich) under similar reaction conditions. The reaction was found to be slow and gave poor yield
of desired product (Table 1, entry 11). The high catalytic activity of 16 % MoO3/Al2O3 in this reaction is
presumably due to increased Lewis acidity of Mo oxide dispersed on alumina support. Further the use of
8 wt % MoO3/Al2O3 in place of 16 wt % MoO3/Al2O3 resulted in decreasing yield of desired product
(Table 1, entry 12).
Table 1. Alumina supported MoO3 catalyzed cyclocondensation of phenols and β-ketoestersa
Reaction
Time (h)
Melting Point oC
Found Reported
Entry
Substrate
Coumarin
Yield (%)b
Me
OH
HO
HO
1
0.5
1.0
1.5
97c, 97d
182-186
182-186
240-242
1858
HO
HO
O
Me
O
O
OH
2
3
92e
89f
185
O
Ph
OH
OH
HO
HO
24417
HO
HO
O
O
OH Me
4
0.75
93c, 91d
281-283
282-28418
OH
O
O

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HETEROCYCLES, Vol. 75, No. 5, 2008
Me
Me
Me
OH
OH
5
6
7
3.0
2.5
4.0
90c, 88d
130-132
246-249
79-81
131.5-13210
248-25019
8220
Me
Me
O
O
O
OH Me
OH
OH
91c, 89d
O
Me
65g c, 63g d
O
O
O
OH
O
8
9
5.0
1.5
88c, 87d
92c, 89d
89c
152-155
160-161
232-244
15521
158-15920
23517
Me
Me
MeO
OH
Me
HO
O
Me
O
HO
HO
10
0.75
O
O
O
OH
OH
Me
OH
HO
11
12
2.5
1.5
60h, c
75i, c
182-186
182-186
185
185
HO
HO
O
Me
OH
HO
O
O
a: Reaction condition: Substrate 1 (1 mmol), β-ketoester 2 (1 mmol), 16 wt % MoO3/Al2O3 (5 mol %) at
o
b
c
d
150 C. : Isolated Yields. : Experiments carried out with ethyl acetoacetate. : Experiments carried out
e
f
with methyl acetoacetate. : Experiments carried with phenyl acetoacetate. : Experiments carried with
ethyl benzoylacetate. g: Reaction was carried out at 120 oC. h: Reaction was carried out using pure MoO3.
i: Reaction was carried out using 8 wt % MoO3/Al2O3 as a catalyst.
To evaluate the effect of solvent, we studied the Pechmann condensation of resorcinol and ethyl
acetoacetate using 5 mol % of 16 % MoO3 supported on alumina as catalyst in various organic solvents
like toluene, nitrobenzene and acetonitrile at their refluxing temperatures under similar reaction
conditions (Table 2). Among the various solvents studied, toluene was found to be efficient but solvent
free conditions remained best both from yield and reaction time points of view. To evaluate the effect of
reaction temperature, condensation of resorcinol and ethyl acetoacetate in presence of catalytic amount of
16 wt % MoO3/Al2O3 was carried out at different temperatures under similar reaction conditions. The
reaction rate was found to be very slow at room temperature, while it increased with increase in
temperature as shown in Table 2. At 150 oC reaction rate was found to be maximum and further increase
in temperature did not show any enhancements. When condensation of resorcinol and ethyl acetoacetate
was carried out in presence of 16 wt % MoO3/Al2O3 under microwave irradiation, coumarin (1a) was
obtained in 92 % yield.

HETEROCYCLES, Vol. 75, No. 5, 2008
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Table 2: Results of reaction of resorcinol and ethyl acetoacetate under different reaction conditions.a
Entry
Solvent
toluene
nitrobenzene
acetonitrile
-
Temperature
110 oC
110 oC
Time (h)
3.0
Yield (%)b
1
2
3
4
5
6
7
55
40
25
20
40
70
97
3.0
80 oC
5.0
room temp.
80 oC
110 oC
5.0
4.5
-
-
2.5
150 oC
.5
a: Resorcinol (1 mmol), ethyl acetoacetate (1 mmol), 16 wt % MoO3/Al2O3 (5 mol %).
b: Isolated yields.
The recyclabitity of the catalyst was established by carrying out condensation of resorcinol with ethyl
acetoacetate using recovered catalyst under similar reaction conditions. After completion of reaction, the
reaction mixture was diluted with ethyl acetate and catalyst was recovered from reaction mixture by
filtration. The recovered catalyst was reused as such for subsequent experiments (3 times). The observed
fact that yields of coumarin and reaction times remained almost same in these experiments established the
recyclability/reusability of the catalyst (Table 3). There was no catalyst leaching as ascertained by ICP-
AES analysis of Mo content of recovered and fresh MoO3/Al2O3 catalyst.
Table 3. Results of recyclability of the catalyst MoO3/Al2O3 in cyclocondensation of resorcinol and ethyl
acetoacetate.
Catalyst
Run
Reaction Time (h) Yield (%)a
(mol %)
1b
1c
2c
3c
-
5.0
0.5
0.5
0.5
0
5
5
5
97
96
95
a: Isolated yields. b: Blank experiment without using catalyst. c: Reaction
conditions same as per Table 1 entry 1.
In conclusion, we have developed an environmentally acceptable improved protocol for synthesis of
various substituted coumarins using 16 wt % MoO3/Al2O3 as a recyclable heterogeneous catalyst under
solvent free conditions. The key advantages of the developed method are (i) green synthesis as it reduces
the environmental pollution causing by the use of homogeneous metal complexes and volatile organic
solvents (ii) easy work-up (iii) recyclability and reusability of catalyst with consistent activity.

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HETEROCYCLES, Vol. 75, No. 5, 2008
EXPERIMENTAL
All the reactions were carried out without any special precautions in an atmosphere of air. All the phenols
and β-ketoesters used were purchased from Aldrich. Melting points were determined in open capillaries
1
in Büchi apparatus and are uncorrected. The H NMR spectra were recorded on Bruker 300 MHz
spectrometer and the chemical shifts are expressed in δ parts per million relative to tetramethylsilane
(TMS) as internal standard. The IR spectra were recorded on a Perkin Elmer FTIR X 1760 instrument.
Typical Experimental Procedure: To a stirred mixture of phenol (1 mmol) and β-ketoester (1 mmol) in
o
a 25 mL round bottom flask, was added 16 wt % MoO3/Al2O3 (5 mol %) at 150 C under solvent free
condition. The temperature of the reaction vessel was maintained using an oil bath. Progress of the
reaction was monitored by TLC (SiO2). At the end of reaction, reaction mixture got solified. The resulting
solid mixture was cooled to rt and diluted with EtOAc (5 mL) to recover catalyst by filtration. The filtrate
obtained was washed with water, dried over anhydrous MgSO4 and concentrated under reduced pressure
to yield crude product. The crude product was further purified either by recrystalization with EtOH or
flash chromatography using EtOAc:hexane (4:6) as eluent to afford pure coumarin.
1
Product 1a (Table 1, entry 1): H NMR (CDCl3) δ ppm 2.35 (s, 3H), 6.10 (s, 1H), 6.80 (d, J = 8.7 Hz,
1H), 6.90 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H). IR ( KBr) 3200-3000, 1690.
1
Product 3a (Table 1, entry 3): H NMR (CDCl3) δ ppm 6.12 (s, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.90 (s,
1H), 7.30-7.40 (m, 5H), 7.49 (d, J = 8.7 Hz, 1H). IR ( KBr) 3200, 3390, 2890, 1690, 1545.
Product 4a (Table 1, entry 4): 1H NMR (DMSO-d6) δ ppm 2.50 (s, 3H), 5.84 (s, 1H), 6.20 (s, 1H), 6.30
(s, 1H). IR (KBr) 3473, 3200, 1670, 1610.
1
Product 5a (Table 1, entry 5): H NMR (CDCl3) δ ppm 2.42 (s, 3H), 3.85 (s, 3H), 6.14 (s, 1H), 6.80 (s,
1H), 6.88 (d, J= 8.7 Hz, 1H), 7.49 (d, J= 8.7 Hz, 1H). IR (KBr) 3009, 2925, 1680.
1
Product 6a (Table 1, entry 6): H NMR (CDCl3) δ ppm 2.44 (s, 3H), 3.90 (s, 3H), 6.12 (s, 1H), 6.78 (s,
1H), 7.10 (s, 1H). IR (KBr) 3210-3009, 2925, 1680.
1
Product 7a (Table 1, entry 7): H NMR (CDCl3) δ ppm 2.42 (s, 3H), 6.17 (s, 1H), 7.15-7.44 (m, 3H),
7.49(d, J= 6.0 Hz, 1H). IR (KBr) 3010, 2925, 1669, 1140.
Product 8a (Table 1, entry 8): 1HNMR (CDCl3) δ ppm 2.47 (s, 3H), 6.39 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H)
7.55-7.70 (m, 2H), 7.91 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H) 8.63 (d, J = 8.7 Hz, 1H). IR (KBr)
3067, 3020, 2860, 1716, 1081.
1
Product 9a (Table 1, entry 9): H NMR (CDCl3) δ ppm 2.35 (s, 3H), 3.75 (s, 3H), 6.19 (s, 1H), 6.84 (s,
1H), 6.89 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H). IR (KBr) 3067, 2970, 1742, 1625.
Product 10a (Table 1, entry 10): 1H NMR (CDCl3) δ ppm 2.32 (s, 3H), 6.10 (s, 1H), 6.80 (d, 1H, J=8.7
Hz), 7.09 (d, J = 8.7 Hz, 1H), 9.28 (s, 1H), 10.05 (s, 1H). IR (KBr) 3417, 3237, 2965, 2956, 1655, 1604.

HETEROCYCLES, Vol. 75, No. 5, 2008
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ACKNOWLEDGEMENTS
We are thankful to the Director, IIP for his kind permission to publish these results. Suman L. Jain and
Sweety Singhal are thankful to CSIR, New Delhi for the award of Research Fellowships
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