Microwave initiated reactions: Pechmann coumarin synthesis, Biginelli reaction, and acylation

Article abstract of DOI:10.1016/j.tetlet.2006.01.147

An energy-efficient protocol has been developed for solvent-free reactions that are mildly exothermic but not spontaneous. The exothermic reaction mixture-on several g-scale-is exposed for about 30 s to low power (about 200 W) microwaves and then the microwave oven is switched off. After this short burst of energy, the exothermic reaction gets initiated and proceeds on its own to completion. A number of coumarins were synthesized by the Pechmann reaction using this strategy.

Full text of DOI:10.1016/j.tetlet.2006.01.147

Tetrahedron Letters 47 (2006) 2423–2425
Microwave initiated reactions: Pechmann coumarin synthesis,
Biginelli reaction, and acylation
Maghar S. Manhas, Subhendu N. Ganguly, Somdatta Mukherjee,
Amit K. Jain and Ajay K. Bose*
George Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology, Hoboken, NJ 07030, USA
Received 5 November 2005; revised 25 January 2006; accepted 30 January 2006
Available online 20 February 2006
Abstract—An energy-efficient protocol has been developed for solvent-free reactions that are mildly exothermic but not spontane-
ous. The exothermic reaction mixture—on several g-scale—is exposed for about 30 s to low power (about 200 W) microwaves and
then the microwave oven is switched off. After this short burst of energy, the exothermic reaction gets initiated and proceeds on its
own to completion. A number of coumarins were synthesized by the Pechmann reaction using this strategy.
Ó 2006 Elsevier Ltd. All rights reserved.
In 1883, Pechmann described an efficient synthesis of
coumarins (3) that involved the condensation of phenols
(1) with b-keto esters (2) (Scheme 1).1,2
the reactants for an exothermic reaction (and a catalyst,
if required) to a large volume of water with efficient stir-
ring. The exothermic reaction starts in a few minutes
and proceeds to completion. The insoluble reaction
product crystallizes out in a nearly pure form and in
high yield. Thus, the condensation of salicylaldehydes
(5) and malonic esters (6) by this protocol produces cou-
marins (7) in high yield (Scheme 2).
The Pechmann reaction is versatile: a wide variety of
substituted phenols and b-keto esters can generate cou-
marins in good yield with substituents in the phenolic
nucleus and/or in the heterocyclic ring. Various con-
densing agents have been used including metal chlorides
and phosphorus oxychloride. Solvents such as alcohol,
ether, and benzene have been favored. Under some con-
ditions, chromones (4) may also be formed.
It was observed that the Pechmann reaction for couma-
rins (e.g., involving the interaction of resorcinol, ethyl
In an earlier publication, we described the ‘Grindstone
Chemistry’ method for conducting exothermic reactions
in the solvent-free mode.3 When this protocol was ap-
plied to the Pechmann synthesis on a multi-molar scale,
the expected coumarins were obtained in a few minutes
as pure products in high yield by solvent-free grinding.
Since this reaction proved to be exothermic, we tested
energy-saving procedures developed in our laboratory.
R
O
O
O
R
+
H
+
OH
O
CH2CO2Et
O
R'
R
R'
R'
2
1
3
4
Scheme 1.
For a larger scale exothermic reaction, an efficient meth-
od that we4 have developed uses a ‘water-based bipha-
sic’ reaction medium. This method consists of adding
CO2Et
O
CHO
-
B
CH2(CO2Et)2
+
OH
O
R
Keywords: Microwave chemistry; Coumarins; Energy-efficient reac-
R
tion; Solvent-free reaction.
5
6
7
*
Corresponding author. Tel.: +610 258 8624; fax: +610 438 8232;
e-mail: abose@stevens.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.147

2424
M. S. Manhas et al. / Tetrahedron Letters 47 (2006) 2423–2425
acetoacetate, and p-toluenesulfonic acid) under the
water-based biphasic reaction conditions failed to pro-
duce any coumarin (Scheme 3). A different procedure
developed in our laboratory for exothermic reactions
was then tested.
In the course of our recent studies on solvent-free reac-
tion mixtures, it had been noticed that not all exothermic
reactions are spontaneous; many of them require a short
burst of energy for the initiation of the reaction. After
such initiation, the exothermic reaction proceeds on its
own to completion—without additional energy input.
We conducted a test: a solvent-free Pechmann reaction
mixture was irradiated with microwaves of low power
(200 W). The temperature of the reaction mixture
started to rise. After 30 s of irradiation, the microwave
oven was switched off. The reaction mixture continued
to rise in temperature; the reaction was completed in less
than 20 min (monitored by TLC). The target coumarin
CH3
O
H+
+
HO
OH
HO
O
O
EtO2C
Scheme 3.
Table 1. Synthesis of coumarins by our microwave procedure
Phenols
b-Keto esters
Products
Yield (%)
94
HO
OH
O
O
HO
O
O
1
OEt
O
O
O
O
HO
HO
O
HO
HO
OH
OH
2
3
4
5
81
96
92
86
CO2Et
O
O
C2H5
OEt
OEt
C2H5
O
HO
HO
O
HO
HO
OH
OH
O
O
C6H5
C6H5
O
O
O
O
OEt
OH
OH
OH
OH
O
HO
O
O
O
HO
OH
6
90
OEt
OH
OH
O
HO
HO
O
O
O
HO
HO
OH
OH
7
8
82
80
C6H5
OEt
C6H5
O
O
O
CO2Et
OH
OH

M. S. Manhas et al. / Tetrahedron Letters 47 (2006) 2423–2425
2425
H
N
NH2
CH3CO2H
(CH3CO)2O
+
O
MW
O
O
O
O
150 W
HO
HO
p-TSA
NH2
+
+
+
5 min
NH
O
EtO
OEt
H2N
Scheme 4.
H
O
25g
300 g
N
503 g
650 g
H
1.051 kg (92%)
was isolated in high yield. This new energy-saving proce-
dure was found to be useful for the efficient preparation
of several coumarins (Table 1).
Scheme 5.
Various b-keto esters were used successfully for the
Pechmann reaction (catalyzed by p-TSA) with resor-
cinol, pyrogallol and other phenols. A wide variety of
coumarins were obtained by this method in about
20 min, under solvent-free, green reaction conditions.
records it and can duplicate it for future repeat runs.
Since only a very short burst of low level microwave
energy is needed, it is quite sufficient and convenient to
use an inexpensive domestic microwave oven for the pres-
ent work.
The efficacy of our method was examined by conducting
other synthetic reactions. For example, a mixture on
several grams scale of p-aminophenol (4-hydroxyani-
line), acetic anhydride and acetic acid at room tempera-
ture was placed in a domestic microwave oven (800 W)
and the acetylation reaction was initiated by irradiating
for 30 s at a 50% power level. After irradiation, the tem-
perature of the mixture was 56 °C. The reaction mixture
was then placed outside the oven. The temperature of
the reaction mixture continued to rise and reached
121 °C in 2 min. For the next 3 min the temperature
dropped slowly and then rose sharply to 150 °C and
crystals appeared. After filtering, washing with cold
water and drying, the crystalline product was found to
be pure p-acetaminophenol (Tylenol) in 86% yield
(Scheme 4).
Acknowledgements
We are grateful to the Union Mutual Foundation, the
New York Cardiac Center and the Dreyfus Foundation
for financial support. We thank Stevens Institute of
Technology for laboratory facilities and Dr. Mark
Cardillo for useful discussions.
References and notes
1. Pechmann, H.; Duisberg, C. Chem. Ber. 1883, 16, 2119.
2. For a review, see: Org. React. 1953, 7, 1–58.
3. Bose, A. K.; Pednekar, S.; Ganguly, S. N.; Chakraborty,
G.; Manhas, M. S. Tetrahedron Lett. 2004, 45, 8351.
4. Bose, A. K.; Manhas, M. S.; Pednekar, S.; Ganguly, S. N.;
Dang, H.; He, W.; Mandadi, A. Tetrahedron Lett. 2005, 46,
1901.
This microwave protocol was then applied to the cen-
tury old Biginelli reaction involving the interaction of
an aldehyde, an acetoacetate, urea (or thiourea), and
an acid catalyst (such as p-toluenesulfonic acid).4,5 The
test was successful with this multi-component reaction
mixture on a near kg scale with 92% yield of the desired
product as shown in Scheme 5.
5. Biginelli, P. Chem. Ber. 1891, 24, 1317, 2962; Biginelli, P.
Chem. Ber. 1893, 26, 447.
6. Typical procedure for the preparation of coumarin by our
microwave protocol: To a mixture of resorcinol (2.2 g,
20 mmol) and ethyl acetoacetate (2.6 g, 20 mmol) was
added p-TSA (0.18 g, 1.0 mmol) in a 50 mL Erlenmeyer
flask. This reaction mixture was placed in a microwave
oven and irradiated for 30 s at 400 W power and the temp.
of the reaction mixture rose to 85 °C. After removing from
the microwave oven, the reaction mixture was allowed to
cool down to room temp. (20 °C). Water was added to the
mixture and the crystalline material that separated was
collected by filtration to give 7-hydroxy-4-methylcoumarin.
The crude crystals obtained were recrystallized from
methanol, mp 186–187 °C; yield 94%.
In summary, this microwave procedure is an energy-sav-
ing method for initiating exothermic reactions. Some
chemical syntheses using this technique are suitable for
teaching laboratories also.6
It is customary now to use a computerized, expensive
microwave lab station that controls the temperature,