Microwave acceleration of the Pechmann reaction on graphite/montmorillonite K10: Application to the preparation of 4-substituted 7-aminocoumarins

Article abstract of DOI:10.1016/S0040-4039(01)00295-7

Efficient synthesis of 7-aminocoumarins was performed via the Pechmann reaction by microwave irradiation of the reactants on solid support (graphite/montmorillonite K10). In this convenient new methodology, the strong thermal effect due to graphite/microwaves interaction is associated with the acidic catalyst role of the clay.

Full text of DOI:10.1016/S0040-4039(01)00295-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2791–2794
Microwave acceleration of the Pechmann reaction on
graphite/montmorillonite K10: application to the preparation of
4-substituted 7-aminocoumarins
Ste´phane Fre`re, Vale´rie Thie´ry and Thierry Besson*
Laboratoire de Ge´nie Prote´ique et Cellulaire, UPRES EA3169, Groupe de Chimie Organique,
UFR Sciences Fondamentales et Sciences pour l’Inge´nieur, Universite´ de la Rochelle, Avenue Michel Cre´peau,
F-17042 La Rochelle Cedex 1, France
Received 9 February 2001; revised 19 February 2001; accepted 20 February 2001
Abstract—Efficient synthesis of 7-aminocoumarins was performed via the Pechmann reaction by microwave irradiation of the
reactants on solid support (graphite/montmorillonite K10). In this convenient new methodology, the strong thermal effect due to
graphite/microwaves interaction is associated with the acidic catalyst role of the clay. © 2001 Elsevier Science Ltd. All rights
reserved.
Coumarins are common in Nature and find their main
applications as fragrances, pharmaceuticals and agro-
chemical.1 In the course of our recent work on the
preparation of new polyheterocyclic systems with
potent pharmacological value,2 we planned to prepare
aminocoumarins which can be employed as intermedi-
ates in the synthesis of useful bioactive compounds.3
Such molecules are usually synthesized by a Pechmann
reaction, which involves condensation of phenols with
b-ketonic esters in the presence of various reagents (e.g.
H2SO4). In some methods, mixtures of substituted phe-
nols, b-ketoesters and the acidic catalyst were allowed
to stand overnight or for a number of days (depending
on their reactivity) or were heated above 150°C, and
undesired products such as chromones, in addition to
coumarins, have also been reported. In the hope of
developing convenient and reproducible methods for
the preparation of the rare amino compounds, we
Prolabo)4 especially designed for organic synthesis.
There are few papers on the use of microwave activa-
tion of Pechmann reactions and all report reactions
that started from resorcinols or activated alkoxyphe-
nols;5 however, none of them described the prepara-
tions of aminocoumarins. In this paper we report an
original and environmentally friendly solvent-free pro-
cedure and study the opportunity to use solid supports
and acid catalysts in such experiments.
Synthesis of aminocoumarin-4-carboxylic acid
derivatives
Synthesis of the methylester of 7-aminocoumarin-4-car-
boxylic acid 1 usually consists of the heating of the
starting m-aminophenol with dimethyloxalacetate, at
130°C for 2 h (Scheme 1).6
transposed this Pechmann reaction to
a
focused
The amount of coumarins obtained in such conditions
is variable and sometimes low (e.g. 36%, see Table 1),
microwave oven (open oven, monomode system S402
Scheme 1.
Keywords: coumarins; Pechmann reaction; microwave irradiation.
* Corresponding author. Fax: (33) (0)5 46 45 82 47; e-mail: tbesson@univ-lr.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00295-7

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S. Fre`re et al. / Tetrahedron Letters 42 (2001) 2791–2794
Table 1. Selected results on the preparation of the 7-aminocoumarin 17,8a
Experimental conditionsa
Conventional heatingb
Reaction time (min) Yield (%)
Microwave irradiation
Reaction time (min)
Yield (%)
Neat (fusion)
120
120
66
36
44
64
85
50
30
39
44
66
Support: graphite
Support: graphite/K10 (2:1)c,d,e
a Reactions performed at 130°C; lowest (110°C) or highest (150 and 170°C) temperatures involved incomplete or complex (degraded) reactions and
poor yields of the attempted products.
b Oil bath.
c The ratio between the quantity of reactant and the graphite is very important; if it is too large or too small, degraded or incomplete reactions
were observed.
d No modifications were observed when a preliminary activation (2 h at 180°C) of the clay was realized.
e No significant results were observed in the absence of graphite (montmorillonite K10+phenol+b-ketoester).
accompanied by complicated mixtures of carbonaceous
compounds and colored impurities which are very
difficult to eliminate, even by column chromatography
and recrystallization. Transposition of this procedure to
a focused microwave reactor (130°C, 60 W) led to a
reduction of the reaction time (85 min) in a similar
yield (39%). Because it is well known that the use of
acid catalysts may play an important role in rate
enhancement in Pechmann reaction,3 a few drops of
sulphuric acid were added to the starting mixture.
Unfortunately, whatever conditions were used (thermal
heating or microwave irradiation) no improvements of
the reactions were observed, the yields became lower
and a lot of by-products were also detected.
marin 1 in a yield of 44% and in a shorter time (50 min)
than for the purely thermal procedures (see Table 1 and
Scheme 1) (in similar experimental conditions with the
same amount of starting materials and graphite, con-
ventional heating needed 120 min to give the expected
product in similar yield). Here again addition of a
catalytic amount of sulphuric acid led to a very com-
plex reaction.
In order to avoid the use of mineral acids (e.g. H2SO4),
we studied the opportunity to associate graphite to
montmorillonite clay, which has been used as an
efficient solid acidic catalyst for a variety of organic
reactions.11 Then, treatment of m-aminophenol with
the tertiary b-ketonic ester was carried out on a mixture
of graphite/montmorillonite K10 under microwave irra-
diation. Various parameters were studied and optimized
(reaction time: 30 min, temperature: 130°C, and ratio of
graphite/montmorillonite“2:1 w/w) and we also found
that the optimum amount of solid support was 75% by
weight of the global reactants (Table 1). An extension
of this procedure to various aminophenols was per-
Graphite is one of the solids most efficiently heated by
microwaves and is also known for its absorbing proper-
ties of organic molecules.9 Inspired by a recent work on
Friedel–Crafts acylation reactions with carbon graphite
as support,10 we showed that irradiation of a mixture of
m-aminophenol and methyl oxalacetate (1 equiv.),
adsorbed on graphite, led to the expected 7-aminocou-
Table 2. Synthesis of 7-aminocoumarins derivatives 2 and 37,8a
Producta
Conventional heating
Reaction time (min) Yield (%)
45 54
Microwave irradiation
Reaction time (min) Yield (%)
8 61
Mp (°C)
148–150
56
68
8
75
156–158b
a Reactions performed at 130°C. Support: graphite/K10 (2:1).
b Mp lit.:13 156°C.

S. Fre`re et al. / Tetrahedron Letters 42 (2001) 2791–2794
Table 3. Synthesis of 7-aminocoumarins derivatives 4 and 57,8b
Producta
2793
Conventional heating
Yield (%)
Microwave irradiation
Reaction time (min) Yield (%)
Mp (°C)
220–224b
Reaction time (min)
30
66
5
65
390
62
12
62
94–96
a Reactions performed at 130°C. Support: graphite/K10 (2:1).
b Mp lit.:15 220–224°C.
formed and results obtained (Table 2) are in accordance
solid starting materials, the use of solid supports offer
operational, economical and environmental benefits
over conventional methods. In contrast, association of
liquid/solid reactants on solid supports may involve
uncontrolled reactions and are generally worse than
comparative thermal reactions. In this case, simple
fusion of the products or addition of an appropriate
solvent may lead to more convenient mixtures or solu-
tions for microwave applications.
with data observed for the synthesis of coumarin 1.12
Synthesis of 7-amino-4-methylcoumarins7,8b (Table 3)
In this case the starting b-ketonic ester (ethyl acetoac-
etate, CH3COCH2COOC2H5) is
a liquid. Mixing
aminophenols14 and ethyl acetoacetate on graphite/K10
(2:1, w/w) led to a heterogeneous mixture and resulted
in hazardous bumping in the reactor and incomplete
reactions with a large amount of by-products (only 5%
yield of attempted compound). The best alternative
consisted of the microwave exposition of phenols and
ethyl acetoacetate in the presence of concentrated sul-
phuric acid. Here again, the comparative study of this
procedure by classical heating and microwave irradia-
tion showed that reaction time was reduced from sev-
eral hours to only a few minutes by using the latest
technique. On this point, these experiments are showing
the difficulties of associating liquid and solid phase in
microwave reactions, but it confirms that, in favorable
conditions, focused microwave irradiation is a very
powerful technique for accelerating thermal organic
reactions.
Acknowledgements
We thank the Comite´ de Charente-Maritime de la
Ligue Nationale contre le Cancer and the Communaute´
d’Agglome´ration de La Rochelle (S.F. PhD grant) for
financial support.
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support (graphite/montmorillonite K10). In this
efficient new methodology, the strong thermal effect
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S. Fre`re et al. / Tetrahedron Letters 42 (2001) 2791–2794
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