Use of microwave irradiation and solid acid catalysts in an enhanced and environmentally friendly synthesis of coumarin derivatives

Article abstract of DOI:10.1055/s-1999-2674

Condensation of phenol, 1,3-dihydroxybenzene and 1,3,5- trihydroxybenzene with propynoic and propenoic acids and ethyl acetoacetate using solid acid catalysts and microwave irradiation produces coumarins in excellent yields. The use of heterogeneous catalysts eliminates the production of acidic waste streams associated with conventional (Lewis) acid catalysts. This quick, efficient and environmentally friendly procedure permits the synthesis of substituted coumarins as well as coumarins without 4-alkyl substituents, which are the most difficult to synthesize.

Full text of DOI:10.1055/s-1999-2674

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08
LETTER
Use of Microwave Irradiation and Solid Acid Catalysts in an Enhanced and
Environmentally Friendly Synthesis of Coumarin Derivatives
Antonio de la Hoz,* Andrés Moreno, Ester Vázquez
Dpto. Química Orgánica, Facultad de Química, Universidad de Castilla-La Mancha, Campus Universitario, Ciudad Real 13071, Spain
Fax +34 926295318
Received 16 February 1999
quire high temperatures, longer reaction times and, in
Abstract: Condensation of phenol, 1,3-dihydroxybenzene and
some cases, give lower yields.
1
,3,5-trihydroxybenzene with propynoic and propenoic acids and
ethyl acetoacetate using solid acid catalysts and microwave irradia- Microwave irradiation in solvent-free conditions has well
tion produces coumarins in excellent yields. The use of heteroge-
demonstrated its utility as a convenient energy source in
many processes. The rapid heating induced by the radi-
neous catalysts eliminates the production of acidic waste streams
associated with conventional (Lewis) acid catalysts. This quick, ef-
ficient and environmentally friendly procedure permits the synthe-
sis of substituted coumarins as well as coumarins without 4-alkyl
substituents, which are the most difficult to synthesize.
15
ation leads to the formation of products under mild reac-
tion conditions with short reactions times, thus avoiding
decomposition or side-reactions and, in many cases, in-
creasing the yields. Recently, the use of H SO under mi-
2
4
Key words: phenols, a,b-unsaturated carboxylic acids, solid acid
catalyst, microwave, coumarin derivatives.
crowave irradiation has played an important role in rate
enhancement in the Pechmann reaction16 and in the syn-
thesis of some 3,4-dihydro-4-phenylcoumarins and 4-
phenylcoumarins when montmorillonite K-10 clay is used
as a catalyst.17
Coumarin and its derivatives find their main application
as fragrances, pharmaceuticals and agrochemicals.1
There have been many synthetic routes to coumarins, in-
,2
In this paper we report on the solid acid-catalysed reaction
of phenols with carboxylic acids possessing either none,
one or two additional functions that are able to alkylate the
benzene nucleus. We examine the condensation of phenol
3
4
Knoevenagel,5
cluding the Pechmann,
Perkin,
6
7
Reformatsky and Wittig reactions. However, the Pech-
mann reaction has been the most widely applied method
for preparing coumarins since it proceeds from very sim-
(1), 1,3-dihydroxybenzene (2) and 1,3,5-trihydroxyben-
zene (3) with propynoic acid (4), propenoic acid (5) and
ple starting materials and gives good yields of 4-substitut-
8
ed coumarins. Various procedures have been developed, ethyl acetoacetate (6) using solid acid catalysts and micro-
and in all of these methods mixtures of the reagents are al- wave irradiation as a quick, simple and environmentally
lowed to stand overnight or for a number of days, depend- friendly preparation of coumarin or substituted coumarins
ing on their reactivity, or were heated above 150 ºC. (Scheme 1). All the reactions were carried out at atmo-
Usually these reactions occur by electrophilic aromatic spheric pressure in a focused microwave reactor with
substitutions and generally employ non-regenerable cata- measurement and control of power and temperature. Con-
densations were performed in the absence of solvent and
reaction conditions were optimised to obtain the best
yield.18
lysts such as metal chlorides and mineral acids. However,
these conventional catalysts have to be used in excess and
they lead to increasing environmental pollution.
On the other hand, a modification of the Pechmann reac-
tion involves the use of an a,b-unsaturated carboxylic acid
and this permits the synthesis of coumarins substituted in
9
either the pyrone, the benzene ring or both. However, it is
one of the few ways to prepare coumarins that do not bear
a 4-alkyl substituent, compounds that are impossible to
obtain by a normal Pechmann reaction approach. The re-
action was shown to proceed through esterification fol-
lowed by ring closure, both of which are proton-
1
0
catalysed.
Consequently, there is a need for efficient and heteroge-
neous catalytic methods for this reaction using inexpen-
sive, easily handled and non-polluting catalysts.
Scheme 1
1
1
Replacement of mineral acids by solid acid catalysts
The results of a comparative study of the synthesis of cou-
marins by classical heating using solid acid catalysts, both
with and without solvent, and microwave irradiation are
shown in Table 1. From these results it is clear that the re-
1
2
13
14
such as zeolites, clays and sulfonic acid resins would
result in simplified product recovery and a reduction in
undesirable waste streams. However, such catalysts re-
Synlett 1999, No. 5, 608–610 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Use of Microwave Irradiation and Solid Acid Catalysts in the Synthesis of Coumarin Derivatives
609
action time is reduced from several hours to only a few yield (97%) by employing Amberlyst-15 under micro-
minutes on using microwave irradiation, indicating that wave irradiation.
microwaves play an important role in rate enhancement in
these reactions. The products are also obtained in excel-
lent yields with the exception of the reaction of phenol
(entry 1), and this is due to the lower activation of the ben-
zene ring. However, a similar reaction between phenol
and propenoic acid catalysed by Zeolite H-Beta in toluene
at 111 ºC after 24 h gave the corresponding coumarin in
Scheme 2
1
0
only 6% yield.
Open-chain products were not detected in any of the
above cases.
On the other hand, on employing microwave irradiation in
the reaction of 1,3-dihydroxybenzene and propynoic acid
(entries 3–6) we selectively obtained coumarins 8 and 9
with an improvement in the yield in the synthesis of 7-hy-
droxycoumarin (8).
Moreover, under microwave conditions (entry 9) we were
able to avoid the formation of 3,4,6,7-tetrahydroben-
zo[1,2-b:5,4-b']-dipyran-2,8-dione, a compound that is As can be seen in Table 2, the reaction time was lower in
formed by two consecutive reactions when a solvent is comparison to classical conditions (entries 1 vs. 3 and 4)
9
used in the reaction (entry 11).
while yields were improved in relation to previously re-
ported microwave conditions using mineral acids (entries
In order to assess the efficiency of our procedure, ethyl ac-
etoacetate was allowed to react with 1,3-dihydroxyben-
zene (Pechmann reaction) as an approach to 4-substituted
-hydroxycoumarins. In this case three steps, i.e. transes-
terification, hydroxyalkylation and dehydration, are in-
volved. It is well know that both transesterification and
hydroxyalkylation reactions can be proton-catalysed. 7- In conclusion, the synthesis of a range of coumarin deriv-
Hydroxy-4-methylcoumarin, which is a useful starting atives has been achieved using heterogeneous catalysts
material in the synthesis of an insecticide (Hymero- under microwave irradiation. Two types of reaction, i.e.
cromone), is obtained in this reaction in quasi quantitative the reaction of phenols with a,b-unsaturated carboxylic
1
vs. 2). These facts demonstrate the utility of using solid
acids. Moreover, under our reaction conditions the hy-
drolysis of the b-keto ester is avoided, whereas this reac-
tion is produced to a significant extent (entry 3) when
cation exchange resins are used.8b
7
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A. de la Hoz et al.
LETTER
acids and the Pechmann reaction, are readily catalysed by (13) For example, see: (a) Biswas, G. K.; Basu, K.; Barua, A. K.;
Bhattacharyya, P. Indian J. Chem. Sect. B 1992, 31, 628. (b)
Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, Ch.-G. J. Chem.
Research (S) 1998, 38.
cation-exchange resins such as Dowex or Amberlyst and
Montmorillonite. By choosing the appropriate reactants a
variety of coumarin derivatives can be synthesized.
(
14) Gunnewegh, E. A.; Hoefnagel, A. J.; Downing R. S.; van
Bekkum, H. Recl. Trav. Chim. Pays-Bas 1996, 115, 226.
15) Loupy, A.; Petit, A.; Hamelin, J.; Teixer-Boullet, F.; Jacquault
P.; Mathé, D. Synthesis 1998, 1213.
(
Acknowledgement
Financial support by the Spanish DGES (Project, PB97-0429) and
a predoctoral grant (E.V.) are gratefully acknowledged.
(16) Singh, V.; Singh, J.; Kaur, K. P.; Kad, G. L. J. Chem.
Research (S) 1997, 58.
(
17) Singh, J.; Kaur, J.; Nayyar S.; Kad, G. L. J. Chem. Research
S) 1998, 280.
18) Typical experimental procedure: A mixture of phenol (1–3)
10 mmol) and a,b-unsaturated carboxylic acid derivative (4
(
References and Notes
(
(
(
1) Murray, R. D. H.; Medez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry and Biochemistry; Wiley:
New York, 1982.
or 5) or ethyl acetoacetate (6) (15–20 mmol) supported on 1 g
of solid acid support (by dissolving the mixture in 5 mL of
diethyl ether followed by evaporation of the solvent) was
exposed to microwave irradiation in a focused microwave
reactor (Prolabo MX350) for the time and power indicated in
Tables 1 and 2. For isolation of the compounds, the solid
support was removed by extraction with ethanol (for reactants
(
(
(
(
(
(
2) Murray, R. D. H. Natural Product Reports 1995, 477.
3) Sethna, S.; Phadka, R. Org. React. 1953, 7, 1.
4) Johnson, J. R. Org. React. 1942, 1, 210.
5) Jones, G. Org. React. 1967, 15, 204.
6) Shirner, R. L. Org. React. 1942, 1, 1.
4
and 6) or acetonitrile (reactions of 5). After solvent
7) For example, see: (a) Harayama, T.; Katsuno, K.; Nishioka,
H.; Fujii, M.; Nishita, Y.; Ishii H.; Kaneko, Y. Heterocycles
evaporation, the products were purified by column
chromatography on silica gel (hexane/ethyl acetate, 3:1). All
1994, 39, 613; (b) Yavari, I.; Hekmat-Shoar R.; Zonouzi, A.
1
compounds were characterised by analytical methods and H-
Tetrahedron Lett. 1998, 39, 2391.
1
3
and C NMR spectroscopy, using mono and two-dimensional
techniques.
(
8) (a) Russel, A.; Frye, J. R. Org. Synth. 1941, 21, 22. (b) John,
E. V. O.; Israelstam, S. S. J. Org. Chem. 1961, 26, 240.
9) Hoefnagel, A. J.; Gunnewegh, E. A.; Downing R. S.; van
Bekkum, H. J. Chem. Soc., Chem. Commun. 1995, 225.
(
19) For example, see: (a) Venuto, P. B. Microporous Mat. 1994,
(
2
, 297. (b) Algerra, F.; Corma, A.; García, H.; Primo, J. Appl.
Catal. A 1995, 128, 119. (c) Climent, M. J.; Corma, A.;
García, H.; Iborra, S. Appl. Catal. A 1995, 130, 5.
(
(
(
10) Gunnewegh, E. A.; Hoefnagel, A. J.; van Bekkum, H. J. Mol.
Catal. A 1995, 100, 87.
11) For a review see: Delaude, L.; Laszlo P.; Smith, K. Acc. Chem.
Res. 1993, 26, 607.
12) Subba Rao, Y. V.; Kulkarni, S. J.; Subrahmanyam M.; Rama
Rao, A. V. J. Chem. Soc., Chem. Commun. 1993, 1456.
Article Identifier:
437-2096,E;1999,0,05,0608,0610,ftx,en;L03599ST.pdf
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Synlett 1999, No. 5, 608–610 ISSN 0936-5214 © Thieme Stuttgart · New York