SHORT PAPER
1231
An Efficient and Practical Procedure for the Synthesis of 4-Substituted
Coumarins
Synthesis of
4
u
-Substituted
rCoumari
y
ns a K. De,* Richard A. Gibbs
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue Cancer Center, Purdue University,
West Lafayette, IN 47907, USA
Fax +1(765)4941414; E-mail: skd125@pharmacy.purdue.edu
Received 19 October 2004; revised 25 January 2005
In view of the recent trend on the catalytic processes to-
wards the development of clean and green chemical pro-
cesses, investigation of new, less hazardous chemical
catalyst has become a priority in synthetic organic chem-
istry. Bismuth(III) halides are inexpensive, relatively non-
toxic, fairly insensitive to small amounts of water, and en-
vironmentally benign reagents, which have been used as
mild Lewis acid catalysts for an array of synthetic organic
reactions.16 In continuation of our work to develop new
synthetic methodologies,17 herein we are gratified to re-
port an efficient and convenient method for the synthesis
of 4-substituted coumarins from very simple starting ma-
terials under solvent-free conditions.
Abstract: BiCl3 is used as an efficient catalyst in the Pechmann
condensation reaction of phenols with b-keto esters leading to the
formation of coumarin derivatives in excellent yields under solvent-
free conditions.
Key words: phenols, b-keto ester, Pechmann reaction, bismuth(III)
chloride, coumarin
Coumarin and its derivatives are widely used as additives
in food, perfumes, cosmetics, pharmaceuticals, and agro-
chemicals.1,2 Thus, the synthesis of coumarin or its nucle-
us is a topic of current interest as a large number of natural
products contain this heterocyclic nucleus.3 There have
been many synthetic routes to coumarins, including Pech-
mann,4 Perkin,5 Knoevenagel,6 Reformatsky,7 and Wittig
reactions.8 However, the Pechmann reaction has been the
most widely applied for synthesis of coumarins as it pro-
ceeds from very simple starting materials and gives very
good yields of 4-substituted coumarins. Several acid cata-
lysts have been used in the Pechmann reaction including
sulfuric acid,4 aluminum chloride,9 phosphorus pentox-
ide,10 trifluoroacetic acid,11 and others. However, these
catalysts have to be used in excess; for instance, sulfuric
acid in ten equivalents, trifluoroacetic acid in three to four
equivalents, and phosphorus pentoxide is required in five
equivalents. In all these methods mixtures of the reagents
were allowed to stand overnight or for a number of days,
depending on their reactivity, or were heated above
150 °C, and unwanted side products such as chromones
were obtained. As a result, the disposal of excess acid
waste leads to increasing environmental pollution. With
increasing environmental concerns it is important to in-
vestigate a new method using less hazardous reagents and
solvents or without harmful organic solvents. Most re-
cently, some environmentally benign procedures have
been reported such as zeolites,12 clays,13 sulfonic acid
resins14 and microwave irradiation techniques.15 Howev-
er, these catalysts require high temperatures, longer reac-
tion times, extreme precautions for microwave irradiation
techniques, and give lower yields in some cases. There-
fore, there is still a need to search for a better catalyst with
regards to toxicity, handling, easy availability, economic
viability, and operational simplicity.
The condensation of resorcinol with ethyl acetoacetate in
the presence of 5 mol% BiCl3 at 75 °C afforded 7-hy-
droxy-4-methylcoumarin in one hour. Similarly, several
phenols underwent the condensation reactions to give 4-
substituted coumarins (Scheme 1) in excellent yields
(Table 1). It should be mentioned that for most of the sub-
strates, the reaction time is reduced drastically even at
ambient conditions in contrast to reported methods. Sub-
strates having electron-donating groups in the para posi-
tion to the site of electrophilic substitution underwent the
reactions in a short period of time (Table, entries 1–4) to
give excellent yields. Phenol required a higher reaction
temperature, as no electron-donating group is present. The
3-aminophenol (entry 6) underwent the condensation re-
action with ethyl acetoacetate to give the desired cou-
marin along with 9% quinoline. The resacetophenone
(entry 9) was condensed with ethyl acetoacetate in the
presence of a catalytic amount of bismuth(III) chloride to
give the desired product, but this reaction failed to give
coumarin derivative in the presence of sulfuric acid.4 The
method has the ability to tolerate other functional groups
such as hydroxyl, methoxy, acetyl, and amino functions.
In conclusion, a very simple and convenient method has
been developed for the synthesis of 4-substituted cou-
marins under solvent-free conditions. The method has ad-
BiCl3 (5 mol%)
ethyl acetoacetate
O
O
SYNTHESIS 2005, No. 8, pp 1231–1233
Advanced online publication: 23.03.2005
x
x
.
x
x
.2
0
0
5
R
OH
R
Scheme 1
DOI: 10.1055/s-2005-865282; Art ID: M08304SS
© Georg Thieme Verlag Stuttgart · New York
De, Surya K.
