An efficient ZrCl4 catalyzed one-pot solvent free protocol for the synthesis of 4-substituted coumarins

Article abstract of DOI:10.1016/j.tetlet.2005.06.166

A versatile and efficient route to 4-substituted coumarins via a Pechmann reaction using ZrCl₄ as the catalyst (10 mol %) is described. This method provides several advantages over alternative procedures such as mild, solvent-free conditions at ambient temperature, and direct isolation of the products in high yields.

Full text of DOI:10.1016/j.tetlet.2005.06.166

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6119–6121
An efficient ZrCl4 catalyzed one-pot solvent free protocol
for the synthesis of 4-substituted coumarinsq
G. V. M. Sharma,* J. Janardhan Reddy, P. Sree Lakshmi and P. Radha Krishna
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 April 2005; revised 22 June 2005; accepted 29 June 2005
Available online 25 July 2005
Abstract—A versatile and efficient route to 4-substituted coumarins via a Pechmann reaction using ZrCl4 as the catalyst (10mol %)
is described. This method provides several advantages over alternative procedures such as mild, solvent-free conditions at ambient
temperature, and direct isolation of the products in high yields.
Ó 2005 Published by Elsevier Ltd.
R'
Coumarins are structural units of several natural prod-
ucts,1 and feature widely in pharmacologically and bio-
logically active compounds.2 Besides functionalized
coumarins,3–7 polycyclic coumarins such as calano-
lides,8 isolated from Calophyllum genus, and others
have shown potent anti-HIV (NNRTI) activity. A vari-
ety of methods viz., Pechmann,9a Perkin,9b Claisen,9c
Knoevenagel,9d Reformatsky9e and Wittig,9f,g have been
developed to synthesize coumarins. The Pechmann
reaction,9h a two component (phenol and b-keto ester)
coupling under acid catalysis,10–13 is a very well estab-
lished protocol for coumarin ring synthesis. It may also
utilize heterogenous catalysis,14 transition metal cata-
lysis,15 ionic liquids16 and microwave irradiation.17
However, most of these procedures suffer from disad-
vantages such as elevated temperatures, longer reaction
times and poor yields. In our earlier work on the synthe-
sis of dihydrocalanolides,18 the coumarin ring was con-
structed in poor yields, using CF3COOH as the
solvent at reflux, for the Pechmann reaction. In connec-
tion with our research on drug discovery, an improved
procedure for the one-pot construction of coumarin ring
systems on large scale was investigated. Based on our
past experience with ZrCl4 as an efficient acid catalyst,19
we report the studies on a ZrCl4 catalyzed solvent-free
one-pot protocol at room temperature for the synthesis
of coumarins (Eq. 1).
O
O
ZrCl4 (10 mol%)
rt
R
R
+
R'
OEt
O
O
OH
R' = CH3,CH2Cl, Ph, Fu
ð1Þ
To establish the reaction conditions, equimolar quanti-
ties of resorcinol 1 (Table 1, entry 1) and ethyl aceto-
acetate were treated with ZrCl4 (10mol %) at room
temperature for 5 min to give the corresponding couma-
rin 1a in 92% yield, mp 184–185 °C (lit.12c 185 °C). Cou-
marin 1a was characterized by IR, NMR and other
spectral data and treated with AcCl in pyridine to afford
its corresponding acetate, whose structure was estab-
lished from spectral data. Similarly, resorcinol 1 was
treated with a variety of b-ketoesters viz., ethyl 4-chloro-
acetoacetate, ethyl benzoylacetate and ethyl furoacetate
(Table 1, entries 2–4) to furnish coumarins 1b, 1c and 1d,
respectively, in 90–95% yields within 5–10 min. Com-
pounds 1b, 1c and 1d had mpÕs corresponding to
reported values.20a,10
Encouraged by the above results, other phenolic sub-
strates were subjected to the Pechmann reaction using
ZrCl4. Pyrogallol 2, phloroglucinol 3, 2-methylresor-
cinol 4 and a-naphthol 5 were subjected to the reaction
with different b-ketoesters as shown in Table 1 to give
the corresponding coumarins. The reaction was found
to be adaptable to a variety of substrates and the yields,
in general, were very high (90–98%). Short reaction
times were observed (5–10min) regardless of structural
variations in the phenols or b-ketoesters. Most of these
Keywords: Coumarins; Phenols; b-Ketoesters; Pechmann reaction and
ZrCl4.
q IICT Communication No. 041103.
*
Corresponding author. Fax: +91 402716 0387; e-mail: esmvee@
iict.res.in
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.06.166

6120
G. V. M. Sharma et al. / Tetrahedron Letters 46 (2005) 6119–6121
Table 1. ZrCl4 (10mol %) catalyzed synthesis of coumarins
Entry
1
Phenol
b-Keto ester
Product
Time (min)
Yield (%)
Mp, °Cref
HO
OH
HO
O
R
O
RCOCH2CO2Et
1
R = CH3
R = CH2Cl
R = Ph
1a R = CH3
1b R = CH2Cl
1c R = Ph
5
5
92
95
256–257
184–18512c
180–18120a
10
1091
1092010
20d
R = Furyl
1d R = Furyl –212
OH
OH
HO
OH
HO
O
R
O
2
RCOCH2CO2Et
2
R = CH3
R = CH2Cl
R = Ph
2a R = CH3
2b R = CH2Cl
2c R = Ph
5
5
96
98
195–197
241–24312c
133–13520b
10
1094
1091090
20c
R = Furyl
2d R = Furyl
decom
HO
OH
HO
O
O
3
4
5
RCOCH2CO2Et
OH
OH
R
3
R = CH3
R = CH2Cl
R = Ph
3a R = CH3
3b R = CH2Cl
3c R = Ph
5
5
1094
93
97
243–246
280–28112c
187–18920b
10
CH3
CH3
HO
O
O
HO
OH
RCOCH2CO2Et
4
R
R = CH3
R = CH2Cl
R = Ph
4a R = CH3
4b R = CH2Cl
4c R = Ph
5
5
95
96
263–26510
284–28610
10
1092084–285
O
O
OH
RCOCH2CO2Et
R
5
10
10
R = CH3
R = CH2Cl
5a R = CH3
5b R = CH2Cl
1092
1095
153–155
165–167
coumarins were characterized from melting points and
M+ peaks in the EIMS. All the coumarins except for
1d, 2d, 5a and 5b were converted into their acetates
(1a0–c0, 2a0–c0, 3a0–c0 and 4a0–c0), which were character-
Acknowledgements
P.S. and J.J.R. are thankful to the CSIR, New Delhi,
India for financial support.
1
ized by H NMR and other spectral techniques.
References and notes
Typical experimental procedure: To an equimolar mix-
ture of the phenol and the b-ketoester, ZrCl4
(10mol %) was added and the mixture stirred at room
temperature for a few minutes (5–10min). After the
completion of the reaction, as indicated by TLC, the
reaction mixture was diluted with water, filtered and
the separated solid was washed with water and dried
to furnish the coumarin.
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