A practical and environmentally friendly preparation of 3-carboxycoumarins

Article abstract of DOI:10.1081/SCC-120023987

The condensation of salicylaldehydes with Meldrum's acid in water at 75°C to produce 3-carboxycoumarin derivatives is described.

Full text of DOI:10.1081/SCC-120023987

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A Practical and Environmentally Friendly Preparation
of 3-Carboxycoumarins
a
a
b
b
b
M. N. Deshmukh , Rahila Burud , Carmen Baldino , Philip C. M. Chan & Jifeng Liu
a
Division of Organic Chemistry: Technology National Chemical Laboratory, Pune, India
b
ArQule Inc., Woburn, Massachusetts, USA
Available online: 15 Aug 2006
To cite this article: M. N. Deshmukh, Rahila Burud, Carmen Baldino, Philip C. M. Chan & Jifeng Liu (2003): A Practical and
Environmentally Friendly Preparation of 3-Carboxycoumarins, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:19, 3299-3303
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 19, pp. 3299–3303, 2003
A Practical and Environmentally Friendly
Preparation of 3-Carboxycoumarins
1
,
1
2
M. N. Deshmukh, * Rahila Burud, Carmen Baldino,
2
Philip C. M. Chan, and Jifeng Liu
2
1
Division of Organic Chemistry: Technology National
Chemical Laboratory, Pune, India
2
ArQule Inc., Woburn, Massachusetts, USA
ABSTRACT
The condensation of salicylaldehydes with Meldrum’s acid in water
ꢀ
at 75 C to produce 3-carboxycoumarin derivatives is described.
Coumarin carboxylic acid derivatives display a large number of
[1]
[2]
[3]
biologicalproperties (anticoagulant andtripletsensitizer )duetowhich
a considerable amount of work in the synthesis of 3-carboxycoumarin
derivatives has been reported. There are several methods available for
[
4]
theirsynthesis such as condensation of salicylaldehydes with malonate
ꢀ
[5]
esters at 150–155 C, treating salicylaldehydes with ethyl cyanoacetate
*
Correspondence: M. N. Deshmukh, Division of Organic Chemistry:
Technology National Chemical Laboratory, Pune 411 008, India; E-mail:
mndesh@dalton.ncl.res.in.
3
299
DOI: 10.1081/SCC-120023987
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3
300
Deshmukh et al.
in presence of NaOEt or KOH at room temperature for 40–80 h followed
by hydrolysis with HCl, treatment of dipotassium o-methoxybenzylidene
[
6]
malonate with trifluoroacetic acid–trifluoroacetic anhydride, reaction
of salicylaldehydes with Meldrum’s acid in the presence of an alkaline
[7]
condensing agent at 0.025–0.25 mol/mol aldehyde in water, reaction of
o-methoxybenzaldehydes with Meldrum’s acid followed by cyclization of
[
the resulting benzylidene derivatives in conc. sulfuric acid, refluxing
8]
o-hydroxybenzaldehydes with 2,2-pentamethylene-1,3-dioxane-4,6-dione
[
9]
in acetic acid in presence of pyridine, reaction of salicylaldehydes with
[
10]
dimedone followed by acetal cleavage with ammonium acetate
reaction of o-hydroxy or o-methoxybenzaldehydes oracetophenones
and
with Meldrum’s acid in the presence of catalysts (kaolinitic clays,
11]
EPZ10 and EPZG) using focused microwaves.
[
Although these methods are suitable for the synthesis of 3-carboxy-
coumarins, the long reaction time at elevated temperatures and the use of
large amount of organic solvents, organic and inorganic bases which
eventually results in generation of large amount of toxic waste during
quenching procedure are problematic. Therefore, we decided to develop a
eco-friendly, efficient alternative method for the synthesis of 3-carboxy-
coumarins which is described herein.
We present in this article a general method for the preparation of
-carboxycoumarin derivatives (3) (Sch. 1). Thus, the reaction of
3
salicylaldehydes (1) with Meldrum’s acid (2) in water at 75 C provides
ꢀ
3-carboxycoumarin derivatives (3). The reaction proceeds to completion
in 2 h and the product precipitates during the course of the reaction and is
separated by filtration.
A wide range of salicylaldehyde derivatives have been condensed
ꢀ
with Meldrum’s acid in water at 75 C (Table 1). We believe that the
salicylaldehyde with Meldrum’s acid first form o-hydroxybenzylidene
Meldrum’s acid, followed by cyclisation to 3.
R
R
O
R1
R2
OH
O
O
Me
Me
R1
R2
O
O
+
CHO
CO H
2
O
1
2
3
Scheme 1. (a) R ¼ R ¼ R ¼ H; (b) R ¼ OMe, R ¼ R ¼ H; (c) R ¼ OMe,
1
2
1
2
1
R ¼ R
2
¼ H; (d) R
2
¼ OMe, R ¼ R
1
¼ H; (e) R ¼ F, R
1
¼ R
2
¼ H; (f ) R ¼ Cl,
2
R ¼ R
1
¼ H.

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Practical Preparation of 3-Carboxycoumarins
3301
Table 1.
e
Salicylaldehyde
used
3-Carboxycoumarin
obtained
M.p.
ꢀ
HPLC purity
area (%)
a
Yield (%)
( C)
b
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
84
92
65
80
82
73
192
219
99
99
99
98
98
95
c
203
d
188
168
195
a
Isolated yield; products fully characterized by spectroscopic data (IR,
NMR, MS).
b
[8]
Lit. 191–192 C.
ꢀ
c
[8]
Lit. 192–193 C.
ꢀ
d
[8]
Lit. 179–180 C.
ꢀ
e
HPLC conditions; Column: C18 Licrocart; Mobile phase: [Acetonitrile–Buffer
pH ¼ 3) 4.5:5.5]; Flow rate: 1 mL/min; UV: 254 nm.
(
In conclusion, the present report describes an efficient and
practical method to prepare 3-carboxycoumarin derivatives 3. We have
shown that the condensation of salicylaldehydes with Meldrum’s acid
ꢀ
occurs in water by heating at 75 C for 2 h providing 3-carboxycoumarins
in excellent yield. The significant advantage of this methodology is the
ease of isolation of the product. The method is eco-friendly as it does not
involve the use of any organic solvent or base/acid in the reaction. The
products are isolated by filtration. In light of its operational simplicity
and simple experimental work-up procedure, the present method is
expected to have broad synthetic utility.
EXPERIMENTAL
1
H NMR spectra were recorded on a Brucker 200 MHz spectrometer
and the chemical shifts are expressed in ꢀ relative to TMS as internal
standard. The starting salicylaldehyde derivatives and Meldrum’s acid
were purchased from Aldrich Chemical Co.

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302
Deshmukh et al.
General Procedure for the Preparation
of 3-Carboxycoumarins
Salicylaldehyde (1a, 0.244 g, 2 mmol), Meldrum’s acid (2, 0.288 g,
ꢀ
2
mmol), and water (10 mL) were stirred at 75 C for2 h. The er action
was cooled to room temperature, solid filtered, and washed with cold
water to get 3a (0.336 g). The precipitate was dried at suction and
characterized by spectral data.
The 3-carboxycoumarins thus obtained were found to be 95–99%
pure by HPLC.
3
Aromatic), 4.03 (s, 3H, OMe). Anal. calcd. for C H O : C, 60.00; H,
1
b. H NMR (CDCl ): ꢀ 8.92 (s, 1H, H-4), 7.44–7.25 (m, 3H,
3
1
1
8
5
3
.66. Found: C, 60.21; H, 3.78.
1
e. H NMR (CDCl ): ꢀ 8.97 (s, 1H, 4-H), 7.70–7.40 (m, 3H, ArH).
3
Anal. calcd. forC H FO : C, 57.61; H, 2.58. Found: C, 57.75; H, 2.69.
3
1
0
5
4
1
f. H NMR (CDCl ): ꢀ 8.88 (s, 1H, 4-H), 7.85–7.70 (m, 2H, ArH),
3
3
7.46 (d, 1H, ArH). Anal. calcd. for C H ClO : C, 53.39; H, 2.40; Cl,
10 5 4
15.76. Found: C, 53.53; H, 2.58; Cl, 15.89.
ACKNOWLEDGMENTS
We thank Dr. M. K. Gurjar for encouragement and fruitful
discussions.
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1

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Practical Preparation of 3-Carboxycoumarins
3303
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Received in the USA March 12, 2003

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