A green method for the synthesis of 3-substituted coumarins catalyzed by L-lysine in water via knoevenagel condensation

Article abstract of DOI:10.2174/157017812799303953

L-lysine was applied to the synthesis of 3-substituted coumarins through the condensation of various salicylaldehyde with reactive methylene compounds in water. In this work, waste minimization, catalyst recovery, simple operation and easier product work-up were achieved.

Full text of DOI:10.2174/157017812799303953

Letters in Organic Chemistry, 2012, 9, 19-23
19
A Green Method for the Synthesis of 3-Substituted Coumarins Catalyzed
by L-Lysine in Water Via Knoevenagel Condensation
Xinwen You, Hua Yu, Mangang Wang, Jun Wu* and Zhicai Shang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P.R. China
Received July 05, 2011: Revised November 04, 2011: Accepted November 04, 2011
Abstract: L-lysine was applied to the synthesis of 3-substituted coumarins through the condensation of various
salicylaldehyde with reactive methylene compounds in water. In this work, waste minimization, catalyst recovery, simple
operation and easier product work-up were achieved.
Keywords: Coumarins, green chemistry, knoevenagel condensation, L-lysine, water.
INTRODUCTION
Knoevenagel reaction in the synthesis of 3-substituted
coumarins [14]. Since L-proline is a useful catalyst in the
organic synthesis, we wonder that whether other ꢀ-amino
acids could have the same effect. To our delight, L-lysine,
which is very cheap, is found to have nearly the same
catalytic activity in water compared to L-proline. In this
paper, we mainly investigate the Knoevenagel condensation
reaction to prepare 3-substituted coumarins catalyzed by L-
lysine in water (Scheme 1).
Currently, green chemistry has gained much attention in
the areas of research and development in both industry and
academia. As we know, most of the chemical processes have
brought serious environmental problems and unexpected
harmful effects in the past. Therefore, finding a way to use
benign solvents and minimize the hazards to environment
has become significant in organic synthesis.
Coumarins are nowadays an important group of organic
compounds that are used as additives to food and cosmetics
[1], optical brightening agents [2] and dispersed fluorescent
and laser dyes [3]. Apart from this, coumarin derivatives are
widely used in pharmaceutical, fragrance, and agrochemical
industries [4]. In this regard, we have great interest to
develop an efficient method for the preparation of
coumarins. In the past decades, several synthetic routes for
the synthesis of coumarins have been developed such as
Pechmann, Perkin, Knoevenagel, Reformatsky, and Wittig
reactions [5]. Generally, the synthesis of 3-substituted
coumarins is particularly accomplished by the century old
Knoevenagel reaction consisting of the condensation
between 2-hydroxybenzaldehydes and active methylene
compounds. The reaction is originally catalyzed by weak
bases under homogeneous reaction conditions [6]. The
catalysts traditionally used for this reaction are ammonia,
primary or secondary amines. In recent years, many new
improved methods are known for the synthesis of coumarins
including transition metal catalysis [7], heterogeneous
catalysis [8], solid phase synthesis [9], ionic liquid approach
[10], solvent-free microwave irradiation [11], and grinding
techniques [12].
RESULTS AND DISCUSSION
Initially, in
a
model experiment,
a
mixture of
salicylaldehyde (2 mmol), ethyl acetoacetate (2 mmol) and
L-lysine (0.4 mmol) in water (2 mL) was stirred for 48 hours
in a 50 ml round bottomed flask at room temperature. A pale
yellow solid was gradually precipitated in the reaction
process, and after completion of the reaction (monitored by
TLC) the mixture was isolated by filtration to give 3-
acetylcoumarin successfully in 85% yield. No side products
were observed under these reaction conditions. The crude
solid thus obtained was recrystallized from ethanol to give
pure yellow crystal. Next, we focused on the optimization of
the reaction conditions, different amounts of L-lysine were
used at a variety of temperatures to obtain the best results.
As indicated in Table 1, the use of 20 mol% of L-lysine was
sufficient to get the best yield, when we increased the
catalyst amount, the yield was not improved but decreased,
and the reaction didn’t occur in the absence of L-lysine.
Furthermore, higher temperature was required to accelerate
the reaction, the time was largely shortened to 6 hours at
60˚C, and the yield was slightly increased from 85% to 86%.
To our knowledge, water is a green solvent for chemical
reactions because it is safe, non-toxic, environmentally
friendly, readily available and cheap compared to organic
solvents [13]. In addition, few articles have reported using
water as solvent in the synthesis of coumarins. In the
previous reports, L-proline has successfully catalyzed the
Further reactions with other 2-hydroxybenzaldehyde
derivatives and methylene compounds were conducted under
the optimized conditions to afford 3-substituted coumarins.
When we used Meldrum’s acid as reactant, coumarin-3-
carboxylic acids were obtained in moderate yields at room
temperature (Table 2, 3d, 3g, 3j and 3m). However, several
reactions were not carried out smoothly under these
conditions. It was probably due to the insolubility of
substrates in water. Therefore, higher temperature was
adopted to improve the reaction activity. The results were
*Address correspondence to these authors at the Department of Chemistry,
Zhengjiang University, Hangzhou 310027, P.R. China; Fax: (+86) 571-
87952379; E-mail: shangzc@zju.edu.cn
1570-1786/12 $58.00+.00
© 2012 Bentham Science Publishers

20
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
You et al.
O
O
O
O
CHO
R3
O
L-lysine
R2
OH
R1
O
H2O, r.t.-80 ˚C
R1
3
1
COOEt
2
R1 = H, OCH3,
Br, NO2
R2 = COMe, COOEt
R3 = COMe, COOEt, COOH
Scheme 1.
Table 1. Effect of Catalyst and Temperature on the Reaction of Salicylaldehyde with Ethyl Acetoacetatea
Entry
L-lysine (mol%)
Temperature (˚C)
Yield (%)b
1
2
0
5
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
60
80
0
35
57
85
78
79
63
82
86
72
3
10
20
40
50
100
20
20
20
4
5
6
7
8
9
10
aThe reaction was conducted with 2 mmol salicylaldehyde and 2 mmol ethyl acetoacetate in the present of L-lysine in 2 mL water; bIsolated yield after filtration.
summarized in Table 2. As can be seen from Table 2, an
electron-donating group such as a methoxy at 3-position of
2-hydroxybenzaldehyde increased the yield of coumarin
products (Table 2, 3e-3g). In contrast, the substrates with
electron-withdrawing substituents expressed lower activities
(Table 2, 3h-3m). In addition, 2-hydroxynapthaldehyde was
also tested under these conditions, but only trace of product
was isolated after column chromatography and some
polymeric by-products were existed with a longer reaction
time.
= 15.1, 8.0 Hz, 2H), 2.73 (s, 3H); IR (KBr)ꢁ1740, 1678,
1614, 1557, 1454, 1334, 1297, 1238, 1211, 977, 758, 639
cm-1; MS (ESI) m/z: 189.1 ([M+H])+.
Ethyl 2-oxo-2-H-chromene-3-carboxylate (3c)
1
Solid; mp 93–94˚C (lit. [11a] 92–93˚C); H NMR (400
MHz, CDCl3) ꢀ 8.51 (s, 1H), 7.79–7.48 (m, 2H), 7.30 (dd, J
= 19.2, 11.8 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.38 (t, J =
7.1 Hz, 3H); IR (KBr)：2979, 2925, 2908, 1777, 1764,
1616, 1607, 1564, 1451, 1375, 1296, 1247, 1207, 1131,
1033, 1023,983, 795, 775 cm-1; MS (ESI) m/z: 218.9
([M+H])+.
We also investigated the reusability of this system of
water and L-lysine. After the reaction was completed, the
product was isolated by simple filtration. Amazingly, the
aqueous solution could be reused without any loss of its
activity even after five runs (Table 3).
2-Oxo-2-H-chromene-3-carboxylix acid (3d)
In conclusion, we have developed a simple and efficient
method for the synthesis of 3-substituted coumarins via
knoevenagel reaction catalyzed by L-lysine in water. Beyond
this, the L-lysine used in this reaction is a reusable,
nonmetallic, and small-molecule organic catalyst. From a
green chemistry perspective, this environmentally benign
synthetic protocol is notably consistent with the
requirements of green chemistry.
1
Solid; mp 190–191˚C (lit. [8a] 190–191˚C); H NMR
(400 MHz, DMSO) ꢀ 8.71 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H),
7.75–7.60 (m, 1H), 7.37 (dd, J = 14.9, 7.6 Hz, 2H), 3.39 (s,
1H, br); IR (KBr): 3430, 3056, 1742, 1685, 1608, 1568,
1420, 1374, 1227, 1207, 1042, 799, 770, 644, 465 cm-1; MS
(ESI) m/z: 188.8 ([M-H])-.
3-Acetyl-8-methoxy-2-H-chromen-2-one (3e)
1
SPECTRAL DATA FOR THE PRODUCTS
3-Acetyl-2H-chromen-2-one (3a)
Solid; mp 175–176˚C (lit. [11a] 173–174˚C); H NMR
(400 MHz, CDCl3) ꢀ 8.48 (s, 1H), 7.27 (dd, J = 8.4, 7.3 Hz,
1H), 7.24–7.17 (m, 2H), 3.99 (s, 3H), 2.73 (s, 3H); IR (KBr):
1731, 1689, 1601, 1568, 1473, 1367, 1279, 1232, 1197,
1
Solid; mp 121–122˚C (lit. [11a] 124˚C); H NMR (400
MHz, CDCl3) ꢀ 8.52 (s, 1H), 7.70–7.63 (m, 2H), 7.36 (dd, J

A Green Method for the Synthesis of 3-Substituted Coumarins Catalyzed
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
21
Table 2. Synthesis of 3-Substituted Coumarins Via Knoevenagel Reaction in Watera
Yieldb
(%)
Substituted Salicylaldehyde
1
Methylene compound
2
Product
3
Entry
Time (h)
Temperature (˚C)
COMe
O
O
a
6
60
86
88
70
OEt
O
O
O
O
COMe
O
O
b
c
6
60
80
OMe
CHO
OH
O
COOEt
O
O
12
EtO
OEt
O
O
COOH
O
O
d
e
f
12
12
12
12
r.t.
80
80
r.t.
89
90
81
84
O
O
O
COMe
O
O
O
O
OEt
OMe
OMe
OMe
CHO
COOEt
O
O
O
OH
O
EtO
OEt
OMe
O
COOH
O
O
g
O
O
O
O2N
COMe
O
O
h
i
12
12
80
80
76
58
OEt
O
O
O2N
COOEt
O
O
O2N
CHO
OH
EtO
OEt
O
O
O
O2N
COOH
O
O
j
12
r.t.
50
O
O
O
Br
COMe
O
O
k
l
12
24
60
80
66
76
OEt
O
O
Br
COOEt
O
O
Br
CHO
OH
EtO
OEt
O
O
O
Br
COOH
O
O
m
24
r.t.
82
O
O
O
aThe reaction was conducted with 2 mmol 2-hydroxybenzaldehyde derivatives and 2 mmol methylene compounds in the present of 20 mol% L-lysine in 2 mL water; The reaction was
followed and monitored by TLC. When the reaction was completed, the solid product was filtrated, dried and recrystallized from an appropriate solvent. bIsolated yield after filtration.

22
Letters in Organic Chemistry, 2012, Vol. 9, No. 1
You et al.
Table 3. Recycling Experiments with L-lysinea
Run
1
2
3
4
5
Yield (%)b
86
85
84
85
84
aThe reaction was conducted with 2 mmol salicylaldehyde and 2 mmol ethyl acetoacetate in the present of 20 mol% L-lysine in 2 mL water; bIsolated yield after filtration.
1094, 950, 793, 763, 537 cm-1; MS (ESI) m/z: 219.0
([M+H])+.
1654, 1608, 1551, 1409, 1357, 1233, 1205, 1066, 980, 965,
831, 766 cm-1.
Ethyl 8-methoxy-2-oxo-2H-chromene-3-carboxylate (3f)
Ethyl 6-bromo-2-oxo-2H-chromene-3-carboxylate (3l)
1
1
Solid; mp 89–90˚C (lit. [11a] 88–90˚C); H NMR (400
Solid; mp 177–178˚C; H NMR (400 MHz, CDCl3) ꢀ
MHz, CDCl3) ꢀ 8.47 (s, 1H), 7.26–7.20 (m, 1H), 7.17–7.11
(m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 1.37 (t, J =
7.1 Hz, 3H); IR (KBr)：2974, 1766, 1756, 1609, 1572,
1480, 1375, 1271, 1243, 1210, 1187, 1138, 1100, 1035, 965,
790, 732 cm-1; MS (ESI) m/z: 249.0 ([M+H])+.
8.42 (s, 1H), 7.75–7.67 (m, 2H), 7.23 (d, J = 8.8 Hz, 1H),
4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); IR (KBr):
2973, 1753, 1701, 1617, 1598, 1560, 1466, 1408, 1367,
1290, 1265, 1240, 1210, 1069, 1023, 987, 840, 790 cm-1; MS
(ESI) m/z: 298.9 ([M+H] +, Br81), 296.9 ([M+H] +, Br79).
8-Methoxy-2-oxo-2H-chromene-3-carboxylic acid (3g)
6-bromo-2-oxo-2H-chromene-3-carboxylic acid (3m)
1
1
Solid; mp 227–228˚C (lit. [8a] 218–219˚C); H NMR
Solid; mp 203–204˚C; H NMR (400 MHz, DMSO) ꢀ
(400 MHz, DMSO) ꢀ 13.29 (s, 1H, br), 8.71 (s, 1H), 7.42
(dd, J = 16.5, 7.8 Hz, 2H), 7.33 (t, J = 7.9 Hz, 1H), 3.92 (s,
3H); IR (KBr): 3435, 2947, 2842, 1773, 1741, 1676, 1605,
1571, 1479, 1459, 1438, 1379, 1277, 1259, 1215, 1195,
1097, 960, 801, 742, 706 cm-1; MS (ESI) m/z: 218.9 ([M-
H])-.
13.42 (s, 1H, br), 8.67 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.85
(dd, J = 8.8, 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H); IR (KBr):
3098, 3045, 1762, 1673, 1611, 1593, 1557, 1493, 1417,
1364, 1281, 1221, 1200, 1146, 1069, 1030, 980, 822, 798,
733, 664 cm-1; MS (ESI) m/z: 268.7 ([M-H])-.
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A Green Method for the Synthesis of 3-Substituted Coumarins Catalyzed
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