Et3N catalyzed cascade reaction of Meldrum’s acid with ortho-hydroxyaryl aldehydes for the synthesis of coumarin-3-carboxylic acids under solvent-less condition

Article abstract of DOI:10.1007/s11164-016-2517-8

Abstract: The synthesis of coumarin-3-carboxylic acids in good yields is realized through a triethylamine catalyzed Knoevenagel-intramolecular cyclization tandem reaction of Meldrum’s acid with various ortho-hydroxyaryl aldehydes. This method expands the catalyst library about the synthesis of coumarin-3-carboxylic acids and also has advantages of using much less water as solvent, a cheap and eco-friendly catalyst, clean reaction conditions, simple workup procedure and easy isolation. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2517-8

Res Chem Intermed
DOI 10.1007/s11164-016-2517-8
Et3N catalyzed cascade reaction of Meldrum’s acid
with ortho-hydroxyaryl aldehydes for the synthesis
of coumarin-3-carboxylic acids under solvent-less
condition
Wan-Yu¨ Pan1 Yu¨-Meng Xiao1 Hou-Qing Xiong1
Cheng-Wei Lu¨1
•
•
•
Received: 2 February 2016 / Accepted: 12 March 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract The synthesis of coumarin-3-carboxylic acids in good yields is realized
through a triethylamine catalyzed Knoevenagel-intramolecular cyclization tandem
reaction of Meldrum’s acid with various ortho-hydroxyaryl aldehydes. This method
expands the catalyst library about the synthesis of coumarin-3-carboxylic acids and also
has advantages of using much less water as solvent, a cheap and eco-friendly catalyst,
clean reaction conditions, simple workup procedure and easy isolation.
Graphical Abstract
Keywords Coumarin-3-carboxylic acids Á Triethylamine Á Water Á
Environmentally friendly
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2517-8)
contains supplementary material, which is available to authorized users.
&
Cheng-Wei Lu¨
chengweilv@126.com
1
School of Chemistry and Chemical Engineering, Liaoning Normal University,
Dalian 116029, People’s Republic of China
123

W.-Y. Pan et al.
Introduction
Over the past few decades, the synthesis of coumarin and its derivatives has
attracted considerable attention from organic and medicinal chemists due to
coumarin (2-oxo-2H-1-benzopyran) heterocyclic moiety being a ‘‘privileged’’
structural motif both in numerous natural products and synthetic organic compounds
of potential pharmacological activities [1–6]. They are also key components for
flavoring of a diverse set of foods [7–11]. Coumarin-3-carboxylic acids are key
precursors for the synthesis of coumarins and also act as vital building blocks of
various natural and semisynthetic pharmacological agents [12]. Because of these
advantages of coumarin-3-carboxylic acids, the search for new and more convenient
methods to accomplish their synthesis is desirable and significant [13]. Several
routes have been reported in the literature for the synthesis of coumarin-3-
carboxylic acid derivatives [14–16]. The Knoevenagel condensation of ortho-
hydroxyarylaldehydes with Meldrum’s acid is one of the simplest methiods because
of several advantages in terms of yields, reaction times and purification of adducts
[17, 18]. Many catalysts like sodium hydroxide [19], ammonium acetate [20, 21],
heteropolyacids [8], potassium phosphate [22], SnCl2Á2H2O [23], FeCl3 [24], clays
[25], lithium salts [26], Yb(OTf)3 [13], silica sulfuric acid [16], K2CO3 or NaN3
[18], and acacic acid [27], coupled with a variety of conditions such as solvent-free,
heating, grinding, microwave irradiation and so on, have been utilized. 3-Carboxy-
coumarins can also be prepared from Meldrum’s acid and salicylaldehyde by
carrying out the reaction in water, avoiding the addition of any catalyst [28, 29].
Although a series of developments and modifications has been achieved, the limited
number of substrates, long reaction time, low yields, tedious workup procedures, co-
occurrence of several side reactions, use of large amount of organic solvents and
need of chromatography for the purification of adducts are problematic [27, 29].
Consequently, there is ample room for further development of milder reaction
conditions, better yields and increased variation in the substituent of both
components [18].
Nowadays, environmental concerns have directly influenced the development of
new methodologies [30]. The solvent-less reaction is an important synthetic
procedure from the view point of green and sustainable chemistry [31]. Triethy-
lamine (Et3N) is a mild and cheap base, but plays an important role in accelerating
the organic reactions [32, 33]. In connection with our efforts to develop mild and
environmentally friendly methods as well as our interest in the application of
Meldrum’s acid to the synthesis of useful organic molecules [34, 35], we report here
the results of our recent efforts devoted to the reaction of 2-hydroxybenzaldehydes
Scheme 1 The preparation of coumarin-3-carboxylic acid
123

Et3N catalyzed cascade reaction of Meldrum’s acid with…
with Meldrum’s acid utilizing Et3N as an efficient and cheap catalyst under solvent-
less condition to afford coumarin-3-carboxylic acid (Scheme 1).
Experimental
General
Unless otherwise stated, all reagents were obtained from commercial sources and
were used without further purification. Melting points were determined on a Beijing
Tech X-5 Melting point detector and were uncorrected. The IR spectra were
1
measured with a Bruker Shimadzu IR-460 spectrometer. H and 13C NMR spectra
were recorded on a Bruker Avance III 400 MHz. The chemical shifts (d) were
reported in parts per million (ppm) and coupling constants (J) in Hertz.
Typical experimental procedure for synthesis of 3
A mixture of Meldrum’s acid (0.5 mmol) and salicylaldehydes (0.55 mmol) was
placed in a 10-mL Schlenk tube, then Et3N (0.015 mmol) and 50 lL water were
Table 1 The screening of reaction conditions
Entrya
Catalyst (mol%)
Solvent
Reaction
temperature (°C)
Time (h)
Yieldb (%)
1
Et3N (30 %)
DIPEA (30 %)
DBU (30 %)
DABCO (30 %)
Et3N (50 %)
Et3N (20 %)
Et3N (30 %)
Et3N (30 %)
Et3N (30 %)
Et3N (30 %)
Et3N (30 %)
Neat
–
60
60
60
60
60
60
50
70
60
60
60
60
60
60
60
60
6
6
6
6
6
6
6
6
6
6
6
6
6
6
4
2
80
38
69
78
81
62
75
68
86
81
77
56
90
79
90
63
2
–
3
–
4
–
5
–
6
–
7
–
8
–
9
Water 50 lL
Water 100 lL
Water 25 lL
Water 50 lL
Water 50 lL
Water 50 lL
Water 50 lL
Water 50 lL
10
11
12
13c
14d
15
16
a
Et3N (30 %)
Et3N (30 %)
Et3N (30 %)
Et3N (30 %)
The reactions were carried out with salicylaldehyde and Meldrum’s acid in equimolecular amounts of
0.5 mmol
b
Isolated yield
c
Salicylaldehyde 0.55 mmol
d
Meldrum’s acid 0.55 mmol
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W.-Y. Pan et al.
added. The reaction mixture was stirred at the indicated temperature for 4 h. After
completion of the reaction, 3 mL aqueous ethanol was added to the mixture and
vigorously stirred for a moment. The pH was adjusted to 2–3 with dilute
hydrochloric acid. Finally, the precipitate was separated by filtration and washed
Table 2 Substrate scope for the synthesis of 3-carboxycoumarins
Entrya
Product
Reaction
temperature (°C)
Yieldb (%)
90
m.p. (°C)
1
60
85
85
85
70
60
188–190
(188–190 [28])
3a
2
3
4
5
6
23
90
85
90
93
230–232
(232–234 [18])
3b
201–202
(194–196 [28])
3c
158–160
(122–123 [18])
3d
163–165
(167–168 [28])
3e
199–201
(193–195 [28])
3f
7
8
60
60
92
268–270
(260–262 [18])
3g
3h
3i
Trace
9
60
85
36
90
201–203
(206–208 [18])
10
239–241
(216–218 [28])
3j
a
The reactions were carried out with salicylaldehyde/Meldrum’s acid (0.55 mmol/0.5 mmol) under
solvent-less condition
b
Isolated yield
123

Et3N catalyzed cascade reaction of Meldrum’s acid with…
with aqueous ethanol without further purification to afford the corresponding pure
adducts.
Results and discussion
In view of the low melting points of the precursors 1 and 2, solvent-free conditions
were attempted. We started our research by carrying out the condensation of
salicylaldehyde with Meldrum’s acid in equimolecular amounts of 0.5 mmol, and
different organic bases were tested to evaluate their ability to promote the reaction
at 60 °C for 6 h (Table 1). It was found that when triethylamine was used as the
catalyst (Table 1, entry 1), the highest yield of the product (80 % yield) was
obtained, and triethylenediamine (DABCO) (Table 1, entry 4) also had good
catalytic ability (78 % yield), but N,N-diisopropylethylamine (DIPEA) gave a
modest result (Table 1, entry 2). Then, we optimized the amount of Et3N required
for this reaction (Table 1, entries 5, 6), and the best load was found to be 30 mol%
(Table 1, entry 1). The effect of the temperature on the reaction was also examined
and the results show that reacted at 60 °C was a feasible option. Further raising or
lowering the temperature is detrimental to the reaction (Table 1, entries 7, 8). As we
know, water can promote the condensation of Meldrum’s acid with aldehydes
avoiding the addition of any catalyst [36] and exhibits unique reactivity in the
reaction of 2-hydroxybenzaldehydes with Meldrum’s acid for the synthesis of
coumarin-3-carboxylic acids [28, 29]. Thus, the effect of adding a little water as
solvent was surveyed (Table 1, entries 9–11). After some experimentation, we were
pleased to find that adding 50 lL water could improve the yield (Table 1, entry 9).
A control experiment without base was also examined in order to recognize the
capability of the Et3N (Table 1, entry 12). The model reaction gave an
unsatisfactory result, which supported the accelerating activity of Et3N. Further,
we examined the fate of varying the ratio of substrates. A better conversion of
reactants to afford the desired product in 90 % yield was observed when employing
1.1 equiv. of salicylaldehyde (Table 1, entry 13). The effect of the reaction time was
also surveyed and the time decreased to 4 h (Table 1, entry 15). Continuously
shortening the reaction time was unfavorable (Table 1, entry 16). So it is clear that
the optimum conditions are salicylaldehyde and Meldrum’s acid in a ratio of 1.1:1
and using 30 mol% Et3N and 50 lL water (550 mol%) as accelerant at 60 °C for
4 h.
With the optimized reaction conditions in hand, we decided to explore the
condensation reaction of Meldrum’s acid with various structural diverse salicy-
laldehydes, and products were obtained in moderate to good yields. As shown in
Table 2, the electronic density of the benzene ring would play an important role in
the reaction. Introduction of a strongly electron-withdrawing group on the benzene
ring reduced the yield of the reaction. Particularly, when employing 5-nitrosalicy-
laldehyde or 3,5-dichlorosalicylaldehyde as substrate, poor yield or little product
was obtained (Table 2, entries 2, 8). On the other hand, the electron-rich aromatic
aldehydes were transformed into the corresponding products in similar or a slightly
higher yield than that of salicylaldehyde (Table 2, entries 5–7). Additionally,
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W.-Y. Pan et al.
naphthyl-based salicylaldehyde also reacted successfully in this process to form the
desired product in 90 % yield (Table 2, entry 10).
Conclusions
In summary, we have successfully elaborated a convenient and environmentally
benign reaction to afford a series of coumarin-3-carboxylic acids with moderate to
good yields. The combination of triethylamine (30 mol%) with 50 lL water plays a
unique role in this reaction. Solvent-less, mild and clean reaction conditions, simple
workup procedure and using an inexpensive catalyst are the best features in this
process.
Acknowledgments We are grateful for financial support from the National Natural Science Foundation
of China (21403100) and Liaoning Province, the Doctoral Scientific Research Foundation (20141100).
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