Knoevenagel reaction in [MMIm][MSO4]: Synthesis of coumarins

Article abstract of DOI:10.3390/molecules16064379

The ionic liquid 1,3-dimethylimidazolium methyl sulfate, [MMIm][MSO ₄], together with a small amount of water (the amount taken up by the ionic liquid upon exposure to air), acts efficiently as both solvent and catalyst of the Knoevenagel condensation reactions of malononitrile with 4-substituted benzaldehydes, without the need for any other solvent or promoter, affording yields of 92%-99% within 2-7 min at room temperature. When L-proline is used as an additional promoter to obtain coumarins from o- hydroxybenzaldehydes, the reaction also proceeds in high yields. Work-up is very simple and the ionic liquid can be reused several times. Some of the coumarins obtained are described for the first time.

Full text of DOI:10.3390/molecules16064379

Molecules 2011, 16, 4379-4388; doi:10.3390/molecules16064379
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Articles
Knoevenagel Reaction in [MMIm][MSO4]:
Synthesis of Coumarins
Pedro Verdía, Francisco Santamarta and Emilia Tojo *
Department of Organic Chemistry, Faculty of Chemistry, University of Vigo, 36310 Vigo, Spain;
E-Mails: pedroverdia@uvigo.es (P.V.); bor164@uvigo.es (F.S.)
* Author to whom correspondence should be addressed; E-Mail: etojo@uvigo.es;
Tel.: +34-986-812290; Fax: +34-986-812262.
Received: 26 April 2011; in revised form: 18 May 2011 / Accepted: 19 May 2011 /
Published: 27 May 2011
Abstract: The ionic liquid 1,3-dimethylimidazolium methyl sulfate, [MMIm][MSO4],
together with a small amount of water (the amount taken up by the ionic liquid upon
exposure to air), acts efficiently as both solvent and catalyst of the Knoevenagel
condensation reactions of malononitrile with 4-substituted benzaldehydes, without the need
for any other solvent or promoter, affording yields of 92%–99% within 2–7 min at room
temperature. When L-proline is used as an additional promoter to obtain coumarins from
o-hydroxybenzaldehydes, the reaction also proceeds in high yields. Work-up is very simple
and the ionic liquid can be reused several times. Some of the coumarins obtained are
described for the first time.
Keywords: ionic liquid; Knoevenagel reaction; synthesis; coumarins
1. Introduction
The Knoevenagel condensation [1] is one of the most useful C=C bond forming reactions in organic
synthesis [2]. The α,β-unsaturated products obtained have been widely used as intermediates in the
synthesis of therapeutic drugs [3], natural products [4], functional polymers [5], fine chemicals [6],
herbicides and insecticides. It is generally performed in organic solvents and catalysed by organic
bases such as piperidine or pyridine [2]. Many of this conditions are associated with disadvantages
such as hazardous and carcinogenic solvents and unrecoverability of the catalysts, which limit the use
of these reactions in industrial processes.

Molecules 2011, 16
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Over the past decade, ionic liquids (ILs) have attracted great interest because of their unusual
properties, including negligible vapour pressure, broad liquid temperature range, and high capacity as
specific solvents [7]. Their use in place of hazardous volatile organic solvents makes organic synthesis
environmentally benign [8]. In recent years they have been used in a number of Knoevenagel reactions
as solvents and/or catalysts with considerable success [9-11], often accelerating the reaction, making
work-up easier, and allowing their recycling [12-14]. In this work we have found that [MMIm][MSO4]
containing a small amount of water, without any other promoter, can act efficiently as the reaction
medium and catalyst of the Knoevenagel condensation of 4-substituted benzaldehydes. We report here
the results of optimizing the amount of water in the medium and of applying this reaction to the
synthesis of coumarins.
2. Results and Discussion
2.1. Knoevenagel Condensation of Benzaldehyde and Malononitrile
In direct continuation of our earlier research [15], we investigated whether anhydrous
[MMIm][MSO4] could act as both solvent and catalyst (Scheme 1). The IL was prepared and
1
characterized by H-NMR and FABMS, as we described in a previous paper [16]. The experimental
procedure for the Knoevenagel reaction was very simple: A mixture of benzaldehyde, malononitrile
and anhydrous IL was stirred at r.t., and the product was extracted from the reaction medium with
ethyl acetate. The result is shown in Table 1, run 1.
Scheme 1. Knoevenagel condensation in [MMIm][MSO4]/H2O.
Table 1. Effect of water on the Knoevenagel reaction in [MMIm] [MSO4].
Run a
Time[min] Yield [%] b % H2O
1
2
3
4
5
6
7
8
1080
2
2
2
8
10
11
300
40
99
98
97
93
86
83
81
-
2
5
10
15
25
50
90
a All runs were conducted at r.t.; b Yields refer to pure isolated product.
Since water can significantly influence the physicochemical properties of ionic liquids, the reaction
was repeated using [MMIm][MSO4] and 25% water. Gratifyingly, the reaction time decreased to 10 min
and the yield increased to 86%. We accordingly undertook to optimize the proportions of IL and water.

Molecules 2011, 16
4381
As Table 1 shows, best results (2 min, 99%) were obtained with 2% of water; water contents
higher than 10% led to increasingly longer reaction times and lower yields. 2-(Phenylmethylene)
malononitrile (1) was obtained as a pure white solid that was identified by comparison of its physical
and spectroscopic data with those reported in the literature [17].
The effect of water in these reactions is attributable in part to its lubricating action, i.e., to its effect
in reducing viscosity by decreasing the coulombic interactions between cation and anion in the IL [18],
thereby allowing the ions greater translational and rotational freedom. Furthermore, the decrease in
coulombic interactions is largely due to hydrogen bonding with anions [19,20] that should favor the
catalytic effect of the IL, which is attributable to hydrogen-bonding between the imidazolium H-2
atom and the carbonyl group of the benzaldehyde [21,22].
Knowing that [MMIm][MSO4] absorbs 2.16% of water when exposed to the atmosphere (water
content was determined using a Karl Fischer 756 coulometer), we then used the IL without drying
and without adding either water or any other promoter. To evaluate the influence of recycling on the
efficiency of undried [MMIm][MSO4], the ethyl acetate used to extract the reaction product was
evaporated under vacuum and the medium was reused for the same reaction. After a total of six such
cycles, yield was still high (96%), though the reaction time had increased to 4 h (Table 2).
Table 2. Reused of undried [MMIm][MSO4] (2.16% H2O) in successive reaction cycles.
Cycle a
Time[min]
Yield [%] b
1
2
3
4
5
6
2
12
19
50
70
240
99
99
99
98
99
96
a All runs were conducted at r.t.; b Yields referred to pure isolated product.
2.2. Knoevenagel Condensation with Different Substrates
To investigate the scope of the reaction by using undried [MMIm][MSO4] as solvent and catalyst, it
was carried out using variously substituted benzaldehydes to obtain compounds 2a–d (Scheme 2,
Table 3). Products with spectral and physical data in agreement with previously reported values were
obtained in yields of 92%–99% and in reaction times that ranged from 3 to 7 min.
2.3. Synthesis of Coumarins
To apply the process to the synthesis of coumarins, we first tried to condense o-hydroxybenzaldehyde
with dimethyl malonate in undried [MMIm][MSO4], with no other promoter, to obtain 3-(methoxy-
carbonyl)coumarin (3, Scheme 3). However, after 18 h at 90 °C, no product had been formed (Table 4,
run 1). By contrast, when the reaction was run in undried IL with L-proline as promoter, compound 3
could be extracted with ethyl acetate as a white solid that was positively identified by comparison of its
physical and spectroscopic data with those reported in the literature [24]. Best results were obtained
using 1 equiv. of L-proline at 90 °C, which afforded a yield of 98% in 30 min (Table 4).

Molecules 2011, 16
Scheme 2. Knoevenagel condensations in undried [MMIm][MSO4].
4382
Table 3. Knoevenagel condensations in undried [MMIm][MSO4] (2.16% H2O) as solvent
and catalyst a.
Entry
R
Cl
NMe2
OMe
Me
Time [min] Yield [%] Product References
1
2
3
4
5
7
3
5
99
98
92
98
2a
2b
2c
2d
[9]
[23]
[9]
[23]
a
All reactions were performed at r.t. following the same procedure as for the
reaction of benzaldehyde with malononitrile.
Scheme 3. Synthesis of 3-(methoxycarbonyl)coumarin (3) in undried [MMIm][MSO4].
Table 4. Synthesis of 3-(methoxycarbonyl)coumarin (3) in undried [MMIm][MSO4] with
or without L-proline as promoter.
L-proline
[equiv.]
Run
T [°C] Time [h] Yield [%]
1
2
3
4
5
6
-
0.2
0.5
1
1
1
90
90
90
90
70
50
18
4.5
1
0.5
2
-
96
90
98
90
80
6
A wide range of aromatic o-hydroxybenzaldehydes underwent condensations with a variety of
active methylene compounds by this procedure to provide the corresponding coumarins as pure solids
in one-pot and high yields (Scheme 4, Table 5).
1
Their structures were characterized by IR, H-NMR, 13C-NMR and MS and confirmed by
comparison of its physical and spectroscopic data when those where previously reported. All the
reactions were in general fast and clean. The results are summarized in Table 5. The coumarins
obtained in entries 5, 7, 11, 13, 14 and 15 have not been previously described. Subsequent
desulfonylation of coumarins 14, 15 and 17 will allow obtaining a series of coumarins present in
sesquiterpenes with very important pharmacological properties, such as galvanic acid [25].

Molecules 2011, 16
Scheme 4. Synthesis of coumarins in undried [MMIm][MSO4] containing L-proline.
4383
Table 5. Synthesis of coumarins in undried [MMIm][MSO4] containing L-proline (1 equiv.) a.
Entry
1
X
H
H
H
H
Y
H
H
H
H
H
H
H
H
R
R’
Time [min] Yield [%] b References
CO2Me
COMe
CO2Et
COPh
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Me
CO2Me
30
15
98
99
98
97
87
88
94
87
90
94
99
99
96
99
93
92
99
[24]
[26,27]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
80
[28,29]
360
90
[30]
-
6-CH3
6-CH3
8-CH3
6-OMe
7-OMe
8-OMe
6-Br
5,6-benzo
H
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
SO2Me
SO2Me
SO2Me
SO2Ph
SO2Ph
30
[31]
70
-
15
[32,33]
H
H
70
[29]
30
[32]
8-OMe
H
15
-
90
[34]
H
H
H
H
90
-
7-OH
7-Br
H
480
360
1440
1140
-
-
[35,36]
[35]
7-OH
H
a All runs were conducted at 90 °C; b Yields refer to pure isolated products.
Evaluation of recycling performance showed that the mixture of undried [MMIm][MSO4] and
L-proline can be reused at least four times without loss of yield, though the reaction time increased to 6 h
(Table 6).
An attractive feature of the methods described above is that [MMIm][MSO4] is easy to prepare; is
one of the least expensive ILs; has desirable physical properties such as good thermal stability and low
viscosity; and, unlike some other ILs, has low cytotoxicity [37].
Table 6. Reuse of undried [MMIm][MSO4] + L-proline (1 equiv.) in successive cycles of
3-(methoxycarbonyl)coumarin (3) synthesis.
Run a
Time [h]
Yield [%] b
1
2
3
4
5
0.5
1
3
5
6
98
98
98
98
98
a All runs were conducted at 90 °C; b Yields refer to pure isolated products.

Molecules 2011, 16
4384
3. Experimental
3.1. General
Reagents were purchased from Aldrich and used as received. IR spectra were recorded on a
MIDAC Prospect FT-IR spectrophotometer. NMR spectra were recorded on a Brucker ARX 400 with
chemical shifts given in ppm and coupling constants in Hertz. Electrospray MS were recorded on a
micrOTOF FOCUS spectrometer. Melting points were measured with a Gallenkamp apparatus.
3.2. General Procedure for Knoevenagel Condensation of Benzaldehyde with Malononitrile
A mixture of benzaldehyde (0.065 g, 0.61 mmol) and malononitrile (0.040 g, 0.61 mmol) in
[MMIm][MSO4] + water (2 mL) was stirred in a round-bottomed flask until completion of the reaction
as indicated by TLC (eluent: 4:1 hexane:AcOEt). The reaction mixture was then extracted with ethyl
acetate (3 × 2 mL), and the pooled organic extract was concentrated under vacuum, affording a pure solid.
3.3. Recycling of Undried [MMIm][MSO4] (2.16% H2O) in the Knoevenagel Reaction of Benzaldehyde
with Malononitrile
Reaction and work-up as above afforded a solid that required no further purification. The reaction
medium was recovered by evaporation of ethyl acetate under vacuum, and was reused.
3.4. General Procedure for the Synthesis of Coumarins
A mixture of salicylaldehyde (0.146 g, 1.2 mmol), dimethyl malonate (0.158 g, 1.2 mmol) and
L-proline (0.156 g, 1.2 mmol) in undried [MMIm][MSO4] (2 mL) was stirred in a round-bottomed
flask until completion of the reaction as indicated by TLC (eluent: 8:2 hexane:AcOEt). The reaction
mixture was then extracted with ethyl acetate (3 × 2 mL), and the pooled organic extract was
concentrated under vacuum, affording a pure solid.
3.5. Recycling of Undried [MMIm][MSO4] (2.16% H2O) + L-Proline in the the Synthesis of
3-(Methoxycarbonyl)coumarin (entry 1, Table 4)
Reaction and work-up as above afforded a solid that required no further purification. The reaction
medium was recovered by evaporation of ethyl acetate under vacuum, and was reused.
3-(Methoxycarbonyl)-6-methyl-2H-chromen-2-one (Entry 5, Table 5): The reaction of 2-hydroxy-5-
methylbenzaldehyde (0.163 g, 1.2 mmol), dimethyl malonate (0.158 g, 1.2 mmol) and L-proline (0.156 g,
1.2 mmol) in undried [MMIm][MSO4] (2 mL) afforded the corresponding product; yield: 0.220 g
(87%); white crystals (EtOH); mp 127–128 °C; 1H-NMR (400 MHz, CDCl3, ppm) δ 8.53 (s, 1H), 7.47
13
(dd, J = 1.8, 8.1 Hz, 1H), 7.40 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H), 2.44 (s, 3H); C-NMR
(100.6 MHz, CDCl3, ppm) δ 163.8, 157.0, 153.4, 149.2, 135.7, 134.8, 129.2, 117.7, 117.6, 116.5, 52.9,
20.7; νmax(NaCl)/cm−1 3034, 2942, 2844, 1755; Electrospray MS (micrOTOF Focus) m/z (%) 241
[M + Na+] (52), 220 [M + H+ + 1] (13), 219.06575 [M + H+] (C12H11O4 requires 219.06519, 100), 203
(30), 189 (18), 171 (17).

Molecules 2011, 16
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3-(Methoxycarbonyl)-8-methyl-2H-chromen-2-one (Entry 7, Table 5): The reaction of 2-hydroxy-3-
methyl-benzaldehyde (0.163 g, 1.2 mmol), dimethyl malonate (0.158 g, 1.2 mmol) and L-proline
(0.156 g, 1.2 mmol) in undried [MMIm][MSO4] afforded the corresponding product; yield: 0.245 g
1
(94%); yellow needles (EtOH); mp 106–107 °C; H-NMR (400 MHz, CDCl3, ppm) δ 8.56 (s, 1H),
7.51 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 3.97 (s, 3H), 2.48 (s, 3H);
13C-NMR (100.6 MHz, CDCl3, ppm): 163.9, 156.9, 153.6, 149.6, 135.7, 127.2, 126.4, 124.4, 117.6,
117.4, 52.9, 15.4; νmax(NaCl)/cm−1 3051, 2953, 2847, 1761; Electrospray MS (micrOTOF Focus) m/z
(%) 257 [M + K+] (7), 242 [M + Na+ + 1] (8), 241 [M + Na+] (65), 220 [M + H+ + 1] (17), 219.06524
[M + H+] (C12H11O4 requires 219.06519, 100), 201 (9), 187 (29), 175 (4).
6-Bromo-8-methoxy-3-(methoxycarbonyl)-2H-chromen-2-one (Entry 11, Table 5): The reaction of
5-bromo-2-hydroxy-3-methoxybenzaldehyde (0.231 g, 1 mmol), dimethyl malonate (0.132 g, 1 mmol)
and L-proline (0.130 g, 1 mmol) in undried [MMIm][MSO4] (2 mL) afforded the corresponding
1
product; yield: 0.310 g (99%); white powder (EtOH); mp 209–210 °C; H-NMR (400 MHz, CDCl3,
ppm) δ 8.45 (s, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H);
13C-NMR (100.6 MHz, CDCl3, ppm) δ 163.4, 155.5, 148.0, 147.7, 144.0, 122.5, 119.3, 119.2, 118.8,
117.1, 56.6, 53.1; νmax(NaCl)/cm−1 3080, 2965, 1761; Electrospray MS (micrOTOF Focus) m/z (%)
337 [M + Na+ + 2] (59), 335 [M + Na+] (60), 315 [M + H+ + 2] (43), 312.97004 [M + H+] (C12H10BrO5
requires 312.97061, 38), 259 (17), 233 (11), 203 (100), 189 (84), 175 (50), 171 (26), 159 (15), 157 (9).
3-(Methylsulfonyl)-2H-chromen-2-one (Entry 13, Table 5): The reaction of salicylaldehyde (0.183 g,
1.5 mmol), ethyl methylsulfonyl acetate (0.166 g, 1 mmol) and L-proline (0.130 g, 1 mmol) in undried
[MMIm][MSO4] (2 mL) afforded the corresponding product; yield: 0.3214 g (96%); white needles
1
(EtOH); mp 184–185 °C; H-NMR (400 MHz, CDCl3, ppm) δ 8.67 (s, 1H), 7.76 (m, 2H), 7.45 (t,
J = 8.1 Hz, 2H), 3.36 (s, 3H); 13C-NMR (100.6 MHz, CDCl3, ppm) δ 156.0, 155.3, 147.6, 135.5, 130.4,
127.6, 125.6, 117.2, 117.1, 41.7; νmax(NaCl)/cm−1 3052, 2933, 1743; Electrospray MS (micrOTOF
Focus) m/z (%) 248 [M + Na+ + 1] (14), 247 [M + Na+] (87), 226 [M + H+ + 1] (10), 225.02098
[M + H+] (C12H9O4S requires 225.02161, 100).
7-Hydroxy-3-(methylsulfonyl)-2H-chromen-2-one (Entry 14, Table 5): The reaction of 2,4-hydroxy-
benzaldehyde (0.154 g, 1.1 mmol), ethyl methylsulfonyl acetate (0.182 g, 1.1 mmol) and L-proline
(0.142 g, 1.1 mmol) in undried [MMIm][MSO4] (2 mL) afforded the corresponding product; yield:
1
0.260 g (99%); yellow needles (EtOH); mp 295–296 °C; H-NMR (400 MHz, MeOD, ppm) δ 8.65
(s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 6.91 (dd, J = 2.2, 8.6 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 3.29 (s, 3H);
13C-NMR (100.6 MHz, MeOD, ppm) δ 166.8, 159.3, 158.4, 149.4, 133.7, 123.4, 115.9, 111.6, 103.5,
42.0; νmax(NaCl)/cm−1 3297, 3062, 2933, 1712; Electrospray MS (micrOTOF Focus) m/z (%) 263
(M + Na+) (100), 241.01573 (M + H+), (C10H9O4S requires 241.01652, 80), 225 (22), 201 (60).
7-Bromo-3-(methylsulfonyl)-2H-chromen-2-one (Entry 15, Table 5): The reaction of 4-bromo-2-
hydroxy-benzaldehyde (0.151 g, 0.75 mmol), ethyl methylsulfonyl acetate (0.083 g, 0.5 mmol) and
L-proline (0.065 g, 0.5 mmol) in undried [MMIm][MSO4] (2 mL) afforded the corresponding product;
1
isolated yield: 0.141 g (93%); yellow powder (EtOH); mp 254–255 °C; H-NMR (400 MHz, CDCl3,
13
ppm) δ 8.61 (s, 1H), 7.65 (s, 1H), 7.58 (s, 2H), 3.35 (s, 3H); C-NMR (100.6 MHz, CDCl3, ppm)

Molecules 2011, 16
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δ 155.3, 155.2, 146.8, 131.0, 130.3, 129.3, 127.7, 120.5, 115.9, 41.7; νmax(NaCl)/cm−1 3066, 2927,
1749; Electrospray MS (micrOTOF Focus) m/z (%) 327 (M + Na+ + 2) (84), 325 (M + Na+) (64), 305
(M + H+ + 2) (88), 302.93216 (C10H8O4SBr requires 302.93212) (100), 201 (56).
4. Conclusions
1,3-Dimethylimidazolium methyl sulfate, [MMIm][MSO4], an inexpensive, easily prepared,
low-viscosity ionic liquid with low cytotoxicity, can act efficiently as the solvent and catalyst of
Knoevenagel condensation reactions between 4-substituted benzaldehydes and active methylene
compounds without any promoter other than a small amount of water (≈2%) such as can be introduced
simply by exposure to air; these reactions are clean and are completed at room temperature within a
few minutes, work-up is simple, and the reaction medium can be reused several times without
significant reduction in yield. When used to cyclize o-hydroxybenzaldehydes with active methylene
compounds to obtain coumarins it was necessary to use L-proline as promoter: Heating the reagents
and promoter at 90 °C in undried [MMIm][MSO4] afforded high yields of the desired coumarins.
Some of the coumarins are described for the first time.
Acknowledgments
We thank the Ministry of Education and Science of Spain (CTQ2007-61788 national project) and
the Xunta de Galicia (PGIDIT04BTF301031PR) for financial support.
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Sample Availability: Samples of all the compounds are available from the authors.
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