Diethylene glycol-bis(3-methylimidazolium) dihydroxide as a dicationic ionic liquid catalyst for the synthesis of 4H-pyrane derivatives in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2015.12.034

Diethylene glycol-bis(3-methylimidazolium) dihydroxide [DiEG(mim)₂][OH]₂ was prepared by the reaction between sodium hydroxide and diethylene glycol-bis(3-methylimidazolium) dibromide in aqueous ethanol at room temperature. This soli

Full text of DOI:10.1016/j.tetlet.2015.12.034

Accepted Manuscript
Diethylene glycol-bis(3-methylimidazolium) dihydroxide as a dicationic ionic
liquid catalyst for the synthesis of 4H-pyrane derivatives in aqueous medium
Khodabakhsh Niknam, Mohsen Khataminejad, Fariba Zeyaei
PII:
S0040-4039(15)30449-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.034
TETL 47081
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 June 2015
23 November 2015
7 December 2015
Please cite this article as: Niknam, K., Khataminejad, M., Zeyaei, F., Diethylene glycol-bis(3-methylimidazolium)
dihydroxide as a dicationic ionic liquid catalyst for the synthesis of 4H-pyrane derivatives in aqueous medium,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.034
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Diethylene glycol-bis(3-methylimidazolium)
dihydroxide as a dicationic ionic liquid
catalyst for the synthesis of 4H-pyrane
derivatives in aqueous medium
Leave this area blank for abstract info.
Khodabakhsh Niknam,* Mohsen Khataminejad, Fariba Zeyaei
Chemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr, 75169, Iran

1
Tetrahedron Letters
Diethylene glycol-bis(3-methylimidazolium) dihydroxide as a dicationic ionic liquid
catalyst for the synthesis of 4H-pyrane derivatives in aqueous medium
Khodabakhsh Niknam,* Mohsen Khataminejad, Fariba Zeyaei
Chemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Diethylene glycol-bis(3-methylimidazolium) dihydroxide [DiEG(mim)2][OH]2 was prepared by
the reaction between sodium hydroxide and diethylene glycol-bis(3-methylimidazolium)
dibromide in aqueous ethanol at room temperature. This solid, quaternized ionic liquid was
employed as a recyclable catalyst for the synthesis of 4H-pyrane derivatives in high yields from
the three-component condensation reaction of malononitrile, aromatic aldehydes and 1,3-
dicarbonyls in water at room temperature. In addition, spiropyrane derivatives were synthesized
from the reaction of isatin, malononitrile and 1,3-dicarbonyls in water at reflux. The dicationic
ionic liquid showed the same efficiency when used in consecutive reactions.
Available online
Keywords:
Dicationic ionic liquid
Catalyst
2009 Elsevier Ltd. All rights reserved.
4H-pyranes
Water
Multi-component reaction
Ionic liquids (ILs) have been reported as green reaction media
owing to their negligible volatility, excellent thermal stability,
and the variety of structures available.1-12 During the past few
years a number of dicationic and polycationic ionic liquids, with
a large variety of tunable interactions, have been explored.13-19
Dicationic ionic liquids (DCILs) have been shown to possess a
larger variety of tunable interactions, better thermal stabilities,
and broader selectivities than conventional ILs.20
Pyrano-pyridines, such as compounds 3 and 4, show in vitro
activity against Mycobacterium tuberculosis H37Rv (MTB),
multi-drug resistant tuberculosis (MDR-TB), and Mycobacterium
smegmatis. They are potent against MTB and MDR-TB, being
100 times more active than isoniazid against MDRTB.33,34
Pyripyropenes 5 are characterized by a decahydro-2H,11H-
naphtho[2,1-b]pyrano[3,4-e]pyran-11-one skeleton and have
been shown as potentially bioactive natural products.35 Related
natural products such as arisugacins and territrems (6) have also
been reported to possess important biological activities, for
example, inhibition of acetylcholinesterase.36,37 Therefore, there
is continued interest to develop efficient synthetic methods for
the assembly of these motifs.38-43
4H-Pyran derivatives represent an important class of
compounds and constitute the structural unit of many natural
products21,22 and biologically interesting compounds possessing
various pharmacological activities,23 such as antiallergic,24
antitumor,25 and antibacterial.26-28 4H-Pyran derivatives are also
potential calcium channel antagonists29 and are structurally
similar to biologically active 1,4-dihydropyridines.
The conventional synthesis of 2-amino-5-oxo-5,6,7,8-
tetrahydro-4H-chromenes involves the condensation of dimedone
with an aromatic aldehyde and malononitrile at reflux in acetic
acid44 or the two-component condensation of dimedone with α-
cyanocinnamonitriles in the presence of ethanolic piperidine.45
Other effective methods include the use of microwave,46
ultrasonic irradiation,47 hexadecyltrimethyl ammonium bromide
(HMTAB),48 triethylbenzylammonium chloride (TEBA),49 KF-
alumina,50 rare earth perfluorooctanoate (RE(PFO)3),51 amino
functionalized ionic liquids,52 tetrabutylammonium fluoride
(TBAF),53
2-hydroxyethylammonium
formate,54
silica
noanoparticles,55 well-ordered mesoporous silica nanoparticles,56
and ZnFe2O4,43 as catalysts in a one-pot reaction.
However, many of these methods suffer from drawbacks such
as low yields, long reaction times, harsh reaction conditions,
tedious work-up procedures and the application of expensive
catalysts.
Figure 1. Representative 4H-pyran derivatives. 1 and 2 (inhibition of
bacterial growth), 3 and 4 (in vitro inhibition of Mycobacterium tuberculosis
H37Rv (MTB)),
5
(in vitro antiproliferative/cytotoxic activity),
6
(acetylcholinesterase inhibition).

2
Tetrahedron Letters
In our initial study, the evaluation of a series of imidazolium
1,3-dicarbonyls and malononitrile to give the corresponding
products in 84-91% yields (Table 2, entries 2-4,11-14).
ionic liquids (7-10) was carried out for the synthesis of 2-amino-
5-oxo-5,6,7,8-tetrahydro-4H-chromenes in aqueous medium
(Scheme 1). After preliminary experiments, it was found that a
mixture of dimedone, benzaldehyde, and malononitrile in water
at room temperature in the presence of catalytic IL and potassium
Table 2: IL 10 catalyzed condensation of aromatic aldehydes, malononitrile,
and 1,3-dicarbonyls to give the corresponding 4H-pyranes.a
carbonate
afforded
2-amino-7,7-dimethyl-5-oxo-4-phenyl-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (11a) in excellent
yield (Table 1).
Entry Aromatic 1,3-Dicarbonyl Product Time Yield
aldehyde
(min) (%)b
1
C6H5-
CHO
Dimedone
20
92,
91,
90,
90
11a
88c
90
Scheme 1. ILs examined as catalysts.
2
3
4
4-Br-
C6H4-
CHO
4-F-
C6H4-
CHO
2,4-
Dimedone
Dimedone
Dimedone
35
30
40
11b
11c
11d
91
90
Table 1: Investigation of solvents and reaction conditions for the
synthesis of 4H-pyran 11a.a
(Cl)2-
C6H3-
CHO
4-NC-
C6H4-
CHO
3-NC-
C6H4-
CHO
4-O2N-
C6H4-
CHO
3-Me-
C6H4-
CHO
4-EtO-
C6H4-
CHO
C6H5-
CHO
4-Br-
C6H4-
CHO
2,4-
(Cl)2-
C6H3-
CHO
4-Cl-
C6H4-
CHO
3-Br-
C6H4-
CHO
3-O2N-
C6H4-
CHO
4-O2N-
C6H4-
CHO
2-O2N-
C6H4-
CHO
Entry IL
IL
(mol%)
-
Base
(mol%)
Time
(min)
70
70
60
20
70
20
30
40
20
60
20
Yield
(%)b
30
20
90
76
87
73
50
90
80
30
92
1
2
NaOH (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
NaOH (10)
K2CO3 (10)
K2CO3 (10)
-
-
-
5
6
7
8
9
Dimedone
Dimedone
Dimedone
Dimedone
Dimedone
25
30
15
45
45
86
85
90
89
92
11e
11f
11g
11h
11i
-
3
10
10
10
10
10
10
10
10
10
5
7
4
7
5
8
6
8
7
9
8
9
9
9
10
11
12
10
10
10
K2CO3 (10)
K2CO3 (10)
90
80
a Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol),
dimedone (1 mmol), water (3 mL). b Isolated yield.
10
11
1,3-
55
55
82
86
12a
12b
The condensation reaction conducted in water at room
temperature in the presence of NaOH or K2CO3 (10 mol%)
without IL gave the corresponding product in 30% and 20%
yield, respectively, after 70 minutes (Table 1, entries 1 and 2).
The best result was obtained using IL 10 (10 mol%) to give a
yield of 92% (Table 1, entry 11). Additionally, this condensation
conducted in the presence of other imidazolium ILs, such as 7, 8,
and 9, gave the corresponding product with slightly longer
reaction times and lower yields (Table 1, entries 3-9). The
reaction without K2CO3 gave only 30% yield after one hour
(Table 1, entry 10).
Cyclohexadione
1,3-
Cyclohexadione
12
1,3-
55
84
12c
Cyclohexadione
13
14
15
16
17
Ethyl
acetoacetate
40
40
35
30
35
86
88
92
91
91
13a
13b
13c
13d
13e
Ethyl
acetoacetate
We employed the optimized conditions, 10 (10 mol%), K2CO3
(10 mol%) in water, for the condensation of various 1,3-
dicarbonyls, malononitrile and aromatic aldehydes to give the
corresponding 4H-pyran derivatives (Table 2). This method
worked with a variety of aromatic aldehydes. Aldehydes bearing
electron-withdrawing groups such as 4-CN, 3-CN, 4-NO2, and 3-
NO2 (Table 2, entries 5-7, 15,16), and electron-donating groups
such as 3-Me, 4-EtO, and 4-iso-Pr (Table 2, entries 8, 9, 18, 19)
were reacted with a variety of 1,3-dicarbonyls including
dimedone, 1,3-cyclohexadione, and ethyl acetoacetate under the
optimized conditions to give the corresponding products in 85-
92% yield. Halogen substituted benzaldehydes were treated with
Ethyl
acetoacetate
Ethyl
acetoacetate
Ethyl
acetoacetate

3
pyrans via the three-component condensation reaction of an
18
19
3-Me-
C6H4-
CHO
Ethyl
acetoacetate
40
40
90
90
13f
aldehyde or isatin, malononitrile, and 1,3-dicarbonyl compounds
in water.
4-iso-Pr-
Ethyl
13g
C6H4-
acetoacetate
Acknowledgments
CHO
a Reaction conditions: aromatic aldehyde (1 mmol), 1,3-dicarbonyl (1 mmol),
malononitrile (1 mmol), 10 (10 mol%), K2CO3 (10 mol%), water (3 mL),
room temperature. aIsolated yield. cRecovered 10 was used.
We are thankful to Persian Gulf University Research Council
for partial support of this work PGU/FS/6-3/1391/886. Also, we
are thankful to the School of Chemistry, Manchester University
for running NMRs.
Spirooxindoles are commonly occurring heterocyclic ring
systems and are important structural motifs that are found in
many natural products and pharmaceuticals.57-61 In recent years,
numerous efficient transformations have been developed for the
construction of the spirooxindole substructure.62-68
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dimedone in water at reflux. After preliminary experiments, the
optimized conditions was found to be isatin (1 mmol),
malononitrile (1 mmol) and 1,3-dicarbonyl (1 mmol) in the
presence of 10 (10 mol%) and K2CO3 (10 mol%) in water (3 mL)
at reflux (Table 3).
4.
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R
H
F
H
H
Br
Cl
NO2
H
Br
F
1,3-Dicarbonyl
Dimedone
Dimedone
Product
14a
14b
14c
15a
15b
15c
15d
16a
16b
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Time (min)
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91
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89
91
3d
4
Dimedone
40
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Barbituric acid
Barbituric acid
Thiobarbituric acid
Thiobarbituric acid
Thiobarbituric acid
40
55
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a
Reaction conditions: isatin (1 mmol), 1,3-dicarbonyl (1 mmol),
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malononitrile (1 mmol), 10 (10 mol%), K2CO3 (10 mol%), water (3 mL),
reflux. aIsolated yield. c Recovered 10 was used. d N-methyl isatin .
Finally, the reusability of the catalyst was studied for the
synthesis of compounds 11a and 14a. After reaction completion,
the precipitate was filtered and washed with ethanol. IL 10 was
recycled by evaporating the aqueous ethanolic phase under
reduced pressure and washing with ethyl acetate. After being air
dried, the recycled catalyst could be reused four times without
any significant loss in activity (Tables 2 and 3, entry 1).
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In conclusion, the dicationic ionic liquid 10 and K2CO3 was
used as an efficient catalytic system for the synthesis of 4H-

4
Tetrahedron Letters
33. Kumar, R. R.; Perumal, S.; Senthilkumar, P.; Yogeeswari, P.;
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quaternized
diethylene
glycol-bis
(3-methylimidazolium)
dibromide was obtained in 95% yield (8.1 g); thick liquid; 1H
NMR (400 MHz, DMSO-d6): δ 3.78 (t, 4H, J = 4.0 Hz, OCH2),
3.91 (s, 6H, NCH3), 4.41 (t, 4H, J = 4.0 Hz, NCH2), 7.82 (d, 4H, J
= 9.6 Hz), 9.37 (s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 36.0,
48.5, 67.9, 122.4, 123.0, 136.7.
36. Tomoda, H., Kim, Y. K.; Nishida, H.; Masuma, R.; Omura, S. J.
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70. Synthesis of diethylene glycol-bis (3-methylimidazolium)
dihydroxide (10): A mixture of dicationic ionic liquid 9 (0.8 g, 2.0
mmol) and sodium hydroxide (0.5 g, 12.5 mmol) in water-ethanol
(1:1) (20 mL) was stirred at room temperature. After 1 h a white
precipitate formed which was filtered and washed with ethanol (3
× 10 mL) to give the quaternized diethylene glycol-bis (3-
methylimidazolium) dihydroxide in 90% yield (0.486 g); white
o
solid mp = >250 C; 1H NMR (400 MHz, D2O): δ 3.74-3.80 (m,
10H, NMe and OCH2), 4.25 (t, 4H, J = 5.0 Hz, NCH2), 7.31 (dd,
4H, J = 6.8 Hz, 2.0 Hz), 8.32 (s, 2H, Ar); 13C NMR (100 MHz,
DMSO-d6): δ 35.7, 49.0, 68.4, 122.5, 123.3, 166.0, 171.1. Mass
m/e (%): [M-34 (2×OH)] 236 (22.9), 207 (14.6), 167 (22.9), 149
(58.3), 111 (14.6), 83 (33.3), 57 (base peak). pH analysis of the
10: The pH of 10 determined by pH-ISE conductivity titration
controller (Denver Instrument Model 270) was 10.23 for 0.011 g
of the solid base at 25 °C.
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71. General procedure for the synthesis of 2-amino-5-oxo-5,6,7,8-
tetrahydro-4H-chromenes: The dicationic ionic liquid 10 (27.03
mg, 10 mol%), was added to a mixture of 1,3-dicarbonyl (1
mmol), aromatic aldehyde (1 mmol), malononitrile (1 mmol), and
K2CO3 (13.8 mg, 10 mol%) in water (3 mL). The reaction mixture
was stirred at room temperature for the appropriate time. After
reaction completion (TLC), the reaction mixture was filtered. The
filtrate was washed with cool ethanol (3 × 5 mL) to obtain the
corresponding 4H-pyran. The crude products were purified by
recrystallization from ethanol (95%). To recover 10, the
ethanol/water phase was evaporated under reduced pressure and
the crude was washed with ethyl acetate (3 × 5 mL) and air dried.
2-Amino-4-(4-bromophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (12b): mp 236-239 ˚C. IR (KBr): 3410,
45.
46.
47.
48.
49.
50.
51.
52.
1
3330, 3210, 2190, 1685, 1650, 1601, 1247 (cm-1). H NMR (400
MHz, DMSO-d6): δ (ppm) 0.85-2.60 (m, 6H), 4.14 (s, 1H), 7.04-
7.46 (m, 6H, Ar and NH2). 13C NMR (100 MHz, DMSO-d6): δ
(ppm) 21.4, 28.1, 36.7, 37.9, 59.2, 114.9, 121.2, 131.1, 132.8,
145.8, 160.1, 166.2, 197.6. Anal calcd for C16H13BrN2O2: C,
55.67; H, 3.80; Br, 23.15; N, 8.12. Found: C, 55.43; H, 3.93; N,
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7.89.
2-Amino-4-(2,4-dichlorophenyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (12c): mp 232-235 ˚C.
IR (KBr): 3415, 3330, 3215, 2196, 1680, 1650, 1600, 1247 (cm-1).
1H NMR (400 MHz, DMSO-d6): δ (ppm) 0.85-2.60 (m, 6H), 4.65
(s, 1H), 7.08-7.50 (m, 5H, Ar and NH2). 13C NMR (100 MHz,
DMSO-d6): δ (ppm) 21.4, 28.1, 34.1, 37.9, 57.9, 114.1, 120.7,
129.3, 130.2, 132.9, 134.6, 142.6, 160.1, 167.0, 197.3. Anal calcd
for C16H12Cl2N2O2: C, 57.33; H, 3.61; Cl, 21.15; N, 8.36. Found:
C, 55.08; H, 3.71; N, 8.14.
72. General procedure for the synthesis of spiropyran derivatives: The
dicationic ionic liquid 10 (27.03 mg, 10 mol%), was added to a
mixture of 1,3-dicarbonyl (1 mmol), isatin (1 mmol),
malononitrile (1 mmol), and K2CO3 (13.8 mg, 10 mol%) in water
(3 mL). The reaction mixture was stirred at reflux for the
appropriate time. After reaction completion (TLC), the reaction
mixture was cooled to room temperature and filtered. The filtrate
was washed with cool ethanol (3
× 5 mL) to obtain the
corresponding 4H-pyran. The crude products were purified by
recrystallization from ethanol (95%). To recover 10, the
ethanol/water phase was evaporated under reduced pressure and
the crude was washed with ethyl acetate (3 × 5 mL) and air dried.
67. Satasia, S. P.; Kalaria, P. N.; Avalani, J. R.; Raval, D. K.
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69. Synthesis of diethylene glycol-bis (3-methylimidazolium)
dibromide (9). The dicationic ionic liquid 9 was synthesized
according to literature procedures17,18 with slight modification. A
mixture of diethylene glycol dibromide (5.0 g, 21.56 mmol) and
N-methylimidazole (3.7 g, 45.07 mmol) in acetonitrile (30 mL)
was stirred at reflux for 48 h in a two necked round bottom flask
equipped with water condenser. After reaction completion (TLC),
the reaction was cooled to room temperature. The solvent was
evaporated under reduced pressure using a rotary evaporator at 55