Crown ether complex cation ionic liquids (CECILs) as environmentally benign catalysts for three-component synthesis of 4,5-dihydropyrano[3,2-c]chromene and 4,5-dihydropyrano[4,3-b]pyran derivatives

Article abstract of DOI:10.1007/s11164-014-1855-7

Crown ether complex cation ionic liquids (CECILs) catalyze three-component reaction of aromatic aldehydes, malononitrile, and 4-hydroxycoumarin or 4-hydroxy-6-methylpyrone, in EtOH under reflux, for synthesis of 4,5-dihydropyrano[3,2-c]chromene and 4,5-di

Full text of DOI:10.1007/s11164-014-1855-7

Res Chem Intermed
DOI 10.1007/s11164-014-1855-7
Crown ether complex cation ionic liquids (CECILs)
as environmentally benign catalysts for three-component
synthesis of 4,5-dihydropyrano[3,2-c]chromene and
4,5-dihydropyrano[4,3-b]pyran derivatives
•
Mehdi Abaszadeh Mohammad Seifi
Received: 16 June 2014 / Accepted: 19 October 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Crown ether complex cation ionic liquids (CECILs) catalyze three-
component reaction of aromatic aldehydes, malononitrile, and 4-hydroxycoumarin
or 4-hydroxy-6-methylpyrone, in EtOH under reflux, for synthesis of 4,5-dihydro-
pyrano[3,2-c]chromene and 4,5-dihydropyrano[4,3-b]pyran derivatives. CECILs are
environmentally benign, easily obtained, stable catalysts. High conversion, short
reaction times, and cleaner reaction profiles are some of the advantages of this
method.
Keywords 4,5-Dihydropyrano[3,2-c]chromene derivatives ꢀ
4,5-Dihydropyrano[4,3-b]pyran derivatives ꢀ Multicomponent reaction ꢀ
Crown ether complex cation ionic liquids (CECILs)
Introduction
Compared with other methods, multicomponent reactions (MCRs) have emerged as
attractive and powerful strategies for organic synthesis [1–3]. MCRs are highly
flexible and enable exceptionally efficient synthesis of complex molecules,
frequently with high stereoselectivity, from simple and readily available substrates
[4–8]. MCRs have been developed for synthesis of a variety small organic
molecules in organic, bioorganic, and medicinal chemistry [9–12] and are regarded
M. Abaszadeh (&)
Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical
Sciences, 76175493 Kerman, Iran
e-mail: abaszadeh@kmu.ac.ir
M. Seifi
Department of Chemistry, Faculty of Sciences, Najafabad Branch, Islamic Azad University,
Najafabad, Esfaha¯n, Iran
123

M. Abaszadeh, M. Seifi
as vital for synthesis of many important heterocyclic compounds, for example 4,5-
dihydropyrano[3,2-c]chromene and 4,5-dihydropyrano[4,3-b]pyran derivatives.
Dihydropyrano[3,2-c]chromenes and their derivatives are of substantial interest
because of their wide range of biological properties [13, 14], for example
spasmolytic, diuretic, anti-coagulant, anticancer, and anti-anaphylactic activity [15,
16]. 4,5-Dihydropyrano[4,3-b]pyran derivatives also have wide range of pharma-
cological and biological applications, because of their fungicidal, insecticidal,
acaricidal [17], antiviral [18], antileishmanial, and anticonvulsant activity [19].
Ionic liquids (ILs), salts with melting points below 100 °C consisting of ions,
have attracted much attention from research groups because of their unique
properties and novel applications. ILs have low vapor pressure, excellent thermal
stability, desirable solvating properties, and are recyclable [20]. They have been
used in many organic reactions, for example, hydrogenation, oxidation [21–25],
three-component reactions [26], and carbon–carbon bond-forming reactions, for
example Michael addition, the Henry reaction, Knoevenagel condensation, and
Heck reaction [27]. Crown ether complex ionic liquids (CECILs), have been
synthesized by chelating crown ethers with alkali metal cations [27]. Because
electrostatic interactions between the large cations and the anions are relatively
weak compared with van der Waals forces, the lattice energy and melting points of
the crystals are low.
In the work reported herein, we synthesized a series of crown ether complex
cation ionic liquids (CECILs), by chelating crown ethers with alkali metal cations,
and used them as environmentally benign catalysts for synthesis of 4,5-dihydro-
pyrano[3,2-c]chromene and 4,5-dihydropyrano[4,3-b]pyran derivatives by three-
component reaction of aromatic aldehydes, malononitrile, and 4-hydroxycoumarin
or 4-hydroxy-6-methylpyrone, in EtOH, under reflux.
Results and discussion
In this work we dissolved the crown ether (1) and inorganic or organic base
(2a–d) in methanol to generate the required CECIL (3a–d) (Scheme 1).
We then used the CECILs as catalysts for three-component reaction of aromatic
aldehydes (4a–p), malononitrile (5), and 4-hydroxycoumarin (6a) or 4-hydroxy-6-
methylpyrone (6b) for synthesis of 4,5-dihydropyrano[3,2-c]chromene (7a–p) and
4,5-dihydropyrano[4,3-b]pyran (7q–f0) derivatives, in EtOH, under reflux
(Scheme 2).
To optimize the reaction conditions, the reaction between benzaldehyde (4a),
malononitrile (5), and 4-hydroxycoumarin (6a) was chosen as a model reaction.
Methanol
stirring at 60oC
Scheme 1 Synthesis of crown
ether complex cation ionic
liquids (CECILs)
18-crown-6
ZX
[18-crown-6Z][X]
1
2a-d
3a-d
Z= Na, K
X= OH, OAc
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Crown ether complex cation ionic liquids (CECILs)
OH
O
NH2
CN
Ar
O
O
O
O
6a
7a-p
O
CN
CN
EtOH, [18-C-6K][OAc] (30 mol%)
reflux
Ar
H
OH
NH2
CN
Ar
O
O
4a-p
5
O
O
O
6b
7q-f'
Scheme 2 Three-component reaction of aromatic aldehydes (4a–p), malononitrile (5) and
4-hydroxycoumarin (6a) or 4-hydroxy-6-methylpyrone (6b) in the presence of catalytic amounts of
[18-C-6 K][OAc]
Table 1 Optimization of the model reaction between benzaldehyde (4a), malononitrile (5) and
4-hydroxycoumarin (6a)
Entry
Solvent
Catalyst
Catalyst (mol%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
EtOH
[18-C-6K][OAc]
[18-C-6K][OAc]
[18-C-6K][OAc]
[18-C-6K][OAc]
[18-C-6Na][OAc]
[18-C-6K][OH]
[18-C-6Na][OH]
[18-C-6K][OAc]
[18-C-6K][OAc]
[18-C-6K][OAc]
30
30
30
30
30
30
30
10
20
40
15
45
40
80
20
27
30
25
20
15
90
78
80
60
88
85
83
82
88
90
Ethyl acetate
Acetonitrile
Toluene
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
When this three-component reaction was performed in the presence of [18-C-
6K][OAc] (30 mol%), in EtOH, under reflux, the 2-amino-5-oxo-4-phenyl-4,5-
dihydropyrano[3,2-c]chromene-3-carbonitrile 7a was obtained in 90 % yield within
15 min. This reaction was also carried out in other solvents (ethyl acetate,
acetonitrile, and toluene), but the best results in terms of reaction time and yield of
the desired product 7a were obtained when the reaction was conducted in EtOH
(Table 1, entries 1–4). Other CECILs were also used as catalysts (Table 1, entries
5–7). We also optimized the quantity of catalysts. The best results were obtained
when the reactions were performed in the presence of 30 mol% [18-C-6K][OAc]
(Table 1, entries 8–10).
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M. Abaszadeh, M. Seifi
On the basis of these results we decided to use this method for synthesis of 4,5-
dihydropyrano[3,2-c]chromene (7a–p) and 4,5-dihydropyrano[4,3-b]pyran (7q–f0)
derivatives by three-component reaction of aromatic aldehydes (4a–p), malononit-
rile (5) and 4-hydroxycoumarin (6a) or 4-hydroxy-6-methylpyrone (6b), in EtOH,
under reflux, in the presence of [18-C-6K][OAc] (30 mol%) (Table 2).
Conclusion
In summary, we report use of crown ether complex cation ionic liquids (CECILs) as
catalysts for three-component reaction of aromatic aldehydes, malononitrile, and
4-hydroxycoumarin or 4-hydroxy-6-methylpyrone, for synthesis of 4,5-dihydropyr-
ano[3,2-c]chromene and 4,5-dihydropyrano[4,3-b]pyran derivatives. These reac-
tions were performed in EtOH under reflux. High yields, operational simplicity,
clean reaction conditions are advantages of this procedure that make it a useful
practical process for synthesis of these compounds.
Experimental
General Melting points were measured on an Electrothermal-9100 apparatus and
are uncorrected. IR spectra were recorded on a Brucker FT-IR Tensor 27 infrared
spectrophotometer. 1H NMR spectra were recorded on a Brucker Avance III
400 MHz spectrometer. 13C NMR spectra were recorded on the same instruments at
100 MHz. TMS was used as internal standard for NMR spectroscopy. Elemental
analysis was performed with a Heraeus CHN-O-Rapid analyzer.
General procedure for synthesis of CECILs (3a–d)
Organic or inorganic potassium or sodium base (2a–d) (2 mol) and 18-crown-6 (1)
(2 mol) in 15 mL methanol was stirred for 1 h at 60 °C. The methanol was removed
under reduced pressure. The residue was dried under vacuum to generate the desired
CECIL in 100 % yield. Synthesis of CECILs 3b and 3d has been reported elsewhere
[27].
[18-C-6Na][OH] (3a)
Liquid; 1H NMR (400 MHz, D2O) dppm: 3.92 (s, 24H); 13C NMR (100 MHz, D2O):
dppm: 69.01. Anal. calcd. for C12H25NaO7: C, 47.36; H, 8.28 %. Found: C, 47.18; H,
8.12 %.
[18-C-6K][OH] (3b)
1
White powder; M.P. 38 °C; H NMR (400 MHz, D2O) dppm: 3.58 (s, 24H); 13C
NMR (100 MHz, D2O): dppm: 68.79. Anal. calcd. for C12H25KO7: C, 44.98; H,
7.86 %. Found: C, 44.80; H, 7.71 %.
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Crown ether complex cation ionic liquids (CECILs)
123

M. Abaszadeh, M. Seifi
123

Crown ether complex cation ionic liquids (CECILs)
[18-C-6Na][OAc] (3c)
White powder; M.P. 56 °C; 1H NMR (400 MHz, D2O) dppm: 3.79 (s, 24H), 1.81 (s,
3H); 13C NMR (100 MHz, D2O): dppm: 179.01, 69.03, 25.12. Anal. calcd. for
C14H27NaO8: C, 48.55; H, 7.86 %. Found: C, 48.36; H, 7.70 %.
[18-C-6K][OAc] (3d)
1
White powder; M.P. 75 °C; H NMR (400 MHz, D2O) dppm: 3.38 (s, 24H), 1.79
(s, 3H); 13C NMR (100 MHz, D2O): dppm: 178.88, 68.26, 24.12. Anal. calcd. for
C14H27KO8: C, 46.39; H, 7.51 %. Found: C, 46.20; H, 7.34 %.
Typical procedure for the of 4,5-dihydropyrano[3,2-c]chromene (7a–p)
and 4,5-dihydropyrano[4,3-b]pyran (7q–f0) derivatives
A mixture of aromatic aldehyde (4a–p) (2 mmol), malononitrile (5) (2 mmol), and
4-hydroxycoumarin (6a) or 4-hydroxy-6-methylpyrone (6b) (2 mmol), and [18-C-
6K][OAc] (30 mol%) in EtOH (10 mL) was heated under reflux for the time
reported in Table 2 (the progress of the reaction being monitored by TLC with
hexane–ethyl acetate as mobile phase). After completion of the reaction, the
reaction mixture was poured into ice-cold water; the crude product was isolated by
filtration, dried, and recrystallized from ethanol.
2-Amino-4-(2-nitrophenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-
carbonitrile (7i)
White powder; IR (KBr, mmax/cm-1): 3,392, 3,312 (NH2), 2,192 (CN), 1,670 (C=O),
1,600, 1,577 (C=C); 1H NMR (400 MHz, DMSO-d6) dppm: 7.89–7.42 (m, 10H, CH–
Ar, NH2), 5.23 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6) dppm: 161.29 (C=O),
160.22 (C6), 155.20 (C2), 153.75, 150.79, 138.95, 135.26, 134.66, 132.77, 130.04,
126.30, 125.57, 124.15, 120.33, 118.18, 114.38 (CN), 104.85 (C5), 57.73 (C3),
33.22 (C4); Anal. calcd. for C19H11N3O5: C, 63.16; H, 3.07; N, 11.63 %. Found: C,
62.95; H, 2.91; N, 11.42 %.
2-Amino-5-oxo-4-(pyridin-3-yl)-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile
(7p)
White powder; IR (KBr, mmax/cm-1): 3,376, 3,280 (NH2), 2,192 (CN), 1,670 (C=O),
1,603, 1,571 (C=C); 1H NMR (400 MHz, DMSO-d6) dppm: 8.52–7.33 (m, 10H, CH–
Ar, NH2), 4.53 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6) dppm: 161.16 (C=O),
159.70 (C6), 155.40 (C2), 153.81, 150.64, 149.83, 140.37, 137.13, 134.58, 126.22,
125.43, 124.14, 120.66, 118.13, 114.52 (CN), 104.52 (C5), 58.65 (C3), 36.33 (C4);
Anal. calcd. for C18H11N3O3: C, 68.14; H, 3.49; N, 13.24 %. Found: C, 67.93; H,
3.30; N, 13.05 %.
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M. Abaszadeh, M. Seifi
2-Amino-4-(2-bromophenyl)-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (7v)
Yellow powder; IR (KBr, mmax/cm-1): 3,456, 3,344 (NH2), 2,192 (CN), 1,664
1
(C=O), 1,603, 1,574 (C=C); H NMR (400 MHz, DMSO-d6) dppm: 7.54–7.15 (m,
6H, CH–Ar, NH2), 6.26 (s, 1H, CH), 4.78 (s, 1H, CH), 2.20 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) dppm: 162.75 (C=O), 160.36 (C6), 159.77 (C2), 143.69,
134.38, 132.18, 130.52, 129.79, 124.47, 120.42, 113.23 (CN), 101.44 (C5), 99.48
(CH), 58.29 (C3), 37.56 (C4), 20.95 (CH3); Anal. calcd. for C16H11BrN2O3: C,
53.50; H, 3.09; N, 7.80 %. Found: C, 53.23; H, 2.92; N, 7.62 %.
2-Amino-7-methyl-4-(2-nitrophenyl)-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (7y)
White powder; IR (KBr, mmax/cm-1): 3,472, 3,360 (NH2), 2,192 (CN), 1,670 (C=O),
1,606, 1,574 (C=C); 1H NMR (400 MHz, DMSO-d6) dppm: 7.84–7.35 (m, 6H, CH–
Ar, NH2), 6.27 (s, 1H, CH), 5.05 (s, 1H, CH), 2.18 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) dppm: 163.05 (C=O), 160.36 (C6), 159.90 (C2), 150.85,
139.15, 135.16, 132.55, 129.92, 125.47, 120.41, 114.04 (CN), 101.67 (C5), 99.57
(CH), 57.56 (C3), 32.57 (C4), 20.91 (CH3); Anal. calcd. for C16H11N3O5: C, 59.08;
H, 3.41; N, 12.92 %. Found: C, 58.89; H, 3.23; N, 12.74 %.
2-Amino-4-(2-methoxyphenyl)-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (7b0)
Yellow powder; IR (KBr, mmax/cm-1): 3,488, 3,344 (NH2), 2,192 (CN), 1,670
1
(C=O), 1,600, 1,574 (C=C); H NMR (400 MHz, DMSO-d6) dppm: 7.17–6.84 (m,
6H, CH–Ar, NH2), 6.22 (s, 1H, CH), 4.48 (s, 1H, CH), 3.69 (s, 3H, OCH3), 2.18 (s,
3H, CH3); 13C NMR (100 MHz, DMSO-d6) dppm: 162.97 (C=O), 160.44 (C6),
160.28 (C2), 158.78, 132.60, 130.67, 129.93, 127.25, 122.05, 121.11, 113.34 (CN),
101.64 (C5), 99.48 (CH), 58.29 (C3), 57.29 (OCH3), 33.26 (C4), 20.89 (CH3); Anal.
calcd. for C14H14N2O4: C, 65.80; H, 4.55; N, 9.03 %. Found: C, 65.62; H, 4.37; N,
8.84 %.
2-Amino-4-(4-hydroxyphenyl)-7-methyl-5-oxo-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (7c0)
Brown powder; IR (KBr, mmax/cm-1): 3,728–3,024 (broad peak, OH, NH2), 2,192
1
(CN), 1,664 (C=O), 1,574, 1,552 (C=C); H NMR (400 MHz, DMSO-d6) dppm
:
9.12 (s, 1H, OH), 7.02–6.73 (m, 6H, CH–Ar, NH2), 6.21 (s, 1H, CH), 4.52 (s, 1H,
CH), 2.20 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) dppm: 162.65 (C=O),
160.36 (C6), 159.74 (C2), 156.43, 132.46, 130.40, 129.16, 126.44, 122.14, 120.21,
113.58 (CN), 101.24 (C5), 99.53 (CH), 58.29 (C3), 37.49 (C4), 20.92 (CH3);
Anal. calcd. for C16H12N2O4: C, 64.86; H, 4.08; N, 9.46 %. Found: C, 64.68; H,
3.91; N, 9.27 %.
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Crown ether complex cation ionic liquids (CECILs)
2-Amino-7-methyl-5-oxo-4-(pyridin-3-yl)-4,5-dihydropyrano[4,3-b]pyran-3-
carbonitrile (7f0)
Yellow powder; IR (KBr, mmax/cm-1): 3,408, 3,392 (NH2), 2,192 (CN), 1,664
1
(C=O), 1,587, 1,523 (C=C); H NMR (400 MHz, DMSO-d6) dppm: 8.43 (s, 2H,
NH2), 7.59–7.28 (m, 4H, CH–Ar), 6.27 (s, 1H, CH), 4.35 (s, 1H, CH), 2.20 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6) dppm: 162.96 (C=O), 160.10 (C6), 159.80
(C2), 150.61, 149.83, 140.52, 136.82, 125.34, 120.75, 113.21 (CN), 101.34 (C5),
99.61 (CH), 58.53 (C3), 35.61 (C4), 20.91 (CH3); Anal. calcd. for C15H11N3O3: C,
64.05; H, 3.94; N, 14.94 %. Found: C, 63.88; H, 3.78; N, 14.76 %.
Acknowledgments The authors express their great appreciation to the Pharmaceutics Research Center,
Institute of Neuropharmacology, Kerman University of Medical Sciences, for supporting this
investigation.
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