A green and efficient one-pot three-component synthesis of dihydropyrano[3,2-c]chromenes using NaCl in hydroalcoholic media

Article abstract of DOI:10.1007/s11164-014-1918-9

An ecofriendly and efficient one-pot procedure for the preparation of dihydropyrano[3,2-c]chromene derivatives via NaCl-catalyzed three-component reaction of aromatic aldehydes, malononitrile and 4-hydroxycoumarin in hydroalcoholic media at ambient temper

Full text of DOI:10.1007/s11164-014-1918-9

Res Chem Intermed
DOI 10.1007/s11164-014-1918-9
A green and efficient one-pot three-component synthesis
of dihydropyrano[3,2-c]chromenes using NaCl
in hydroalcoholic media
•
Seyed Sajad Sajadikhah
Malek Taher Maghsoodlou Nourallah Hazeri
•
•
•
Mahmoud Norouzi Maryam Moein
Received: 25 August 2014 / Accepted: 30 December 2014
Ó Springer Science+Business Media Dordrecht 2015
Abstract An ecofriendly and efficient one-pot procedure for the preparation of di-
hydropyrano[3,2-c]chromene derivatives via NaCl-catalyzed three-component reaction
of aromatic aldehydes, malononitrile and 4-hydroxycoumarin in hydroalcoholic media at
ambient temperature has been reported. Greenness of the process was well established,
as a mixture of water–ethanol was used as reaction media. Furthermore, the presented
methodology offers several advantages such as inexpensive catalyst, high to excellent
yields, short reaction times, simple procedure and lack of need for column
chromatography.
Graphical abstract
S. S. Sajadikhah
Department of Chemistry, Payame Noor University, P. O. Box 19395-3697, Tehran, Iran
M. T. Maghsoodlou (&) Á N. Hazeri Á M. Norouzi Á M. Moein
Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan,
P. O. Box 98135-674, Zahedan, Iran
e-mail: mt_maghsoodlou@chem.usb.ac.ir
123

S. S. Sajadikhah et al.
Keywords Dihydropyrano[3,2-c]chromene Á Sodium chloride Á Three-component
reaction Á Malononitrile Á 4-hydroxycoumarin
Introduction
The development of efficient, practical and eco-friendly methodologies for the
preparation of compounds with biological significance is one of the main priorities for
green chemistry [1]. Among the several aspects of green chemistry, the replacement of
volatile organic solvents with green solvents such as water and ethanol is of greatest
concern. One of the most useful tools for the synthesis of chemically and biologically
important compounds is multicomponent reactions (MCRs), which combine three or
more substrates, either simultaneously, leading to domino processes, or through the
sequential addition of one or more reactants without isolating intermediate species or
changing the solvent. MCRs offer remarkable advantages including operational
simplicity, facile automation and minimized waste generation due to the reduction in
the number of work-up, extraction and purification steps [2–4].
Dihydropyrano[3,2-c]chromenes are very interesting compounds due to their
biologicaland pharmaceutical activities, such as anti-HIV, antimicrobial, antibacterial,
anticancer, spasmolytic and anticoagulant [5–8]. Dihydropyrano[3,2-c]chromene
derivatives have also been reported as potential drugs for the treatment of
neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease,
amyotrophic lateral sclerosis, AIDS-associated dementia, Down’s syndrome, and
Huntington’s disease as well as schizophrenia and myoclonus [8]. As a result,
considerable efforts have been made for the synthesis of this important class of
compounds. These heterocycles are generally prepared by means of reaction between
aldehydes, activated methylene compounds and phenol derivatives in the presence of
catalysts such as piperidine [9, 10], cetyltrimethylammonium chloride (CTAC) [11],
and cetyltrimethylammonium bromide (CTAB) coupled with ultrasound [12], c-
alumina [13], K2CO3 under microwave irradiation [14], MgO nanoparticles [15],
heteropolyacid [16], hexadecyltrimethylammonium bromide (HTMAB) [17], trieth-
ylbenzylammonium chloride (TEBA) [18], TiCl4 [19], (NH4)2HPO4, (S)-proline [20],
sodiumcarbonate [21], NaOAc/KF [22], NaBr coupled with electrochemicaltechnique
[23], indium with NaI [24], sodium dodecyl sulfate (SDS) [25], tetrabutylammonium
chloride [26], and 3-hydroxypropanaminium acetate (HPAA) [27]. However, some of
these methods have displayed drawbacks, such as environmental pollution caused by
utilization of toxic solvents, long reaction times, moderate yields, and using
stoichiometric amounts of catalyst. Therefore, it is necessary to further develop an
efficient and convenient method to construct such a significant scaffold.
In continuation of our ongoing research to develop mild and efficient catalyst
systems for the synthesis of heterocycle compounds [28–31], we wish to report
commercially available NaCl, as an inexpensive catalyst for the one-pot synthesis of
dihydropyrano[3,2-c]chromene derivatives 4 via three-component reaction of
aromatic aldehydes 1, malononitrile 2 and 4-hydroxycoumarin 3 in water–ethanol
media (3:1) at ambient temperature (Scheme 1).
123

Synthesis of dihydropyrano[3,2-c]chromenes using NaCl
NH2
CN
Ar
OH
O
O
CN
O
NaCl
+
+
H2O:EtOH (3:1)
rt
Ar
H
CN
O
O
O
1
2
4
3
Scheme 1 Synthesis of dihydropyrano[3,2-c]chromenes 4
Experimental
General procedure for the synthesis of dihydropyrano[3,2-c]chromene
A mixture of aromatic aldehyde (1 mmol), malononitrile (1 mmol), 4-hydroxy-
coumarin (1 mmol) and NaCl (5 mol%) in water:ethanol (3:1, 5 mL) was stirred at
ambient temperature for the appropriate time (Table 3). The progress of the reaction
was monitored by TLC. After completion, the solid precipitate was filtered off and
washed with ethanol and purified by recrystallization from hot ethanol, if necessary.
Spectral data of selected products are represented below.
2-Amino-4,5-dihydro-5-oxo-4-phenylpyrano[3,2-c]chromene-3-carbonitrile (4a)
IR (KBr, cm-1): 3,375, 3,285 (NH2), 2,197 (CN), 1,708 (C=O), 1,674, 1,605, 1,380.
1H NMR (400 MHz, DMSO-d6): d, 4.57 (1H, s, CH), 6.70 (2H, brs, NH2),
7.25–7.50 (7H, m, ArH), 7.69–7.73 (1H, m, ArH), 7.97–8.00 (1H, m, ArH) ppm.
2-Amino-4,5-dihydro-5-oxo-4-p-tolylpyrano[3,2-c]chromene-3-carbonitrile (4b)
IR (KBr, cm-1): 3,388, 3,310 (NH2), 2,194 (CN), 1,715 (C=O), 1,675, 1,610, 1,375.
1H NMR (400 MHz, DMSO-d6): d 2.42 (3H, s, CH3), 4.49 (1H, s, CH), 7.27 (2H, d,
J = 8.0 Hz, ArH), 7.33 (2H, brs, NH2), 7.38–7.41 (2H, m, ArH), 7.45 (1H, d,
J = 7.8 Hz, ArH), 7.61–7.76 (3H, m, ArH) ppm. 13C NMR (100 MHz, DMSO-d6):
d 20.1, 33.4, 58.1, 102.4, 116.2, 118.5, 119.86, 122.7, 126.7, 127.9, 131.0, 131.8,
134.9, 143.8, 152.5, 153.7, 157.8, 159.4 ppm.
2-Amino-4,5-dihydro-4-(3-nitrophenyl)-5-oxopyrano[3,2-c]chromene-3-
carbonitrile (4g)
IR (KBr, cm-1): 3,402, 3,322 (NH2), 2,202 (CN), 1,703 (C=O), 1,670, 1,606, 1,538,
1,380. 1H NMR (400 MHz, DMSO-d6): d 4.70 (1H, s, CH), 7.35–7.44 (3H, m, NH2
and ArH), 7.53–7.80 (7H, m, ArH) ppm.
123

S. S. Sajadikhah et al.
Table 1 Investigation of solvent effects on the model reaction
NH2
CN
OH
O
CHO
O
O
CN
CN
NaCl
+
+
O
O
4a
Entry
Solvent (ratio)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
H2O
120
200
60
65
48
70
82
91
73
51
EtOH
H2O:EtOH (1:1)
H2O:EtOH (2:1)
H2O:EtOH (3:1)
H2O:EtOH (5:1)
H2O:EtOH (10:1)
45
20
40
90
Experimental conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), 4-hydroxycoumarin
(1 mmol), NaCl (5 mol%) in solvent (5 mL) at ambient temperature
a
Isolated yield
Table 2 Optimization of
catalyst effects in the synthesis
of compound 4a
Entry
Catalyst (mol %)
Time (min)
Yield (%)a
1
NaCl (2.5)
NaCl (5)
NaCl (10)
NaCl (20)
NaCl (30)
NaCl (40)
NaBr (5)
NaOH (5)
LiCl (5)
50
84
91
88
80
82
79
55
84
25
24
37
61
58
74
18
2
20
3
35
4
30
5
35
6
30
7
90
8
40
9
120
120
120
6 h
180
180
24 h
10
11
12
13
14
15
LiBr (5)
Experimental conditions:
benzaldehyde (1 mmol),
malononitrile (1 mmol),
KCl (5)
AgCl (5)
Na2SO4 (5)
CaSO4 (5)
No catalyst
4-hydroxycoumarin (1 mmol) in
5 mL of H2O:EtOH (3:1)
solvent at room temperature
a
Isolated yield
2-Amino-4,5-dihydro-4-(3,4-dimethoxyphenyl)-5-oxopyrano[3,2-c]chromene-3-
carbonitrile (4l)
IR (KBr, cm-1): 3,401, 3,320 (NH2), 2,199 (CN), 1,711 (C=O), 1,670, 1,605, 1,524,
1,381. 1H NMR (400 MHz, DMSO-d6): d 3.71 (3H, s, OCH3), 3.73 (3H, s, OCH3),
123

Synthesis of dihydropyrano[3,2-c]chromenes using NaCl
Table 3 Synthesis of dihydropyrano[3,2-c]chromenes 4a–l
Entry Ar
Product
Time
(min)
Yield
(%)a
M.p.
(°C)
Lit. M.p.
(°C)b
NH2
1
2
3
4
5
6
7
8
Ph
20
15
15
12
10
10
10
10
91
84
90
89
92
90
89
91
257–259 256–258 [25]
249–251 251–253 [25]
235–237 229–230 [27]
244–246 243–244 [27]
260–262 263–265 [20]
257–259 257–259 [20]
261–263 262–264 [20]
254–256 258–260 [20]
CN
CN
CN
CN
CN
CN
CN
CN
O
O
O
4a
NH2
4-Me-C6H4
4-MeO-C6H4
3-Cl-C6H4
4-Cl-C6H4
2,4-Cl2-C6H3
3-NO2-C6H4
4-NO2-C6H4
O
O
O
4b
NH2
O
O
O
OMe
Cl
4c
NH2
O
O
O
4d
NH2
O
O
O
Cl
4e
NH2
O
O
Cl
O
Cl
4f
NH2
O
O
NO2
O
4g
NH2
O
O
O
NO2
4h
123

S. S. Sajadikhah et al.
Table 3 continued
Entry Ar
Product
Time
(min)
Yield
(%)a
M.p.
(°C)
Lit. M.p.
(°C)b
NH2
9
4-HO-C6H4
4-Br-C6H4
4-F-C6H4
20
20
25
25
83
89
91
85
258–260 259–260 [27]
250–252 247–249 [25]
256–258 260–262 [25]
222–224 228–230 [25]
CN
CN
CN
CN
O
O
O
OH
Br
F
4i
NH2
10
11
12
a
O
O
O
4j
NH2
O
O
O
4k
NH2
3,4-MeO2-
C6H3
O
O
OMe
OMe
O
4l
Isolated yield
b
The known products were characterized by comparison of their IR and NMR spectra and melting points
with those of authentic samples
4.45 (1H, s, CH), 6.72 (1H, m, ArH), 6.90 (2H, d, J = 8.2 Hz, ArH), 7.35 (2H, brs,
NH2), 7.38–7.45 (2H, m, ArH), 7.63–7.66 (1H, m, ArH), 7.90 (1H, J = 7.8 Hz,
ArH) ppm. 13C NMR (100 MHz, DMSO-d6): d 36.1, 55.4, 55.5, 58.0, 103.5, 110.9,
111.5, 112.7, 115.9, 119.5, 119.8, 122.2, 122.5, 124.6, 132.5, 136.0, 148.4, 152.1,
153.3, 157.5, 159.5 ppm.
Results and discussion
Initially, the mixture of benzaldehyde (1 mmol), malononitrile (1 mmol) and
4-hydroxycoumarin (1 mmol) in water (5 mL) was treated with 5 mol% of NaCl at
ambient temperature. The corresponding dihydropyrano[3,2-c]chromene 4a was
obtained in 65 % yield after 2 h. This reaction was chosen as a model and was carried
out in ethanol and mixtures of water and ethanol, and the results are summarized in
Table 1. The best result was obtained in the mixture of water:ethanol (3:1).
123

Synthesis of dihydropyrano[3,2-c]chromenes using NaCl
OH
O
CN
Na
CN
2
O
O
O
CN
CN
NaCl
Cl
3
Ar
H
Ar
H
Ar
1
NH
NH2
N
O
CN
H
Ar
CN
Ar
CN
Ar
O
O
O
O
H
O
O
O
O
4
Scheme 2 The proposed mechanism for the synthesis of dihydropyrano[3,2-c]chromenes
Next, to find out the optimum quantity of catalyst, the model reaction was
performed in the presence of different amounts of NaCl. Increasing the catalyst
loading to 40 mol% did not improve the reaction yield. Notably, when the reaction
was examined in the absence of the catalyst, a low yield (18 %) of the target product
was obtained. Some potential catalysts such as NaBr, NaOH, LiCl, LiBr, KCl,
AgCl, Na2SO4 and CaSO4 were also tested for the synthesis of product 4a, and the
results are listed in Table 2.
With the above optimized reaction conditions, a series of the dihydropyrano[3,2-
c]chromenes 4a–l were synthesized (Table 3). As shown in Table 3, the reaction
was found to be compatible with various functional groups such as F, Cl, Br, NO2,
OH, Me and OMe. In all cases, the reaction proceeded smoothly to produce the
corresponding product in good to high yield.
In general, at the beginning of the reaction, the chemicals themselves were
dissolved completely in the reaction medium to form a homogeneous mixture. But,
at the end of the reaction, the system became a suspension and finally the product
was precipitated. The products were obtained through simple filtration and washed
with ethanol and recrystallized in hot ethanol to afford pure products. The structure
of the products 4a–l was characterized by IR, 1H and 13C NMR spectral data and by
comparison of their melting points with those of authentic samples.
As reported in the literature [20, 21, 27], a possible mechanism for the formation
of dihydropyrano[3,2-c]chromene 4 is shown in Scheme 2.
Conclusion
In conclusion, we have developed a green and efficient synthesis of dihydropyr-
ano[3,2-c]chromene derivatives via a one-pot three-component reaction using NaCl
as an inexpensive catalyst. The noteworthy features of this methodology are mild
123

S. S. Sajadikhah et al.
reaction conditions, operational simplicity, readily available starting materials and
catalyst, short reaction times and good to high yields. Moreover, all products were
obtained through simple filtration with no need for column chromatography, which
reduces the waste as well as environmental pollution.
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