K2CO3/cyanuric acid catalyzed synthesis of 2-amino-4H-chromene derivatives in water

Article abstract of DOI:10.1007/s11164-017-2900-0

Abstract: Three-component processes for the synthesis of 2-amino-4H-chromenes catalyzed by potassium carbonate/cyanuric acid in water as a safe solvent were developed. These reactions were performed at room temperature through one-pot reactions. The benef

Full text of DOI:10.1007/s11164-017-2900-0

Res Chem Intermed
DOI 10.1007/s11164-017-2900-0
K2CO3/cyanuric acid catalyzed synthesis of 2-amino-
4H-chromene derivatives in water
Reza Heydari1 Ramin Shahraki1 Mahshid Hossaini1
Alireza Mansouri1
•
•
•
Received: 17 October 2016 / Accepted: 7 February 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract Three-component processes for the synthesis of 2-amino-4H-chromenes
catalyzed by potassium carbonate/cyanuric acid in water as a safe solvent were devel-
oped. These reactions were performed at room temperature through one-pot reactions.
The benefits of this research are short reaction time, excellent yield, clean reaction
media, simple work-up and easy purification.
Graphical Abstract
R
OH
CN
OH
HO
O
NH2
R
OH
CHO
K2CO3/ Cyanuric acid
H2O , r.t
CN
NC CN
R
O
R
NH2
O
O
O
CN
O
NH2
&
Reza Heydari
heydari@chem.usb.ac.ir
1
Department of Chemistry, The University of Sistan and Baluchestan,
P.O. Box 98135-674, Zahedan, Iran
123

R. Heydari et al.
Keywords 2-Amino-4H-chromene Á Aldehyde Á Cyanuric acid Á Potassium
carbonate Á Green chemistry Á Water
Introduction
The main challenges in recent decades in organic chemistry are the synthesis of new
compounds with economical, high-efficiency and eco-friendly processes. According
to the principles of ‘‘Green Chemistry’’, energy requirements should be recognized
for their environmental impacts and should be minimized. Synthetic methods should
be conducted at ambient pressure and temperature, also using solvent-free or
recyclable environmentally benign solvent systems. In this regard, water can be the
best replacement for an rganic solvent, as it is nonvolatile, nonflammable, nontoxic,
and inexpensive [1, 2].
Chromenes consist of bicyclic oxygen heterocycles resulting from the fusion of
the benzene ring with 5, 6-positions of either a 2H- or a 4H-pyran ring system are
designated as 2H-chromene and 4H-chromene (Fig. 1) [3]. The diverse pharmaco-
logical activities of this class of molecules, with antimicrobial [4] anti-antiviral [5],
anti-inflammatory [6], anti-influenza [7] and anticancer activity [8] have been
reported. Moreover, in recent decades, among various chromene derivatives,
2-amino-4H-chromene with cyano-functionality has a wide range of applications in
the many fields of chemistry such as lasers, optical brighteners, fluorescence
markers, pigments, and cosmetics [9].
Generally, the synthesis of 2-amino-4H-chromene performs by the cyclization of
an aromatic or aliphatic aldehyde, malononitrile (or ethyl cyanoacetate), with
enolizable C–H activated acidic compounds, such as phenol [10], naphthol [1],
resorsinol [11], 4-hydroxycoumarin [12] or dimedone [13, 14]. Various catalysts
have been reported for the synthesis of these compounds, such as DABCO [15],
PEG-400 [16], thiourea dioxide [17], LiOHÁH2O [18], poly (4-vinylpyridine) [19],
sulfamic acid [20], Ca(OH)2 [21], Fe3O4 nanoparticles [22], bakers’ yeast [23],
sodium acetate [24], ceric ammonium nitrate (CAN) [25], and nanocomposites such
as Fe3O4@SiO2–NH2 [26], nano-powder ZnAl2O4–Bi2O3 [27] nano-cellulose/Ag
[28], but most of them are associated with several drawbacks, such as long reaction
time, high cost, harsh conditions, toxic organic solvents, difficult work-up
procedures and multi-step reaction conditions with reduced yields.
O
O
O
O
O
O
I
II
III
IV
Fig. 1 2H-chromene (I), 4H-chromene (II), 2H-chromene-2-one (III), and 4H-chromene-4-one (IV)
123

K2CO3/cyanuric acid catalyzed synthesis of 2-amino-4H-…
In this paper, we studied the one-pot and multicomponent synthesis of 2-amino-
4H-chromenes by the reaction of malononitrile and various aldehydes with phenols,
resorsinol and dimedone in the presence of potassium carbonate/cyanuric acid as an
available, economic and nontoxic catalyst in water
Experimental
Materials and solvents
The reagents and solvents were purchased from Merck and Aldrich and were used
as received. The samples were analyzed by FT-IR spectroscopy (JASCO FT/IR-460
1
plus spectrometer) and melting point by Electrothermal 9100 apparatus. H NMR
and 13C NMR spectra of compounds were recorded on a Bruker DRX-400 Avance
instrument in DMSO-d6.
General procedure for the synthesis of 2-amino-4H-chromenes
A mixture of aldehyde (1 mmol), malononitrile (1 mmol) and 1 mmol of enolizable
C–H activated acidic compound (resorcinol, phenol, or dimedone) was stirred in the
presence of 10 mol% of potassium carbonate/cyanuric acid (3:1 mol%) in water at
room temperature. The reaction process was monitored by thin layer chromatog-
raphy. After completion of the reaction, the precipitate was filtered, washed with
distilled water and crystallized from ethanol.
Table 1 Optimization of the reaction conditions for the synthesis of 2-amino-4-(4-chlorophenyl)-7-
hydroxy-4H-chromene-3-carbonitrile
Cl
CHO
OH
K2CO3 / Cyanuric acid
NC CN
+
+
CN
H2O, r.t
OH
Cl
(3)
HO
O
NH2
Entry
Catalyst
mol% (catalyst)
Time (min)
Yield (%)a
1
2
3
4
5
6
K2CO3
Cyanuric acid
10
10
10
10
5
25
45
20
20
16
6
75
70
82
85
84
92
K2CO3/cyanuric acid (1:1)
K2CO3/cyanuric acid (2:1)
K2CO3/cyanuric acid (3:1)
K2CO3/cyanuric acid (3:1)
10
Reaction conditions: resorcinol (1 mmol), 4-chlorobenzaldehydes (1 mmol), and malononitrile (1 mmol)
a
Isolated yields
123

R. Heydari et al.
Selected spectral data
2-amino-4-(2,4-dichlorophenyl)-7-hydroxy-4H-chromene-3-carbonitrile (Table 4,
1
Entry 3d) m.p. = 252–254 °C, literature 256–258 °C [11], H NMR (400 MHz,
DMSO-d6): 5.12 (s, 1H), 6.40 (d, 1H), 6.46 (d, 1H), 6.70 (d, 1H), 6.96 (s, 2H, NH2),
Table 2 Optimization of the reaction conditions for the synthesis of 2-amino-4-(4-chlorophenyl)-4H-
chromene-3-carbonitrile
Cl
CHO
OH
K2CO3 / Cyanuric acid
NC CN
+
+
CN
H2O, r.t
Cl
(4)
O
NH2
Entry
Catalyst
K2CO3
mol% (catalyst)
Time (min)
Yield (%)a
1
2
3
4
5
6
10
10
10
10
5
45
120
80
30
20
8
71
78
80
85
80
94
Cyanuric acid
K2CO3/cyanuric acid (1:1)
K2CO3/cyanuric acid (2:1)
K2CO3/cyanuric acid (3:1)
K2CO3/cyanuric acid (3:1)
10
Reaction conditions: Phenol (1 mmol), 4- chlorobenzaldehyde (1 mmol), and (1 mmol) malononitrile
a
Isolated yields
Table 3 Optimization of the reaction conditions for the synthesis of 2-amino-4-(4-chlorophenyl)-7,7-
dimethyl-5-oxo-4a,5,6,7,8,8a-hexahydro-4H-chromene-3-carbonitrile
Cl
CHO
O
K2CO3/ Cyanuric acid
H2O, r.t
O
+
+
NC CN
CN
O
Cl
(5)
O
NH2
Entry
Catalyst
K2CO3
mol% (catalyst)
Time(min)
Yield (%)a
1
2
3
4
5
6
10
10
10
10
5
45
120
90
71
78
78
82
80
90
Cyanuric acid
K2CO3/cyanuric acid (1:1)
K2CO3/cyanuric acid (2:1)
K2CO3/cyanuric acid (3:1)
K2CO3/cyanuric acid (3:1)
30
25
10
18
Reaction conditions: Dimedone (1 mmol), 4- chlorobenzaldehyde (1 mmol), and (1 mmol) malononitrile
a
Isolated yields
123

K2CO3/cyanuric acid catalyzed synthesis of 2-amino-4H-…
Table 4 The condensation of aromatic aldehydes with malononitrile and resorcinol in aqueous media
R
OH
CHO
CN
Catalyst / H2O
r.t
NC
CN
HO
O
NH2
OH
R
(3)
(2)
(1)
3a-3m
Entry
Aldehyde
Time (min)
8
Product
Yield (%)a
m.p. (°C)
CHO
3a
88
230–232 [232–234] [15]
N
C
H
O
NH2
O
CHO
Cl
l
C
O
O
3b
6
92
160–162 [160–162] [29]
N
C
H
H
NH2
O
CHO
Cl
3c
8
6
85
87
200–203 [200–202] [15]
252–254 [256–258] [11]
l
C
N
C
NH2
O
CHO
Cl
l
C
O
O
3d
l
C
Cl
N
C
H
H
NH2
O
CHO
Cl
3e
3f
7
8
78
93
218–220 [217–220] [11]
162–164 [165–168] [31]
Cl
l
C
l
C
N
C
NH2
O
CHO
Br
r
B
N
C
H
O
NH2
O
123

R. Heydari et al.
Table 4 continued
Entry
Aldehyde
Time (min)
9
Product
Yield (%)a
82
m.p. (°C)
CHO
e
M
3g
180–182 [180–182] [15]
210–212 [215–217] [29]
112–114 [112–114] [30]
244–246 [248–250] [15]
188–190 [190–192] [29]
Me
N
C
H
O
H
O
H
O
H
O
NH2
O
CHO
e
e
3h
10
12
7
M
M
H
91
87
86
90
O
OMe
e
M
N
O
C
OMe
CHO
NH2
O
O
3i
OMe
CHO
N
C
NH2
O
O
3j
OH
N
C
NH2
O
CHO
e
)
3k
10
N M
(
2
N
N(Me)2
CHO
C
H
H
NH2
O
O
O
N
O2
3l
6
6
85
80
170–172 [168–170] [11]
210–212 [210–212] [29]
NO2
N
C
NH2
O
CHO
NO2
N
O2
3m
N
C
H
O
NH2
O
Reaction conditions: resorcinol (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), 10 mol% of
K2CO3/cyanuric acid (3:1) in water
a
Isolated yields
123

K2CO3/cyanuric acid catalyzed synthesis of 2-amino-4H-…
Table 5 The condensation of aromatic aldehydes with malononitrile and phenol in aqueous media
R
CHO
OH
Catalyst / H2O
r.t
CN
NC
CN
R
X
O
NH2
(1)
(4)
(2)
4a-4g
Entry
Aldehyde
Time (min)
12
Product
Yield (%)a
m.p. (°C)
CHO
Cl
4a
90
88
94
88
90
94
162–164 [165–168] [10]
192–194 [195–197] [10]
178–180 [178–180] [10]
162–164 [167–169] [10]
162–164 [165–167] [10]
200–202 [200–203] [10]
Cl
CN
NH2
O
CHO
Cl
Cl
4b
4c
4d
4e
4f
18
l
C
Cl
N
C
NH2
O
CHO
e
8
M
Me
CN
NH2
O
O
CHO
e
M
12
10
8
OMe
CHO
CN
NH2
O
OH
OH
CN
NH2
NO3
O
CHO
NO2
CN
NH2
O
123

R. Heydari et al.
Table 5 continued
Entry
Aldehyde
Time (min)
10
Product
Yield (%)a
91
m.p. (°C)
212–214 [215–217] [10]
CHO
N
O2
4g
NO2
CN
NH2
O
Reaction conditions: phenol (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), 10 mol% of K2-
CO3/cyanuric acid (3:1) in water
a
Isolated yields
7.17 (d, 1H), 7.38 (d, 1H), 7.55 (d, 1H), 9.87 (s, 1H, OH) ppm, 13C NMR (100 MHz,
CDCl3 DMSO-d6): d (ppm) 56.63, 102.72, 112.71, 112.91, 113.83, 113.97, 121.13,
121.63, 129.75, 129.95, 130.37, 142.04, 149.35, 155.62, 159.94, 160.69.
2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-car-
bonitrile (Table 6, Entry 5a) m.p. = 228–230 °C, literature 227–229 [33], 1H
NMR (400 MHz, CDCl3): d (ppm):1.07 (s, 3H), 1.13 (s, 3H), 2.21 (d, 1H,
J = 16.4 Hz), 2.27 (d, 1H, J = 16.4 Hz), 2.45 (s, 2H), 4.41 (s, 1H), 4.56 (s, 2H,
NH2), 7.23- 7.34 (m, 5H). 13C NMR (100 MHz, CDCl3): d (ppm) 200.1, 159.2,
155.0, 145.4, 127.6, 128.6, 126.0, 119.2, 112.5, 57.9, 50.8, 39.6, 37.9, 32.4, 27.1.
Results and discussion
According to the principles of green chemistry, we studied the developed synthesis
of 2-amino-4H-chromenes using benzaldehyde (1), malononitrile (2), and enolizable
C–H activated acidic compound (resorcinol (3a), phenol (4a), or dimedone (5a) at
room temperature in the presence of potassium carbonate/cyanuric acid as a catalyst
in water. First, 4-chlorobenzylaldehyde was selected as a model substrate for the
investigated amounts of the catalyst (Tables 1, 2, 3). In all the reactions, different
ratios and amounts of cyanuric acid and K2CO3 were examined. A longer reaction
time was necessary and a lower yield was obtained when we used cyanuric acid or
K2CO3 alone, while the best result was obtained for 10 mol% of catalyst with a
mole ratio of 3:1 (K2CO3:cyanuric acid). For the next step, the reaction between
malononitrile and an enolizable C–H activated acidic compound with various
aldehydes, in the presence of a catalytic amount of K2CO3/cyanuric acid was
investigated (Tables 4, 5, 6). Benzaldehydes with electron-withdrawing groups,
such as chloro and nitro, had quicker reactions than those with electron-donating
groups such as methoxy, methyl, etc. In addition, when using dimedone as an
enolizable C–H activated acidic compound, this reaction occurs more slowly and
less efficient. A suggested mechanism for the synthesis of 4H-chromene-3-
carbonitrile is shown in Scheme 1.
123

K2CO3/cyanuric acid catalyzed synthesis of 2-amino-4H-…
Table 6 The condensation of aromatic aldehydes with malononitrile and dimedone in aqueous media
R
CHO
O
O
Catalyst / H2O
r.t
CN
NC
CN
R
O
O
NH2
(1)
(5)
(2)
Time (min)
5a-5m
Entry
Aldehyde
Product
Yield (%)a
m.p. (°C)
CHO
5a
14
92
228–230 [227–229] [33]
O
N
C
NH2
O
CHO
Cl
l
C
5b
18
90
212–214 [212–214] [33]
O
O
N
C
NH2
O
O
CHO
Cl
5c
22
45
79
75
214–216 [208–210] [34]
178–180 [180–182] [32]
l
C
N
C
NH2
CHO
Cl
l
C
O
O
5d
l
N
O
C
C
Cl
NH2
CHO
Cl
5e
5f
20
15
90
89
180–182 [182–183] [33]
198–200 [197–198] [36]
l
C
l
C
C
Cl
O
N
NH2
CHO
Br
r
B
O
N
C
NH2
O
123

R. Heydari et al.
Table 6 continued
Entry
5g
Aldehyde
Time (min)
30
Product
Yield (%)a
80
m.p. (°C)
CHO
e
M
200–202 [196–198] [32]
218–220 [221–223] [32]
194–196 [198–200] [33]
201–203 [208–210] [35]
216–218 [223–225] [33]
O
Me
N
C
NH2
O
CHO
e
5h
40
40
25
20
OM
85
78
84
94
e
M
O
C
OMe
OMe
O
O
O
N
NH2
O
CHO
e
5i
M
O
OMe
CHO
N
C
NH2
O
O
H
5j
OH
N
C
NH2
O
CHO
e
)
5k
N M
(
2
O
O
N
N(Me)2
C
NH2
O
O
CHO
N
O2
5l
25
15
90
93
212–214 [213–214] [32]
178–180 [176–178] [32]
NO2
N
C
NH2
CHO
NO2
N
O2
5m
O
N
C
NH2
O
Reaction conditions: dimedone (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), 10 mol% of
K2CO3/cyanuric acid (3:1) in water
a
Isolated yields
123

K2CO3/cyanuric acid catalyzed synthesis of 2-amino-4H-…
CN
CN
CN
CN
2-
+
CO3
H
O
O
N
CN
CN
CN
CN
H
+
N
N
+
HO
OH
OH
OH
2-
CO3
+
O
O
H
2-
CO3
O-
OH
H
CN
CN
CN
N
N
C
N
C
HO
O
NH2
OH
HO
O
O
H
N
OH
NH
Scheme 1 Suggested mechanism for the preparation of 4H-chromene-3-carbonitrile
Conclusion
We have reported a rapid, green, and highly efficient method for the synthesis of
2-amino-4H-chromene with cyano-functionality derivatives. The present work
describes a simple and appropriate method for the one-pot reaction between various
benzaldehyde, malononitrile and enolizable C–H activated acidic compounds. The
reaction was performed in the presence of K2CO3/cyanuric acid as a mixture of
organic and inorganic catalysts in aqueous solution. The main advantages of this
approach are short reaction time, excellent yield, clean reaction media, simple work-
up and easy purification.
Acknowledgement We gratefully acknowledge financial support from the Research Council of the
University of Sistan and Baluchestan.
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