Disodium hydrogen phosphate as an efficient and cheap catalyst for the synthesis of 2-aminochromenes

Article abstract of DOI:10.1080/00397911.2010.518299

An efficient and convenient method for the synthesis of 2-aminochromene by the one-pot, three-component reaction of an aromatic aldehyde, malononitrile, and-or-naphthol in the presence of a catalytic amount of disodium hydrogen phosphate under solvent-fre

Full text of DOI:10.1080/00397911.2010.518299

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Disodium Hydrogen Phosphate as an
Efficient and Cheap Catalyst for the
Synthesis of 2-Aminochromenes
Xin-Ying Meng a , Hong-Juan Wang a , Chun-Ping Wang a & Zhan-Hui
Zhang a
a College of Chemistry and Material Science, Hebei Normal
University, Shijiazhuang, China
Accepted author version posted online: 30 Jun 2011.Published
online: 01 Jun 2011.
To cite this article: Xin-Ying Meng , Hong-Juan Wang , Chun-Ping Wang & Zhan-Hui Zhang
(2011) Disodium Hydrogen Phosphate as an Efficient and Cheap Catalyst for the Synthesis of 2-
Aminochromenes, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:23, 3477-3484, DOI: 10.1080/00397911.2010.518299
To link to this article: http://dx.doi.org/10.1080/00397911.2010.518299
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Synthetic Communications1, 41: 3477–3484, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518299
DISODIUM HYDROGEN PHOSPHATE AS AN EFFICIENT
AND CHEAP CATALYST FOR THE SYNTHESIS OF
2-AMINOCHROMENES
Xin-Ying Meng, Hong-Juan Wang, Chun-Ping Wang, and
Zhan-Hui Zhang
College of Chemistry and Material Science, Hebei Normal University,
Shijiazhuang, China
GRAPHICAL ABSTRACT
Abstract An efficient and convenient method for the synthesis of 2-aminochromene by the
one-pot, three-component reaction of an aromatic aldehyde, malononitrile, and a- or
b-naphthol in the presence of a catalytic amount of disodium hydrogen phosphate under
solvent-free conditions is described.
Keywords 2-Aminochromenes; disodium hydrogen phosphate; multicomponent
coupling reactions; solvent-free conditions
INTRODUCTION
Multicomponent coupling reactions (MCRs), powerful synthetic tools for the
creation of complex molecular structures from simple precursors via one-pot proce-
dures, have received much attention in recent years.[1] Three-component coupling of
an aromatic aldehyde, an active methylene derivative, and an activated phenol or
naphthol (A3 coupling) is one of the best examples of such a process. Substituted
2-aminochromenes obtained from this A3 coupling reaction are known to possess
multiple biological activities.[2] They can also serve as versatile intermediates for
the preparation of esoteric condensed heterocycles[3] and as components of many
natural products.[4] Traditionally, this A3-coupling reaction was catalyzed by
Received October 7, 2009.
Address correspondence to Zhan-Hui Zhang, College of Chemistry and Material Science, Hebei
Normal University, Shijiazhuang 050016, China. E-mail: zhanhui@126.com
3477

3478
X.-Y. MENG ET AL.
Scheme 1. Synthesis of 2-aminochromenes catalyzed by Na2HPO4.
piperidine, for example, using acetonitrile or ethanol as a solvent under conventional
heating or microwave irradiation.[5] A variety of catalysts such as heteropolyacids,[6]
iodine and K2CO3,[7] Amberlyst A-21,[8] tetrabutylammoniumbromide (TBABr),[9]
cetyltrimethylammonium bromide (CTABr),[10] hexadecyltrimethylammonium
bromide (HTMAB),[11] tricaprylmethylammonium bromide (Aliquat 336),[12]
methanesulfonic acid,[13] basic ionic liquid,[14] cetyltrimethylammonium chloride
(CTAC1),[15] nanosized magnesium oxide,[16] basic alumina,[17] diazabicyclo[2.2.2]
octane,[18] and Mg=Al hydrotalcite[19] have also been reported to promote this
reaction. Although these methods worked nicely in many cases, some of these
procedures are associated with one or more shortcomings such as long reaction time,
poor yield, use of volatile organic solvents, requirement for excess reagents or
catalysts, special apparatus, and harsh reaction conditions. Consequently, the devel-
opment of convenient, environmentally benign, high-yielding, and clean approaches
is in high demand.
Disodium hydrogen phosphate is a very inexpensive, nontoxic, and commer-
cially available compound that can be used in the laboratory without special pre-
cautions. Furthermore, solvent-free organic synthesis has been developed as an
environmentally friendly process.[20] As part of our ongoing interest in the use of
cheap and ecofriendly materials as catalysts for various transformations,[21] we
herein report a new method for the synthesis of 2-aminochromenes by the one-pot,
three-component reaction of an aromatic aldehyde, malononitrile, and naphthol in
the presence of a catalytic amount of disodium hydrogen phosphate under
solvent-free conditions (Scheme 1).
RESULTS AND DISCUSSION
To find a suitable catalyst for the synthesis of 2-aminochromenes, the coupling
reaction of 4-chlorobenzaldehyde, malononitrile, and a-naphthol was chosen as a
model reaction. The effects of different catalysts were tested under solvent-free
conditions at 120 ꢀC, and the results are displayed in Table 1. As seen from
Table 1, the activity of Na2HPO4 for this A3-coupling reaction is clearly greater than
that of nanocrystalline metal oxides such as ZnO, CuO, Al2O3, In2O3, Y2O3, Fe2O3,
TiO2, ZrO2, and Fe3O4; organic acids such as p-toluenesulfonic acid; heteropoly

SYNTHESIS OF 2-AMINOCHROMENES
3479
Table 1. Influence of different catalysts for the reaction of 4-chlorobenzaldehyde,
malononitrile, and a-naphthola
Entry
Catalyst
Time (h)
Yield (%)b
1
2
Nano-ZnO
Nano-CuO
1.5
1.5
1.5
1.5
1.5
1.0
1.5
1.5
1.0
1.0
1.0
1.0
1.0
20
40
80
60
85
30
35
70
39
30
30
90
95
3
Nano-Al2O3
Nano-In2O3
Nano-Y2O3
4
5
6
Nano-a-Fe2O3
Nano-c-Fe2O3
Nano-Fe3O4
p-Toluenesulfonic acid
12-Phosphotungstic acid
LiBr
7
8
9
10
11
12
13
(NH4)2HPO4
Na2HPO4
aReaction condition: 4-chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), and
a-naphthol (1 mmol), catalyst (10 mmol%), 120 ꢀC.
bYields refer to isolated pure products.
acids such as 12-phosphotungstic acid; and inorganic salts such as LiBr and
(NH4)2HPO4. Next, the effect of temperature on the rate of reaction was studied
for the model reaction. The reaction did not proceed at room temperature. At
120 ꢀC, the reaction proceeded smoothly, and almost complete conversion of pro-
duct was observed. To compare the efficiency as well as capacity of the solvent-free
conditions with respect to solution conditions, various solvents were examined, and
it was found that the solvent-free condition is more efficient (Table 2, entry 7). The
effect of amount of catalyst on the yield and rate was also investigated. It was found
that 5 mmol% of catalyst was enough for a fairly good yield. A control experiment
Table 2. Optimization of reaction conditionsa
Entry
Catalyst (mol%)
Solvent
Temperature (ꢀC)
Time (h)
Yield (%)b
1
2
10
10
10
10
10
10
10
5
AcOEt
CH2Cl2
CH3CN
EtOH
H2O
DMF
—
Reflux
Reflux
2.0
2.0
2.0
2.0
1.5
2.0
1.0
1.0
1.0
1.5
2
30
50
85
93
85
60
95
72
83
95
0
3
Reflux
Reflux
4
5
Reflux
Reflux
6
7
120
80
8
—
—
9
5
100
10
11
12
5
—
—
120
Room temperature
120
5
—
—
2.0
0
aReaction conditions: 4-chlorobenzaldehyde (1 mmol), malononitrile (1 mmol), and a-naphthol
(1 mmol).
bYields are related to isolated pure products.

3480
X.-Y. MENG ET AL.
Table 3. Synthesis of 2-aminochromenes catalyzed by Na2HPO4
Entry
Aldehyde
Phenol
Product Time (h) Yield (%)a
Mp (ꢀC)=(lit.)
1
2
4-MeC6H4CHO
2,3-(OMe)2C6H3CHO
3,4-(OMe)2C6H3CHO
a-Naphthol
a-Naphthol
a-Naphthol
4a
4b
4c
4d
4e
4f
1.0
1.5
1.5
1.0
1.0
1.0
1.5
1.0
0.8
0.8
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.0
1.5
86
82
83
90
90
95
87
85
90
93
90
88
85
84
89
92
95
85
90
83
205–206 (206–207[14b]
205–207
)
3
209–210 (210–211[12]
185–186 (186–187[12]
)
)
4
3,4,5-(OMe)3C6H2CHO a-Naphthol
PhCHO
5
a-Naphthol
a-Naphthol
a-Naphthol
a-Naphthol
a-Naphthol
a-Naphthol
a-Naphthol
b-Naphthol
b-Naphthol
b-Naphthol
b-Naphthol
b-Naphthol
b-Naphthol
b-Naphthol
b-Naphthol
218–219 (216–217[14b]
235–236 (231–232[14b]
240–242
)
)
6
4-ClC6H4CHO
2-BrC6H4CHO
4-BrC6H4CHO
2-NO2C6H4CHO
4-NO2C6H4CHO
4-CNC6H4CHO
4-MeC6H4CHO
3-MeC6H4CHO
4-OHC6H4CHO
PhCHO
7
4g
4h
4i
8
240–241 (241–243[18]
209–210 (208–210[12]
)
)
9
10
11
12
14
15
16
17
18
19
20
21
4j
241–242 (240–241[14b]
259–260 (258–260[18]
)
)
4k
5a
5b
5c
5d
5f
271–272 (270–271[14b]
237–238
304–306
)
288–289 (287–288[14b]
210–211 (209–210[14b]
)
)
4-ClC6H4CHO
2,4-Cl2C6H3CHO
2-BrC6H4CHO
4-CNC6H4CHO
5g
5h
5i
254–255 (255–257[22]
247–248
)
284–286 (285–287[18]
261–262
)
Pyridine-4-carbaldehyde b-Naphthol
5j
aIsolated yield.
was also carried out to confirm that no product was obtained in the absence of
catalyst (Table 2, entry 12).
The general applicability of this method was further evaluated for structurally
diverse aldehydes under optimized reaction conditions, and the results are depicted
in Table 3. The reactions proceeded smoothly with different aldehydes substituted
with electron-donating and electron-withdrawing groups to givie good to excellent
yields. Also, on replacing a-naphthol with b-naphthol, the reaction reached success-
ful completion under the same conditions. Remarkably, pyridine-4-carbaldehyde
(Table 3, entry 21) also reacted with b-naphthol and malononitrile under identical
experimental conditions and furnished the expected products in good yields. How-
ever, this reaction resulted in only traces of the respective products under similar
conditions when the aliphatic aldehyde was used as a starting material. Additionally,
we attempted to form 2-aminochromenes using phenols rather than naphthol; unfor-
tunately, these substrates failed to provide the expected chromenes but produced the
arylidenemalomonitriles from aldehydes and malononitrile.
In conclusion, we have developed a novel, simple, and very efficient procedure
for the synthesis of 2-aminochromenes with the advantages of operational simplicity,
good yield, shorter reaction time, solvent-free conditions, and the use of nontoxic
and inexpensive catalyst.
EXPERIMENTAL
Melting points were determined using an X-4 apparatus and are uncorrected.
Infrared (IR) spectra were obtained using a Shimadzu Fourier transform (FT)–IR

SYNTHESIS OF 2-AMINOCHROMENES
3481
8900 spectrometer. NMR spectra were taken with a Bruker DRX-500 spectrometer.
Elemental analyses were carried out on a Vario EL III CHNOS elemental analyzer.
Procedure for Synthesis of 2-Aminochromenes
A mixture of aldehydes (1 mmol), malononitrile (1 mmol), a- or b-naphthol
(1 mmol), and Na2HPO4 (0.05 mmol, 5 mol%) was placed in a round-bottomed flask
(25 ml) fitted with a condenser. The flask was placed in an oil bath and heated to
120 ꢀC. After completion of the reaction (monitored by thin-layer chromatography,
TLC), the mixture was diluted with water (10 ml), and the resulting solid was sepa-
rated by filtration. The crude product was recrystallized from ethanol to give the
pure product.
Selected Data
2-Amino-4-(2,3-dimethoxyphenyl)-4H-benzo[h]chromene-3-carbonitrile
(4b). Pale brown solid, mp 205–207 ꢀC; IR (KBr): 3300, 2194, 1654, 1608, 1481,
1
1375, 1263, 1105, 1066, 999, 952, 761 cmꢁ1; H NMR (500 MHz, DMSO-d6) dH
3.64 (s, 3H), 3.80 (s, 3H), 5.15 (s, 1H), 6.71 (dd, J ¼ 7.5, 1.5 Hz, 1H), 6.92 (dd,
J ¼ 8.5, 1.5 Hz, 1H), 6.99 (t, J ¼ 7.5 Hz, 1H), 7.03 (d, J ¼ 8.5 Hz, 1H), 7.11 (s, 2H),
7.54–7.58 (m, 2H), 7.63 (td, J ¼ 9.0, 1.5 Hz, 1H), 7.87 (d, J ¼ 8.0 Hz, 1H), 8.24
(d, J ¼ 7.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) dC 55.5, 55.6, 60.3, 111.5,
117.8, 120.6, 120.7, 121.0, 122.7, 123.7, 124.1, 125.9, 126.5, 126.6, 127.6, 132.6,
138.5, 142.8, 146.1, 152.4, 160.3. Anal. calcd. for C22H18N2O: C, 73.73; H, 5.06;
N, 7.82. Found: C, 73.92; H, 5.27; N, 7.61.
2-Amino-4-(2-bromophenyl)-4H-benzo[h]chromene-3-carbonitrile (4g).
Yellow powder, mp 240–242 ꢀC; IR (KBr): 3138, 2200, 1652, 1635, 1375, 1259,
;
1122, 1066, 995, 950, 864, 750 cmꢁ1 1H NMR (500 MHz, DMSO-d6) dH 5.43
(s, 1H), 7.01 (d, J ¼ 8.0 Hz, 1H), 7.18–7.23 (m, 4H), 7.34 (t, J ¼ 7.5 Hz, 1H),
7.58–7.67 (m, 4H), 7.89 (d, J ¼ 8.5 Hz, 1H), 8.25 (d, J ¼ 8.5 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6) dC 55.1, 116.6, 120.6, 120.7, 122.4, 122.6, 124.1, 125.2,
126.7, 126.9, 127.6, 128.5, 129.1, 131.4, 132.8, 132.9, 142.8, 143.9, 160.2. Anal. calcd.
for C20H13BrN2O: C, 63.68; H, 3.47; N, 7.43. Found: C, 63.82; H, 3.65; N, 7.28.
3-Amino-1-m-tolyl-1H-benzo[f]chromene-2-carbonitrile
(5b). Yellow
powder; mp 237–238 ꢀC; IR (KBr): 3458, 2189, 1658, 1591, 1409, 1228, 1082,
1
812 cmꢁ1; H NMR (500 MHz, DMSO-d6) dH 2.20 (m, 3H), 5.24 (s, 1H), 6.94–
6.97 (m, 4H), 7.00 (d, J ¼ 7.5 Hz, 1H), 7.15 (t, J ¼ 8.0 Hz, 1H), 7.34 (d, J ¼ 8.5 Hz,
1H), 7.15 (td, J ¼ 1.5, 7.5 Hz, 1H), 7.45 (td, J ¼ 1.5, 7.5 Hz, 1H), 7.84 (d, J ¼
8.0 Hz, 1H), 7.91 (d, J ¼ 9.0 Hz, 1H), 7.94 (d, J ¼ 9.0 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6) dC 21.1, 57.9, 115.7, 116.8, 120.5, 123.6, 124.1, 124.8, 127.0,
127.3, 127.4, 128.4, 128.5, 129.4, 130.1, 130.7, 137.7, 145.6, 146.7, 159.6. Anal. calcd.
for C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.90; H, 5.32; N, 9.10.
3-Amino-1-(4-hydroxyphenyl)-1H-benzo[f]chromene-2-carbonitrile (5c).
White powder; mp 304–306 ꢀC; IR (KBr): 3452, 2194, 1651, 1589, 1415, 1236, 1083,
812 cmꢁ1; 1H NMR (500 MHz, DMSO-d6) dH 5.17 (s, 1H), 6.63 (d, J ¼ 8.5 Hz, 2H),

3482
X.-Y. MENG ET AL.
6.90 (s, 2H), 6.98 (d, J ¼ 8.5 Hz, 2H), 7.31 (d, J ¼ 9.0 Hz, 1H), 7.40–7.46 (m, 2H),
7.84 (d, J ¼ 9.0 Hz, 1H), 7.90–7.92 (m, 2H), 9.27 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) dC 58.4, 115.3, 116.1, 116.7, 120.6, 123.7, 124.8, 126.9, 127.9, 128.4,
129.2, 130.2, 130.7, 136.2, 146.6, 155.9, 159.4. Anal. calcd. for C20H14N2O2: C,
76.42; H, 4.49; N, 8.91. Found: C, 76.60; H, 4.62; N, 8.79.
3-Amino-1-(2-bromophenyl)-1H-benzo[f]chromene-2-carbonitrile (5h).
Pale yellow powder; mp 247–248 ꢀC; IR (KBr): 3138, 2193, 1654, 1635, 1593,
1
1406, 1242, 1122, 1066, 951, 864 cmꢁ1; H NMR (500 MHz, DMSO-d6) dH 5.69 (s,
1H), 6.93 (d, J ¼ 6.5 Hz, 1H), 7.07 (s, 2H), 7.11 (t, J ¼ 7.5 Hz, 1H), 7.21 (t, J ¼ 7.5 Hz,
1H), 7.36 (d, J ¼ 9.0 Hz, 1H), 7.43 (t, J ¼ 7.5 Hz, 1H), 7.48 (t, J ¼ 7.5 Hz, 1H), 7.64
(d, J ¼ 6.5 Hz, 2H), 7.93 (d, J ¼ 8.0 Hz, 1H), 7.97 (d, J ¼ 9.0 Hz, 1H); 13C
NMR (125 MHz, DMSO-d6) dC 56.4, 115.0, 116.8, 119.7, 121.8, 122.8, 125.0,
127.4, 128.6, 128.7, 128.8, 129.9, 130.0, 130.1, 130.7, 132.7, 144.4, 147.1, 159.8. Anal.
calcd. for C20H13BrN2O: C, 63.68; H, 3.47; N, 7.43. Found: C, 63.89; H, 3.68;
N, 7.20.
3-Amino-1-pyridin-4-yl-1H-benzo[f]chromene-2-carbonitrile (5j). Yellow
powder; mp 261–262 ꢀC; IR (KBr): 3446, 2177, 1662, 1647, 1591, 1409, 1232, 1080,
1
806 cmꢁ1; H NMR (500 MHz, DMSO-d6) dH 5.40 (s, 1H), 7.15 (s, 2H), 7.19 (d,
J ¼ 6.5 Hz, 2H), 7.39 (d, J ¼ 9.0 Hz, 1H), 7.42–7.48 (m, 2H), 7.80 (d, J ¼ 8.0 Hz,
1H), 7.94 (dd, J ¼ 2.0, 6.5 Hz, 1H), 7.98 (d, J ¼ 9.0 Hz, 1H), 8.45 (dd, J ¼ 1.5,
4.5 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) dC 56.3, 114.2, 116.8, 120.1, 122.2,
123.4, 125.1, 127.3, 128.6, 129.9, 130.0, 130.8, 147.0, 150.1, 153.7, 160.0. Anal. calcd.
for C19H13N3O: C, 76.24; H, 4.38; N, 14.04. Found: C, 76.02; H, 4.25; N, 13.88.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural Science
Foundation of China (20872025 and 21072042), the Natural Science Foundation
of Hebei Province (B2011205031), and the Research Foundation for Undergraduate
Scientific and Technological Innovation Project (0911105004).
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