SiO2-OSO3H nanoparticles: An efficient, versatile and new reagent for the one-pot synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b] pyran-3-carbonitrile derivatives in water, a green protocol

Article abstract of DOI:10.3184/174751914X13866053657371

In a one-pot three-component reaction, an aromatic or aliphatic aldehyde, malononitrile and 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one were condensed for the synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile derivatives in the presence of nano-silica sulfuric acid (SiO ₂-OSO₃H nanoparticles) in improved yields. The catalyst is recoverable by simple filtration and can be used in the subsequent reactions.

Full text of DOI:10.3184/174751914X13866053657371

54 RESEARCH PAPER
JANUARY, 54–57
JOURNAL OF CHEMICAL RESEARCH 2014
SiO2–OSO3H nanoparticles: an efficient, versatile and new reagent for the
one-pot synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-
carbonitrile derivatives in water, a green protocol
Bahareh Sadeghi*, Parinaz Farokhi Nezhad and Saeedeh Hashemian
Department of Chemistry, Yazd Branch, Islamic Azad University, PO Box 89195-155, Yazd, Iran
In a one-pot three-component reaction, an aromatic or aliphatic aldehyde, malononitrile and 5-hydroxy-2-hydroxymethyl-4H-
pyran-4-one were condensed for the synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile derivatives in
the presence of nano-silica sulfuric acid (SiO –OSO3H nanoparticles) in improved yields. The catalyst is recoverable by simple
filtration and can be used in the subsequent r2eactions.
Keywords: nano-silica sulfuric acid, solid acid, kojic acid, malononitrile, green chemistry, one-pot synthesis
Organic reactions in water without using hazardous organic
solvents have attracted a great deal of interest in both academic
and industrial research because, in addition to environmental
concerns, there are beneficial effects of aqueous solvents on
rate and selectivity of important organic transformations.1–4
The pyran ring is an important class of structural motif of
many numerous natural products, synthetic pharmaceuticals
and molecular material which possess a high activity profile due
to their wide range of biological activities such as anticancer,5,6
anti-HIV,7 antimicrobial,8 anti-inflammatory9 and calcium
channel antagonist activity.10 Therefore, considerable attention
has been paid to develop efficient methods for the synthesis of
pyrans or fused pyran derivatives.
Application of environmentally benign water and solid
acid catalyst is a powerful green procedure. In this work, the
application of a solid phase acidic green nano catalyst (SiO2–
OSO3H nanoparticles) was investigated for the synthesis of
2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile
derivatives by the reaction between aldehydes, malononitrile
and 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one under reflux
in water.
The study was initiated by using benzaldehyde, malononitrile
and kojic acid as model substrates for the preparation of 4a.
There was no reaction without nano-silica sulfuric acid in
H2O under reflux (Table 1, entry 1). The transformation of
benzaldehyde with malononitrile and kojic acid proceeded
smoothly with nano-silica sulfuric acid (0.006 g) in H2O (5 mL),
and at the end of the reaction (about 15 min later), the product
was collected by filtration and recrystallised from ethanol,
affording the nicely crystalline 4a in good yield (95%, Table 1,
entry 2). Different solvents and catalysts were screened in the
model reaction, and the results are collected in Table 1. In the
presence of pyridine, Na2CO3, ZrCl4, SnCl2.2H2O, SbCl3 and
ZnCl2 in H2O, the reactions became sluggish (Table 1, entries
3–8). Different solvents, for example, CH2Cl2, EtOH, CH3CN
and DMF were tested in the presence of nano-silica sulfuric
acid as the catalyst, but unfortunately they resulted in low yields
or no reaction (Table 1, entries 9–13). Decreasing the catalyst
loading from 0.006 to 0.002 g, lowered the yield of the reaction
significantly (Table 1, entries 14 and 15). The yields of 4a were
not further improved using increased amount of the catalyst
(Table 1, entry 16). Thus, it is clear from the experiments that
the best conditions for 4a could be entry 2, employing nano-
silica sulfuric acid (0.006 g) as the solid acid and H2O as the
solvent under reflux. An interesting feature of this method is
that the reagent can be regenerated at the end of the reaction and
can be used several times without losing its activity. To recover
the catalyst, after completion of the reaction, the mixture was
filtered and recrystallised from hot ethanol, the catalyst was
separated and washed with ethanol and then dried. This process
was repeated for two cycles and the yield of product 4a did not
change significantly (Table 1, entries 17 and 18).
Results and discussion
In continuation of our investigations of the application of
solid acids in organic synthesis11–15 we have investigated the
synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-
carbonitrile derivatives by the three-component condensation
of 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one (kojic acid)
1, malononitrile 2 and an aliphatic or aromatic aldehyde 3 in
the presence of 0.006 g nano-silica sulfuric acid as catalyst
(Scheme 1).
Ar(R)
O
O
CN
CN
CN
2
HO
HO
SiO2-OSO3H NPs
Reflux, H2O
+
(R)Ar-CHO
+
OH
O
NH2
O
O
1
4
3
Scheme 1 Synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile derivatives by condensation of an aldehyde, kojic acid and
malononitrile using SiO2–OSO3H nanoparticles as catalyst.
* Correspondent. E-mail: bsadeghia@gmail.com
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JOURNAL OF CHEMICAL RESEARCH 2014 55
Table 1 Optimisation of the reaction conditions for synthesis of 4aa
O
O
O
O
CN
CN
+
CN
HO
HO
+
OH
NH2
O
CHO
Entry
1
2
3
4
5
6
7
8
Catalyst/g
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
EtOH
CH3CN
DMF
n-Hexane
H2O
H2O
H2O
H2O
H2O
Time/h
24
Yield/%b
0
95
Trace
18
27
Trace
15
Trace
Trace
35
Trace
46
0
79
82
96
93
89
Nano-silica sulfuric acid (0)
Nano-silica sulfuric acid (0.006)
Pyridine (0.006)
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.5
0.5
0.5
0.5
0.5
0.25
0.25
0.25
0.25
0.25
Na2CO3 (0.006)
ZrCl4 (0.006)
SnCl2.2H2O (0.006)
SbCl3 (0.006)
ZnCl2 (0.006)
9
Nano-silica sulfuric acid (0.006)
Nano-silica sulfuric acid (0.006)
Nano-silica sulfuric acid (0.006)
Nano-silica sulfuric acid (0.006)
Nano-silica sulfuric acid (0.006)
Nano-silica sulfuric acid (0.002)
Nano-silica sulfuric acid (0.004)
Nano-silica sulfuric acid (0.008)
10
11
12
13
14
15
16
17
18
Nano-silica sulfuric acid (0.006) 2nd run
Nano-silica sulfuric acid (0.006) 3rd run
aReaction condition: 5 mL of solvent under reflux, 1 mmol of benzaldehyde, 1 mmol of kojic acid, and 1 mmol of malononitrile.
bIsolated yields.
After optimising the reaction conditions, a series of aromatic
aldehydes were employed under similar circumstances to
evaluate the substrate scope of this reaction. The results are
summarised in Table 2. In all cases, aromatic aldehydes
substituted with either electron-donating or electron-
withdrawing groups underwent the reaction smoothly and
gave products in excellent yields. As a result, aldehydes with
electron-withdrawing groups reacted rapidly, while electron-
donating groups decreased the reactivity, requiring longer
reaction times. Having these data in hand, we have decided to
apply this method for heterocyclic benzaldehydes. Furfural,
thiophene-2-carbaldehyde and pyridine-4-carboxaldehyde
reacted with malononitrile and kojic acid under optimum
reaction conditions, and gave products 4i–k in somewhat
lower yields than those with aromatic aldehydes (Table 2,
entries 9–11). To our surprise, aliphatic aldehydes did react
Table 2 Synthesis of 2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile derivativesa
M.p./ºC
Entry
Ar (R)
Product
Time/min
Yield/%b
Found
Rep.16
220–222
240–242
210–213
207–208
248–250
242–244
219–221
271–273
223–225
235–237
233–235
–
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
15
20
16
10
25
20
33
30
20
25
25
15
20
12
15
20
95
90
88
96
95
94
86
84
88
87
91
96
92
98
94
91
220–221
239–241
211–213
206–208
248–249
243–245
220–222
271–273
223–225
236–237
234–236
258–260
248–250
245–247
239–241
184–186
2,4-Cl2C6H3
2-ClC6H4
2-FC6H4
4-FC6H4
3-BrC6H4
3-CH3C6H4
3,5-(CH3O)C6H3
2-Furyl
2-Thienyl
4-Pyridyl
3-O2NC6H4
2-HO-3-CH3OC6H3
4-Cl-3-O2NC6H3
4-NCC6H4
n-Butyl
–
–
–
–
aReaction condition: 1 mmol of aldehyde, 1 mmol of kojic acid, 1 mmol of malononitrile, 5 mL of water under reflux condition.
bIsolated yields.
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56 JOURNAL OF CHEMICAL RESEARCH 2014
of the solvent, the crude product was recrystallised from hot ethanol to
obtain the pure compound.
with malononitrile and kojic acid as well as aromatic aldehydes.
Butyraldehyde reacted with malononitrile and kojic acid
under optimum reaction conditions with good yield (Table 2,
entry 16).The compounds 4a–k were characterised by their 1H
NMR and IR spectroscopy and elemental analyses. Spectral
data were compared with the literature data.16 Compounds 4l–p
were new and their structures were deduced by elemental and
spectral analysis. The IR spectrum of compound 4n shows
two sharp bands at region 3395 and 3373 cm–1 one broad band
at region 3245 cm–1. These bands are due to the NH2 and OH
groups, respectively. The predominant absorbance peak at
2235 cm–1 was due to the nitrile group. The 1H NMR spectrum
of compound 4n exhibited a proton of methine at 5.08 ppm and
the NH2 protons are observed at 7.41 ppm, and the OH proton
is observed as a triplet signal at 5.70 ppm which disappears
after addition of some D2O to the DMSO solution of 4n.
The diastereotopic hydrogens of the methylene group on the
hydroxymethyl substituent shows two doublets for each of the
hydrogens between 4.12 and 4.23 ppm. Such signals are often
complex because of small differences in the chemical shift,
overlap and an additional strong coupling between the geminal
hydrogens. Aromatic protons are observed between 7.69 and
8.10 ppm. The 13C NMR spectrum of compound 4n showed 16
signals in agreement with the proposed structure. The mass
spectrum of compound 4n showed the molecular ion peak at
375.
In conclusion, an efficient, environmentally benign, atom
economical, and simple methodology for the preparation of
2-amino-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile
derivatives in a three-component reaction in water has been
reported. Prominent among the advantages of this method are
operational simplicity, mild reaction conditions, higher yields,
and environmental friendliness. Meanwhile, solid phase acidic
catalyst could be reused a number of times without appreciable
loss of activity. The present method does not involve any
hazardous organic solvent. Therefore, this procedure can be
classified as green chemistry.
2-Amino-6-hydroxymethyl-4-(3-nitrophenyl)-8-oxo-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitrile (4l): Reddish-brown solid,
m.p. 258–260 °C; IR (νmax, cm–1): 3384 and 3375 (NH2), 3315 (OH),
1
2245 (CN), 1675 (C=O), 1530 and 1345 (NO2); H NMR (400 MHz,
DMSO-d6): δ 4.14 (dd, 1H, J=16.4, J=6.0 Hz, aliphatic), 4.18 (dd, 1H,
J=16.4, J=6.0 Hz, aliphatic), 5.12 (s, 1H, methine), 5.65 (t, 1H, J=6.0 Hz,
OH), 6.32 (s, 1H, =CH), 7.37 (s, 2H, NH2), 7.71 (d, 1H, J=8 Hz, aromatic),
7.80 (d, 1H, J=6.4 Hz, aromatic), 8.16–8.20 (m, 2H, aromatic) ppm; 13
C
NMR (100 MHz, DMSO-d6): δ 55.1, 59.5, 111.9, 114.7, 114.8, 119.1, 122.9,
123.5, 131.1, 135.1, 143.3, 148.2, 148.5, 159.9, 168.7, 170.0 ppm; MS (m/z,
%): 341 (M+, 5). Anal. calcd for C16H11N3O6: C, 56.30; H, 3.25; N, 12.31;
found: C, 56.29; H, 3.28; N, 12.23%.
2-Amino-4-(2-hydroxy-3-methoxyphenyl)-6-hydroxymethyl-8-oxo-
4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (4m): Cream solid,
m.p. 248–251 °C; IR (νmax, cm–1): 3375 and 3345 (NH2, OH), 2190 (CN),
1660 (C=O) cm–1; 1H NMR (400 MHz, DMSO-d6): δ 3.80 (s, 3H, OCH3),
4.10–4.19 (m, 2H, CH2), 5.15 (s,1H, methine), 5.58 (t, 1H, J=6.0 Hz, OH),
6.25 (s, 1H, =CH), 6.97–7.05 (m, 3H, aromatic), 7.09 (s, 2H, NH2), 9.23 (s,
1H, OH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 55.2, 55.3, 59.1, 105.8,
111.3, 114.3, 119.1, 123.7, 132.4, 136.4, 136.9, 143.3, 148.7, 159.3, 160.7,
168.3, 169.5 ppm; MS (m/z, %): 342 (M+, 8). Anal. calcd for C17H14N2O6:
C, 59.65; H, 4.12; N, 8.18; found: C, 59.58; H, 4.10; N, 8.16%.
2-Amino-4-(4-chloro-3-nitrophenyl)-6-hydroxymethyl-8-oxo-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitrile (4n): Bright cream solid,
m.p. 228–234 °C; IR (νmax, cm–1): 3395 and 3373 (NH2), 3245 (OH),
2235 (CN), 1677 (C=O); 1H NMR (400 MHz, DMSO-d6): δ 4.15 (dd, 1H,
J=16, J=6.0 Hz, aliphatic), 4.20 (dd, 1H, J=16, J=6.0 Hz, aliphatic),
5.08 (s,1H, methine), 5.70 (t, 1H, J=6.4 Hz, OH), 6.34 (s, 1H, =CH),
7.41 (s, 2H, NH2), 7.70 (dd, 1H, J=8.4, J=2.0 Hz, aromatic), 7.81 (d, 1H,
J=8.4 Hz, aromatic), 8.10 (d, 1H, J=2 Hz, aromatic) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 54.3, 59.0, 111.4, 118.9, 124.3, 124.9, 132.1,
133.3, 136.9, 141.6, 147.1, 147.8, 159.3, 159.3, 168.2, 169.5 ppm; MS (m/z,
%): 375 (M+, 7). Anal. calcd for C16H10ClN3O6: C, 51.14; H, 2.68; N, 11.18;
found: C, 51.12; H, 2.65; N, 11.10%.
2-Amino-4-(4-cyanophenyl)-6-hydroxymethyl-8-oxo-4,8-
dihydropyrano[3,2-b]pyran-3-carbonitrile (4o): Cream solid, m.p.
239–242 °C; IR (νmax, cm–1): 3340 and 3315 (NH2), 3215 (OH), 2190 (CN),
2185 (CN), 1662 (C=O); 1H NMR (400 MHz, DMSO-d6): δ 4.13 (dd, 1H,
J=15.9 Hz, J=6.0 Hz, aliphatic), 4.21 (dd, 1H, J=15.9 Hz, J=6.0 Hz,
aliphatic), 4.99 (s,1H, methine), 5.69 (t, 1H, J=6.0 Hz, OH), 6.34 (s, 1H,
=CH), 7.36 (s, 2H, NH2), 7.53 (d, 2H, J=8.3 Hz, aromatic), 7.87 (d, 2H,
J=8.3 Hz, aromatic) ppm; 13C NMR (100 MHz, DMSO-d6): δ 54.6, 58.9,
110.7, 111.4, 115.3, 117.9, 118.5, 128.9, 130.6, 132.9, 133.1, 136.6, 146.0,
147.7, 159.6, 168.2, 169.4 ppm; MS (m/z, %): 321 (M+, 10). Anal. calcd
for C17H11N3O4: C, 63.55; H, 3.45; N, 13.07; found: C, 63.47; H, 3.40; N,
13.05%.
Experimental
Melting points were determined with an Electrothermal 9100
apparatus. Elemental analyses were performed using a Costech ECS
4010 CHNS-O analyser of the analytical laboratory of the Science
and Research Unit of the Islamic Azad University. Mass spectra were
recorded on a Finnigan-Mat 8430 mass spectrometer operating at an
ionisation potential of 70 eV. IR spectra were recorded on a Shimadzu
IR-470 spectrometer. 1H and 13C NMR spectra were recorded on
Bruker DRX-400 Avance spectrometer at solution in DMSO using
TMS as internal standard. The chemicals used in this work were
purchased from Fluka (Buchs, Switzerland) and were used without
further purification.
2-Amino-6-hydroxymethyl-8-oxo-4-propyl-4,8-dihydropyrano[3,2-b]
pyran-3-carbonitrile (4p): Bright cream solid, m.p. 184–188 °C; IR (νmax
,
cm–1): 3335 and 3315 (NH2, OH), 2955 (C–H, aliphatic), 2195 (CN), 1640
(C=O); 1H NMR (400 MHz, DMSO-d6): δ 0.94 (t, 3H, J=7.6 Hz, CH3),
1.35–1.48 (m, 2H, CH2), 1.63–1.81 (m, 2H, CH2), 3.71 (t, 1H, J=4.4 Hz,
OH), 4.34–4.39 (dd, 2H, J=12, J=6 Hz, CH2), 5.83 (t, 1H, J=6 Hz,
methine), 6.4 (s,1H, =CH), 7.1 (s, 2H, NH2) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 13.81, 17.58, 35.46, 53.30, 59.17, 111.30, 119.54, 136.99,
139.21, 150.26, 156.48, 160.09, 167.99 ppm; MS (m/z, %): 262 (M+, 4).
Anal. calcd for C13H14N2O4: C, 59.53; H, 5.38; N, 10.68; found: C, 59.50;
H, 5.34; N, 10.59%.
The stable silicagel nanoparticles was prepared17 and used for the
preparation of the catalyst (nano-silica sulfuric acid).
Synthesis of nano-silica sulfuric acid
The reagent was prepared by combination of chlorosulfonic acid
(23.3 g) drop by drop over 10 min via a syringe to nano-silica gel
powder (60 g) in a 100 mL flask at 0 °C. The reaction mixture was then
stirred and then after 30 min, the white powder was centrifuged and
separated. The dimensions of nanoparticles were observed with SEM.
The size of particles is between 28 and 32 nm.
The research Council of the Islamic Azad University of Yazd is
gratefully acknowledged for the financial support for this work.
Synthesis of compounds 3a–p; general procedure
A mixture of aromatic aldehyde (1 mmol), malononitrile (1 mmol),
kojic acid (1 mmol) nano-silica sulfuric acid as catalyst (0.006 g) and
H2O (5 mL) was placed in a round-bottomed flask. The materials
were stirred magnetically and refluxed for the appropriate time as
mentioned in Table 2. After completion of the reaction, by evaporation
Received 16 October 2013; accepted 22 November 2013
Paper 1302240 doi: 10.3184/174751914X13866053657371
Published online: 8 January 2014
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