One-pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyranes and pyridopyrimidines under mild conditions

Article abstract of DOI:10.1002/jccs.201800048

1,8-Diazabicyclo[5.4.0]undec-7-ene immobilized on silica (SB-DBU)Cl as a reusable and heterogeneous catalyst was applied for the one-pot, three-component synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles and pyridopyrimidines, under solvent-free conditions. The reaction was carried out at room temperature, and pure products were obtained in high yields and short reaction times (3–7 min). This work introduced an environmentally benign procedure for the synthesis of these classes of biological active compounds.

Full text of DOI:10.1002/jccs.201800048

Received: 3 February 2018
Revised: 22 September 2018
Accepted: 25 September 2018
DOI: 10.1002/jccs.201800048
A R T I C L E
One-pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyranes
and pyridopyrimidines under mild conditions
Fatemeh Rigi | Hamid Reza Shaterian
Department of Chemistry, Faculty of Sciences,
1
,8-Diazabicyclo[5.4.0]undec-7-ene immobilized on silica (SB-DBU)Cl as a
University of Sistan and Baluchestan,
Zahedan, Iran
reusable and heterogeneous catalyst was applied for the one-pot, three-component
synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles and pyrido-
pyrimidines, under solvent-free conditions. The reaction was carried out at room
temperature, and pure products were obtained in high yields and short reaction
times (3–7 min). This work introduced an environmentally benign procedure for
the synthesis of these classes of biological active compounds.
Correspondence
Fatemeh Rigi, Department of Chemistry, Faculty
of Sciences, University of Sistan and Baluchestan,
Zahedan, Iran.
Email: rigi.fatemeh625@gmail.com
KEYWORDS
ambient conditions, kojic acid, pyridopyrimidines
1
| INTRODUCTION
component reaction of aromatic aldehyde, malononitrile, and
kojic acid in the presence of (SB-DBU)Cl as a catalyst
Multicomponent reactions (MCRs) are one of the most dom-
inant approaches for the green synthesis of organic com-
pounds. They are atom economic and efficient, and they
show a high bond-forming index. Therefore, MCRs have
been considered a suitable and green alternative to sequential
(
Scheme 1). We also report the synthesis of corresponding
pyridopyrimidine derivatives by the replacing 6-amino1,
-dimethyl uracil for kojic acid in the mentioned reaction
Scheme 1).
3
(
[1]
[
2–6]
multistep synthesis.
However, not all MCRs are actually
[
7]
green if 1 or more of the 12 green chemistry principles are
violated, such as utilization of nonrecoverable catalysts, poi-
sonous solvents, pollutants chemical reagents, etc.
2
| RESULTS AND DISCUSSION
[8–10]
To find the optimum conditions, the reaction of benzaldehyde
(1 mmol), malononitrile (1 mmol), and kojic acid (1 mmol)
was selected as a model under solvent-free conditions. Vari-
ous amounts of (SB-DBU)Cl as a catalyst were investigated
in this reaction at room temperature. The results are
Polysubstituted 2-amino-4H-dihydropyrano-pyranes are
important biologically active compounds that have profound
[11,12]
medical applications.
Furthermore, pyridopyrimidine
derivatives have attracted significant attention due to their
[
13]
various biological activities, including antitumor,
O
[14]
[15]
antimicrobial,
antileishmanial,
and calcium channel
antagonist activities. In this regard, many MCRs have been
OH
Ar
N
Cl
O
O
CN
NH
[16]
N
HO
HO
3
MeO
O
O
O
2
O
reported for the synthesis of polysubstituted 2-amino-4H-
O
O
SiO
O Si
CN
2
N
N
5a-5i
[17–20]
pyran-3-carbonitrile and pyridopyrimidine derivatives.
O
Cl
Ar
H
O
Ar
CN
However, most of these methods suffer from disadvantages
such as long reaction times, use of toxic solvents, and nonreu-
sable catalysts.
Solvent-free
r.t
2
H
C
O
CN
3
N
1
O
N
N
NH2
3
H C
N
4
CH
3
6a-6f
In continuation of our developments for the synthesis of
organic compounds using MCRs, herein, we report a
green and practical method for the preparation of 2-amino-
O
N
NH
2
[21–23]
CH
3
SCHEME 1 Preparation of 2-amino-4,8-dihydropyrano[3,2-b]pyrane-
3-carbonitriles (5a–5i) and pyridopyrimidines (6a–6f )
4
,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles via a three-
©
2018 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2018;1–4.
http://www.jccs.wiley-vch.de
1

2
RIGI AND SHATERIAN
TABLE 2 Preparation of 2-amino-4,8-dihydropyrano[3,2-b]
pyrane-3-carbonitriles (5a–5h) and pyridopyrimidines (6a–6f )
summarized in Table 1. As shown as Table 1, the best result
was obtained at 0.10 g of the catalyst at room temperature.
Using this optimization, we applied a wide variety of
aryl aldehydes containing electron-withdrawing and
electron-donating groups to afford the corresponding
Mp. [find]
Mp. [literature]
a
Entry
Substrate
Time
Yield (%)
1
CHO
3
98
90
93
218–220
[24]5a
2
19–221
2-amino-4,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles in
Me
high yields (Table 2, Entries 1–8).
2
3
Cl
5
5
211–215
[
In such a previous method, we used various aromatic
aldehydes in the reaction of 6-amino1,3-dimethyl, malononi-
trile, and aldehydes to obtain the desired substituted pyrido-
pyrimidines (Table 2, Entries 9–14).
24]5b
24]5c
210–213
CHO
Cl
242–243[
240–242
[24,25]
CHO
According to literature,
the plausible mechanism
for the synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyr-
ane-3-carbonitriles was described in Scheme 2. (SB-DBU)Cl
catalyzed the Knoevenagel reaction from aryl aldehyde
Cl
4
5
CHO
CHO
4
3
96
94
217–219
[
24]5d
220–222
(1) and malononitrile (2). Afterward, kojic acid (5) was
220–223
reacted with Knoevenagel product (4) via 1,4-Michael addi-
tion, followed by cyclization, to give compound (9). Com-
pound 9 was converted to the final product 10 after proton
transfer and tautomerization (Scheme 2).
[20]5e
2
25–227
OMe
Cl
6
CHO
5
92
237–239
[
25]5f
2
38–240
To demonstrate the importance of this research, we com-
pared the results of the present method with the other
[24–28]
reported works in the literature
(Table 3). The results
7
8
CHO
4
5
90
95
231–233
[
25]5g
25]5h
2
30–232
show that our protocol is the most efficient with respect to
the reaction time and yield.
O N
2
CHO
233–236
35–237
Finally, reusability of the catalyst was investigated. For
this purpose, the reaction of benzaldehyde (1 mmol), malo-
nonitrile (1 mmol), and kojic acid (1 mmol) was considered
a model in the presence of (SB-DBU)Cl (0.1 g) as a catalyst
at room temperature. After completion of the reactions, the
catalyst was separated by simple filtration, washed with eth-
[
2
Cl
9
CHO
3
97
220–222
[
25]5i
2
21–223
Me
10
CHO
CHO
7
3
87
89
263
268
[
[
26]6a
26]6b
ꢀ
anol, and dried in the oven at 65 C. The recovered catalyst
was reused for at least four runs without any significant loss
of its activity (Figure 1).
1
1
1
2
CHO
270
272
MeO
4
90
289
[
26]6c
284
3
3
| EXPERIMENTAL
NO2
.1 | Materials and measurements
1
1
3
4
CHO
3
3
89
91
288
91
[
26]6d
2
All reagents were purchased from Merck or Aldrich and
used without further purification. All yields refer to isolated
Cl
CHO
279
[26]6e
TABLE 1 Optimization of the reaction conditions for the synthesis of
276
2
-amino-4,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles under solvent-free
F
and ambient conditions
15
CHO
6
86
271
[26]6f
b
a,b
Entry
Catalyst (g)
Time (min)
Yield (%)
2
76
MeO
1
2
3
4
5
6
0.07
0.08
0.09
0.1
8
7
6
4
3
3
83
85
90
91
91
91
OH
a
Yields refer to the isolated pure products.
products after purification. Nuclear magnetic resonance
NMR) spectra were recorded using a Bruker Advance
0.2
(
0.25
DPX 400 MHz instrument. The spectra were measured in
a
Yields refer to the isolated pure products.
b
dimethyl sulfoxide-d relative to tetramethylsilane. Infrared
6
Reaction of kojic acid (1 mmol), malononitril (1 mmol), and benzaldehyde
1 mmol).
(
(IR) spectra were recorded using a JASCO FT-IR 460 Plus

RIGI AND SHATERIAN
3
O
SiO2 O Si
N
N
O
Cl
CN
H
CN
H
Knoevenagel Condensation
CN
CN
Ar
H
H
O
NC
CN
3
H2O
O
FIGURE 1 The reusability of the catalyst
Ar
H
1
3
.3 | General procedure for the preparation of
Ar
H
CN
CN
O
N
N
SiO2 O Si
pyridopyrimidines
Cl
4
O
O
A mixture of aromatic aldehyde (1 mmol), malononitrile
(1 mmol), 6-amino1,3-dimethyl uracil (1 mmol), and
O
O
HO
Michael addition
OH
O
6
(SB-DBU)Cl (0.1 g) was stirred at room temperature. The
HO
O
completion of the reaction was monitored by TLC. After
completion of reaction, the mixture was dissolved in hot
ethanol, and the catalyst was filtered. The filtrated solution
was concentrated, and the solid product was recrystallized
in EtOH to give pure products.
5
O
O
O
O
O
HN
NC
O
N
OH
O
N
N
OH
SiO2 O Si
O
Ar
NC
Cl
8
Ar
7
Cyclization
O
O
O
The structure of all known products was confirmed by
comparing their physical properties with those of known
samples in the literature.
H2N
O
HN
O
H
NC
OH
OH
9
NC
O
[24–28]
Ar
Ar
Products
10
2-amino-4-(2-chlorophenyl)-4,8-dihydro-6-(hydroxy-
SCHEME 2 The suggested mechanism for the preparation of 2-amino-
,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles
methyl)-8-oxopyrano[3,2-b]pyran-3-carbonitrile
Table 1 Entry 2): Mp. 211–215 C; IR (KBr) cm :3,365,
(5b,
ꢀ
−1
4
3
,190, 2,195, 1,646, 1,620, 1,591, 1,439, 1,409, 1,310, 1,256,
1
1,198, 1,046, 741. H NMR (400 MHz, DMSO-d ): 4.17 (m,
6
spectrophotometer. Melting points were determined in open
capillaries using a BUCHI 510 melting point apparatus.
Thin-layer chromatography (TLC) was performed on silica-
gel Poly Gram SIL G/UV 254 plates. (SB-DBU)Cl was pre-
2H), 5.36 (s, 1H), 5.66 (t, 1H, J = 6.0 Hz), 6.30 (s, 1H),
13
7.23–7.433 (m, 4H), 7.91 (s, 2H) ppm; C NMR (100.6 MHz,
DMSO-d ) δ: 59.3, 59.6, 111.8, 128.2, 129.3, 129.8, 130.6,
33.1, 136.4,141.1, 151.1, 160.3, 167.9 (6, 168.7, 170.0 ppm.
-amino-4-(4-Nitrophenyl)-4,8-dihydro-6-(hydroxy-
6
1
[29]
2
pared according previous procedure.
methyl)-8-oxopyrano[3,2-b]pyran-3-carbonitrile
(5g,
ꢀ
−1
Table 1 Entry 7): Mp. 230–232 C; IR (KBr) cm :3,538,
3
2
.2 | General procedure for the preparation of
-amino-4,8-dihydropyrano[3,2-b]pyrane-3-carbonitriles
1
3
,452, 3,329, 2,195, 1,649, 1,591, 1,340. H NMR
(
400 MHz, DMSO-d ): 4.19 (m, 2H), 5.0 (s, 1H), 5.69 (t,
6
A mixture of aromatic aldehyde (1 mmol), malononitrile
1 mmol), kojic acid (1 mmol), and (SB-DBU)Cl (0.10 g)
1
H, J = 6.0 Hz), 6.33 (s, 1H), 7.55 (d, 2H, J = 8.8 Hz),7.95
13
(
(
(
s, 2H), 8.20 (d, 2H, J = 8.8 Hz) ppm;
100 MHz, DMSO-d ) δ: 40.3, 59.5, 111.9, 124.3, 129.6,
C NMR
was stirred at room temperature. The completion of the reac-
tion was monitored by TLC. After completion of reaction,
the mixture was dissolved in hot ethanol, and the catalyst
was filtered. The filtrated solution was concentrated, and the
solid product was recrystallized in EtOH to give pure
products.
6
136.6, 147.1, 150.6, 151.0, 160.1, 167.7, 168.7 ppm.
7-amino-5-(3-nitrophenyl)-2,4-dioxo-1,2,3,4-tetrahy-
dropyrido[2,3-d]pyrimidine-6-carbonitrile (6c, Table 1
Entry 11): Mp. 289 C; IR (KBr) cm :3,540, 3,385, 2,215,
1,706, 1,664, 1,630, 1,560, 1,531, 1,436, 1,348, 1,091,
ꢀ
−1
TABLE 3 Comparison results of (SB-DBU)Cl for the preparation of 2-amino-4,8-dihydropyrano[3,2-b]pyranes as a catalyst with the other reported catalyst
b
a
Entry
Catalyst
Conditions
Time (min)
3–7
Yield (%)
89–98
5–25
1
2
3
4
5
(SB-DBU)Cl (0.10 g), this work
Solvent-free, r.t
[
24]
ꢀ
Ultrasound irradiation
MCM-41-SO H (30 mg)
Nano-ZnO (0.03 g)
H
H
2
O, 50 C
5–25
[
25]
ꢀ
3
2
O, 90 C
35–50
60–120
60–90
87–95
81–94
83–89
[
27]
28]
EtOH, reflux
EtOH, reflux
[
Imidazol (20 mol%)
a
Yields refer to the isolated pure products.
The reaction of kojic acid (1 mmol), malononitril (1 mmol), and aromatic aldehydes (1 mmol).
b

4
RIGI AND SHATERIAN
1
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6
13
3H, s), 7.61–7.71 (4H, m), 8.07 (1H, s), 8.24 (1H, s);
NMR (75 MHz, DMSO-d ): δ 28.1, 30.0, 89.1, 115.2,
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C
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(
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ACKNOWLEDGMENTS
[
[
[
We are thankful to the University of Sistan and Baluchestan
Research Council for the partial support of this research.
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ORCID
Fatemeh Rigi
http://orcid.org/0000-0002-9241-2891
SUPPORTING INFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
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pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b]
pyranes and pyridopyrimidines under mild conditions.
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