Synthesis of benzopyrano[2,3-d]pyrimidines using silica-bonded N-propylpiperazine sodium N-propionate as heterogeneous solid base catalyst under solvent-free conditions

Article abstract of DOI:10.1007/s00706-015-1552-2

Silica-bonded N-propylpiperazine sodium Npropionate is employed as a recyclable heterogeneous solid base catalyst for the synthesis of benzopyrano[2,3-d]pyrimidines through one-pot condensation reaction of salicylaldehydes, malononitrile, and secondary amines at room temperature under solvent-free conditions. The catalyst could be recycled several times without appreciable loss in catalytic activity.

Full text of DOI:10.1007/s00706-015-1552-2

Monatsh Chem
DOI 10.1007/s00706-015-1552-2
ORIGINAL PAPER
Synthesis of benzopyrano[2,3-d]pyrimidines using silica-bonded
N-propylpiperazine sodium N-propionate as heterogeneous solid
base catalyst under solvent-free conditions
Khodabakhsh Niknam1 Nassim Borazjani1
•
Received: 4 June 2015 / Accepted: 3 August 2015
Ó Springer-Verlag Wien 2015
Abstract Silica-bonded N-propylpiperazine sodium N-
propionate is employed as a recyclable heterogeneous solid
base catalyst for the synthesis of benzopyrano[2,3-
d]pyrimidines through one-pot condensation reaction of
salicylaldehydes, malononitrile, and secondary amines at
room temperature under solvent-free conditions. The cat-
alyst could be recycled several times without appreciable
loss in catalytic activity.
Introduction
Benzopyranopyrimidines have provided an important
pharmacophore-synthesized research platform for che-
mists. This is because of their specific characteristics which
consist of anti-inflammatory, analgesic, in vivo antitumor,
in vitro anti-aggregating activities as well as cytotoxic
activity against cancer cell lines, and causing significant
perturbation in cell cycle kinetics [1–5]. In this respect,
several pyrimidine derivatives such as compounds 1–3
showed good in vitro antiplatelet activity, being able to
inhibit arachidonic acid (AA), ADP, and collagen-induced
aggregation, together with a good in vivo antithrombotic
effect (Fig. 1) [3, 6–9]. Some of these compounds were
also found to be interesting as analgesic and/or anti-
phlogistic agents [6]. The basic function in
benzopyranopyrimidine scaffold was also investigated and
it was concluded that it has a pivotal role in the expression
of antiphlogistic/analgesic activities without adverse gas-
trolesive effects [10].
Graphical abstract
Keywords Benzopyrano[2 Á 3-d]pyrimidines Á
Heterogeneous catalyst Á Solid base Á
Silica-bonded N-propylpiperazine sodium N-propionate Á
Synthesis Á Solvent-free conditions
In this respect, lots of methods have been developed for
the preparation of benzopyranopyrimidine derivatives [1–
5, 11–13] while none of them contain recyclable and reu-
sable catalysts in their protocols. Bazgir and co-workers for
the first time have reported the synthesis of benzopy-
rano[2,3-d]pyrimidines
via
pseudo-four-component
reaction of salicylic aldehyde, malononitrile, and amine in
the presence of LiClO4 in EtOH at room temperature for
24 h [14]. Very recently, this multi-component protocol
has been developed by ionic liquid [Bmim]BF4 [15],
Brønsted acidic ionic liquids [16], ZrOCl2•8H2O [17],
silica nanoparticles immobilized benzoylthiourea ferrous
complex [18], manganese(III) salen complex immobilized
on Fe3O4 magnetic nanoparticles [19], and choline chlo-
ride-based deep eutectic solvent [20].
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1552-2) contains supplementary
material, which is available to authorized users.
& Khodabakhsh Niknam
khniknam@gmail.com;
niknam@pgu.ac.ir
1
Department of Chemistry, Faculty of Sciences, Persian Gulf
University, 75169 Bushehr, Iran
123

K. Niknam, N. Borazjani
Several types of propyl amine functionalized silica,
hydrotalcites, and basic zeolites (microporous and meso-
porous) have been synthesized and applied as an alternative
to traditional amines in base catalyzing chemical trans-
formations [21–30].
sodium N-propionate (SBPPSP) [31], silica-bonded N-
propylpiperazine (SBPP) [32], silica-bonded N-propyl-
morpholine (SBPM) [33], and 3-silicapropylamine (3-
SPA) [34], and investigated their applications as
heterogeneous solid bases in organic reactions [35] or
using as ligand for stabilizing Pd nanoparticles [36–38]
(Fig. 2).
Recently, we prepared some silica immobilized
amines such as, silica-bonded N-propylpiperazine
Fig. 1 The structure of some bio-active compounds
Fig. 2 The structure of used solid bases
123

Synthesis of benzopyrano[2,3-d]pyrimidines using silica-bonded N-propylpiperazine sodium N-…
In continuation our research on the design and appli-
cation silica functionalized solid acids and bases as
heterogeneous catalysts in organic transformations [26, 27,
31–40], we describe the application of silica-bonded N-
propylpiperazine sodium N-propionate (SBPPSP) in the
synthesis of benzopyrano[2,3-d]pyrimidine derivatives via
pseudo four-component condensation of salicylaldehydes,
malononitrile, and secondary amine at room temperature
and solvent-free conditions. To the best of our knowledge,
there is no other report about the synthesis of benzopyra-
nopyrimidines via pseudo-four-component condensation
reaction of salicylic aldehyde, malononitrile, and sec-
ondary amines using solid bases as catalysts.
For this purpose, the reaction between salicylaldehyde
(2 mmol), malononitrile (1 mmol), and morpholine
(1 mmol) was selected as a model reaction at room tem-
perature in order to establish the feasibility of the strategy
and optimize the reaction conditions. As shown in
Table 1, the catalytic effect of solid amines SBPPSP,
SBPP, SBPM, and 3-SPA was studied as a heterogeneous
base catalysts. All of these silica immobilized propy-
lamines were accomplished this pseudo-four-component
condensation reaction at room temperature under solvent-
free conditions. The model reaction was converted into
corresponding product in a higher yield using solid base
SBPPSP as catalyst (Table 1, entry 3). The lower amounts
of SBPPSP (0.03 g) were converted the model reaction in
longer reaction time and lower yield (Table 1, entry 5)
and using higher amounts of the catalyst (0.07 g) did not
improve the result to an appreciable extent (Table 1, entry
6). The model reaction was treated in solvents such as
ethanol, water, toluene, and acetonitrile in the presence of
0.05 g SBPPSP as catalyst at room temperature (Table 1,
entries 7–10), but the best result was under solvent-free
conditions. Also, the model reaction was treated with
commercially available bases such as triethylamine and
Results and discussion
The catalytic activity of silica immobilized bases (SBPPSP,
SBPP, SBPM, and 3-SPA) was investigated as a hetero-
geneous solid base catalysts in one-pot synthesis of
benzopyranopyrimidines through pseudo-four-component
reaction of salicylaldehyde, malononitrile, secondary
amine and the results are summarized in Table 1.
Table 1 Investigation the effect of catalysts and solvents on the reaction of salicylaldehyde, malononitrile, and morpholine at room temperature
O
N
H
N
Catalyst
CHO
OH
N
+
2
NC
CN
+
O
N
Conditions
O
HO
Entry
Catalyst
Catalyst loading/g
Conditions
Time/h
Yield/%a
1
3-SPA
0.05
0.05
0.05
0.05
0.03
0.07
0.05
0.05
0.05
0.05
0.30
0.30
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Ethanol
7
7
80
82
85
80
72
86
75
30
40
N.R.
58
60
2
SBPP
3
SBPPSP
SBPM
6
4
9
5
SBPPSP
SBPPSP
SBPPSP
SBPPSP
SBPPSP
SBPPSP
6
6
6
7
8
8
Toluene
8
9
Acetonitrile
Water
8
10
11
12
8
Triethylamine
Morpholine
Ethanol
12
12
Ethanol
Reaction conditions: salicylaldehyde (2 mmol) and malononitrile (1 mmol) at room temperature (in the case of solvent 3 cm3)
a
Isolated yield
123

K. Niknam, N. Borazjani
Table 2 Synthesis of benzopyranopyrimidines using SBPPSP as catalyst at room temperature and under solvent-free conditions for 6 h
Entry
Amine
R
Product
Yield/ %a
M.p./°C
Lit. m.p./°C
1
Morpholine
Dimethylamine
Piperidine
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
197–199
179–181
170–172
211–213
204–206
194–196
189–193
227–230
180–182
172–174
–
196–197 [15]
177–179 [14]
168–170 [14]
235–237 [18]
198–200 [17]
200–201 [16]
187–189 [17]
225–226 [18]
174–176 [17]
–
2
H
83
3
H
80
4
Pyrrolidine
H
75
5
Morpholine
Dimethylamine
Piperidine
5-Br
5-Br
5-Br
4-CH3O
4-CH3O
3-OH
H
75
6
73
7
70
8
Morpholine
Dimethylamine
Morpholine
Diethylamine
Dibutylamine
75
9
25
10
11
12
a
6j
–
20
N.R.
N.R.
–
H
–
–
–
Isolated yield
morpholine the corresponding product was obtained in the
presence of 0.30 mmol of these bases after 12 h in
58–60 % yields (Table 1, entries 11 and 12). The opti-
mum conditions was a-hydroxybenzaldehyde (2 mmol),
malononitrile (1 mmol), secondary amine (1 mmol), and
SBPPSP (0.05 g) at room temperature under solvent-free
conditions.
The possibility of recycling the catalyst SBPPSP was
examined using by the reaction of salicylaldehyde,
malononitrile, and morpholine under the optimized condi-
tions. Upon completion, 10 cm3 ethanol was added and
filtered. The remaining was washed with warm ethanol
(2 9 5 cm3). The separated catalyst was dried and reused
as such for subsequent experiments under similar reaction
conditions. The results showed that the catalyst could be
effectively used for at least four consecutive cycles without
much appreciable loss in its catalytic activity (Fig. 3).
To show the advantages of these solid bases (3-SPA,
SBPP, SBPPSP, and SBPM) as a catalyst in this pseudo-
four-component reaction, our results and reaction condi-
tions for synthesis of 2-(4-morpholino-5H-chromeno[2,3-
d]pyrimidin-2-yl)phenol (6a) were compared with previ-
ously reported data as shown in Table 3. The results show
that our method is quite comparable with the former
methods in yields and reaction times. Moreover, the
amounts of these solid bases are low and they could be
recycled and reused again for several times while most of
the former methods using catalyst which could not
recyclable.
The reaction can tolerate a-hydroxybenzaldehydes and
some of its derivatives carrying both electron-donating
such as MeO and halogen such as Br and the results were
reasonable (Table 2). Aliphatic amines such as diethy-
lamine and dibutylamine did not react while the best results
were achieved with cyclic secondary amines such as
morpholine, piperidine, and pyrrolidine.
Proposed mechanism for the synthesis of benzopyra-
nopyrimidine derivative 6 was described in Scheme 1 [18,
35]. The process represents a typical cascade reaction in
which the catalyst facilitates the Knoevenagel condensa-
tion reaction through activate malononitrile for
nucleophilic attack to the salicylic aldehyde. The catalyst
can activate O–H groups so that the Pinner reaction occurs
and intermediate II was formed. Next, the cyano group of
intermediate II can be attacked by the amine to produce
intermediate III. Finally, intermediate III reacts with
another molecule of salicylic aldehyde followed by proton
transfer to afford the final benzopyranopyrimidine 6. Also,
catalyst could be able to facility of the capture and losing
the proton process.
In conclusion, this work shows that silica-bonded solid
bases which can be prepared by simple operation from
commercially available and relative cheap starting materials
efficiently catalyzed the synthesis of benzopyranopyrim-
idines. It could also be recovered and reused for several times
without noticeable loss of reactivity.
123

Synthesis of benzopyrano[2,3-d]pyrimidines using silica-bonded N-propylpiperazine sodium N-…
Scheme 1
123

K. Niknam, N. Borazjani
pionate (SBNPPSP) [31], silica-bonded N-propylpiperazine
(SBNPP)
[32],
silica-bonded
N-propylmorpholine
(SBNPM) [33], and 3-silicapropylamine (3-SPA) [34] were
prepared according to our previously reported procedure.
General procedure for the synthesis
of benzopyranopyrimidines
A mixture of 2-hydroxybenzaldehyde derivative (2 mmol),
malononitrile (1 mmol), secondary aliphatic amine
(1 mmol), 0.05 g SBPPSP (4.3 mol %) [31], under sol-
vent-free conditions was stirred at room temperature for
6 h (the progress of the reaction was monitored by TLC, by
taking a small part of reaction mixture and solving in ethyl
acetate). After completion, 10 cm3 warm ethanol was
added and filtered. The remaining was washed with warm
ethanol (2 9 5 cm3) in order to separate catalyst. After
cooling the organic phase, the crude was precipitated and
filtered to obtained products. For further purification the
crude was recrystallized from ethanol (95 %). The recov-
ered catalyst was dried and reused for subsequent runs.
Fig. 3 Recyclability of SBPPSP as catalyst in the reaction of
salicylaldehyde (2 mmol), malononitrile (1 mmol), and morpholine
(1 mmol) in the presence of 0.05 g of SBPPSP at room temperature
under solvent-free conditions. Reaction time = 6 h
Experimental
Chemicals were purchased from Merck and Aldrich
1
chemical companies. For recorded H NMR spectra, we
were using Bruker Ultrashield (400 MHz) in pure deuter-
ated DMSO-d6 solvent with tetramethylsilane (TMS) as
internal standard. Melting points were determined in open
capillary tubes in a Barnstead Electrothermal 9100 BZ
circulating oil melting point apparatus. The reaction mon-
itoring was accomplished by TLC on silica gel Poly Gram
SILG/UV254 plates. All the products are known com-
pounds and were characterized by comparison of their IR,
1H NMR, and 13C NMR spectroscopic data and their
melting points with reported values [13–20]. Solid bases
such as silica-bonded N-propylpiperazine sodium N-pro-
3-Hydroxy-2-(8-hydroxy-4-morpholino-5H-chromeno[2,3-
d]pyrimidin-2-yl)phenol (6j, C21H19N3O5)
White solid; m.p.: 172-174 °C; IR (KBr): = 3450, 3060,
2965, 2890, 2830, 1601, 1508, 1430, 1260, 1103 cm-1; 1H
NMR (400 MHz, DMSO-d6): d = 3.55 (t, 4H, J = 3.8 Hz,
N(CH2)2), 3.81 (t, 4H, J = 3.8 Hz, O(CH2)2), 4.00 (s, 2H,
CH2), 6.71-6.76 (m, 2H, Ar), 6.81 (d, 1H, J = 6.3 Hz, Ar),
6.89–6.95 (m, 2H, Ar), 7.76 (d, 1H, J = 6.3 Hz, Ar), 8.56
(brs, 1H, OH), 9.50 (brs, 1H, OH), 13.09 (brs, 1H, OH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 24.6, 47.9,
Table 3 Comparison the results of SBPPSP, SBPP, SBPM, and 3-SPA with other catalysts reported in the literature for the synthesis of 6a
Entry
Catalyst
Conditions
Time/h
Yield/%a
Ref.
1
LiClO4 (20 mol %)
[Bmim]BF4 (5 mol %)
[Hnhp][HSO4] (5 mol %)
Piperidine (20 mol %)
Piperidine (20 mol %)
ZrOCl2•8H2O (30 mol %)
Fe(II)-BTU-SNPs (15 mg)
Fe3O4/SiO2/Salen/Mn MNP (0.8 mg)
–
Ethanol, rt
24
0.33
0.2
11
0.1
15
4
95
76
87
78
92
88
93
96
75
80
82
85
80
[11]
2
Solvent-free, rt
[12]
3
Solvent-free, rt
[13]
4
Solvent-free, 100 °C
MW (180 W), 100 °C
Solvent-free, rt
[10]
5
[10]
6
[14]
7
Ethanol, rt
[15]
8
Solvent-free, rt
Choline chloride-urea (0.5 cm3), rt
0.83
1
[16]
9
[17]
10
11
12
13
a
3-SPA (0.05 g)
Solvent-free, rt
8
This work
This work
This work
This work
SBPP (0.05 g)
Solvent-free, rt
7
SBPPSP (4.3 mol %, 0.05 g)
SBPM (0.05 g)
Solvent-free, rt
6
Solvent-free, rt
9
Isolated yield
123

Synthesis of benzopyrano[2,3-d]pyrimidines using silica-bonded N-propylpiperazine sodium N-…
14. Ghahremanzadeh R, Amanpour T, Bazgir A (2010) Tetrahedron
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123.9, 138.4, 145.1, 145.8, 148.6, 160.7, 163.2, 163.9 ppm.
Acknowledgments We are thankful to the Persian Gulf University
Research Council for the partial support of this work. Also, we are
thankful to the School of Chemistry, Manchester University for
running NMRs and Dr. Paul Mears for helpful comments.
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