Mild preparation of chromeno[2,3-d]pyrimidines catalyzed by Bronsted acidic ionic liquids under solvent-free and ambient conditions

Article abstract of DOI:10.1007/s11164-012-0889-y

Bronsted acidic ionic liquids, namely 2-pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hydrogensulfate, N-methyl-2- pyrrolidonium dihydrogenphosphate, (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensulfate, triphenyl(propyl-3-sulfonyl)phosp

Full text of DOI:10.1007/s11164-012-0889-y

Res Chem Intermed
DOI 10.1007/s11164-012-0889-y
Mild preparation of chromeno[2,3-d]pyrimidines
catalyzed by Brønsted acidic ionic liquids
under solvent-free and ambient conditions
•
Hamid Reza Shaterian Morteza Aghakhanizadeh
Received: 11 September 2012 / Accepted: 26 October 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract Brønsted acidic ionic liquids, namely 2-pyrrolidonium hydrogensulfate,
N-methyl-2-pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium dihydro-
genphosphate, (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensulfate, tri-
phenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate, L-prolinium sulfate, and
L-prolinium nitrate, catalyzed efficient one-pot pseudo-four-component reaction of
salicylaldehydes, malononitrile, and secondary amine for preparation of chro-
meno[2,3-d]pyrimidines under solvent-free conditions at room temperature. The
catalysts show environmentally benign character and can be easily prepared, stored,
and recovered without obvious significant loss of activity.
Keywords Ionic liquid Á Catalyst Á Solvent free Á Salicylaldehyde Á
Chromeno[2,3-d]pyrimidine
Introduction
Some of the most important principles of green chemistry are elimination of
hazardous solvents from chemical synthesis and avoidance of toxic solvents and
waste generation [1]. Ionic liquids (ILs) were initially introduced as alternative
green reaction media because of their unique chemical and physical properties. ILs
show a significant role in controlling reactions as solvent or catalyst [2]. Another
feature of ILs is their ability to be reused many times [3–6]. ILs are mainly classified
into categories of acidic ILs, basic ILs, metal-containing ILs, chiral ILs,
guanidinium ILs, and ILs containing –OH group [7].
H. R. Shaterian (&) Á M. Aghakhanizadeh
Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan,
P.O. Box 98135-674, Zahedan, Iran
e-mail: hrshaterian@chem.usb.ac.ir
123

H. R. Shaterian, M. Aghakhanizadeh
In continuation of our research into new synthetic methods of organic synthesis using
ILs as green catalysts [8–11], we developed a synthesis of chromeno[2,3-d]pyrimidine
derivatives via pseudo-four-component condensation of salicylaldehydes, malononit-
rile, and secondary amine (Scheme 1) by using seven Brønsted acidic ionic
liquids (BAILs), namely 2-pyrrolidonium hydrogensulfate ([Hnmp][HSO4]),
N-methyl-2-pyrrolidonium hydrogensulfate ([NMP][HSO4]), N-methyl-2-pyrrolidoni-
um dihydrogenphosphate ([NMP][H2PO4]), (4-sulfobutyl)tris(4-sulfophenyl)phospho-
nium hydrogensulfate, triphenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate,
L-prolinium sulfate [L-Pro2][SO4], and L-prolinium nitrate [L-Pro][NO3] (Fig. 1), as
catalysts under mild, ambient, and solvent-free conditions.
Results and discussion
To prepare chromeno[2,3-d]pyrimidine derivatives more efficiently, the reaction of
salicylaldehyde (2 mmol), malononitrile (1 mmol), and morpholine (1 mmol) was
selected as a model system under solvent-free conditions at room temperature to
optimize conditions. Preparation of 2-(4-morpholino-5H-chromeno[2,3-d]pyrimi-
din-2-yl)phenol in different amounts of acidic ILs as catalyst (5, 10, 15, and
20 mol%) (Table 1) was studied. The best result was obtained by using 5 mol% of
[Hnhp][HSO4], 5 mol% of [NMP][HSO4], 5 mol% of [NMP][H2PO4], 5 mol% of
(4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensulfate, 5 mol% of tri-
phenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate, 5 mol% of [L-Pro2][SO4],
and 5 mol% of [L-Pro][NO3] at room temperature (Table 1).
Using these optimized reaction conditions, the scope and efficiency of the
procedure were explored for synthesis of chromeno[2,3-d]pyrimidine derivatives via
pseudo-four-component condensation of salicylaldehydes, malononitrile, and sec-
ondary amine at room temperature (Table 2). As shown in Table 2, salicylaldehydes
with both electron-withdrawing and electron-donating substituents reacted efficiently
with malononitrile and secondary amine in the presence of a catalytic amount of
[Hnmp][HSO4] (5 mol%), [NMP][HSO4] (5 mol%), [NMP][H2PO4] (5 mol%),
(4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensulfate (5 mol%), triphenyl-
R2
R1
R2
R1
N
N
H
N
N
CHO
+
Ionic Liquids (Catalyst)
Solvent-free, r.t
(3)
X
2
X
X
OH
O
(1)
HO
N
N
(4)
(2)
X= H, 5-Cl, 5-Br, 5-MeO, 3-MeO
Ionic Liquids
phosphonium hydrogensulfate, triphenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate, [
-Pro][NO3]
=
[Hnmp][HSO4], [NMP][HSO4], [NMP][H2PO4], (4-sulfobutyl)tris(4-sulfophenyl)
L-Pro2][SO4], and
[
L
Scheme 1 Preparation of chromeno[2,3-d]pyrimidine derivatives
123

Mild preparation[2,3-d]pyrimidines catalyzed by Brønsted acidic ILs
CHO
X
+
N
N
OH
O
(2)
(1)
CN
CN
X
OH
(5)
CN
NH
H
HSO4
N
H
X
H
O
(6)
R2
R1
R2
R1
N
N
H
N
N
(3)
R2 R1
N
X
X
O
H
NH
X
R2
R1
N
HO
N
N
O
NH
(7)
X
X
O
CHO
OH
(4)
product
X
HO
(1)
Scheme 2 Proposed mechanism for 2-pyrrolidonium hydrogensulfate as a selected IL catalyzing
preparation of chromeno[2,3-d]pyrimidine derivatives
(propyl-3-sulfonyl)phosphonium toluenesulfonate (5 mol%), [L-Pro2][SO4] (5 mol%)
or [L-Pro][NO3] (10 mol%), forming the corresponding chromeno[2,3-d]pyrimidine
derivatives without formation of any side-products in good to high yields.
The suggested mechanism is presented according to the proposed mechanism in the
literature [18]. Initial Knoevenagel condensation of salicylaldehyde (1) and malon-
onitrile (2) afforded (5), followed by Pinner reaction to form (6). Next, the cyano group
of intermediate (6) can be attacked by the secondary amines (3) to produce
intermediate (7). Finally, intermediate (7) reacts with another molecule of salicylic
aldehyde (1) followed by proton transfer to afford the product (4) (Scheme 2).
We also compared the results of the present BAILs with other catalysts reported in
the literature such as lithium perchlorate (LiClO4) [18], 1-butyl-3-methylimidazolium
tetrafluoroborate ([Bmim]BF4) [19], and piperidine [20] for preparation of chro-
meno[2,3-d]pyrimidine derivatives (Table 3). Table 3 clearly demonstrates that
2-pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hydrogensulfate,
N-methyl-2-pyrrolidonium dihydrogenphosphate, (4-sulfobutyl)tris(4-sulfophe-
nyl)phosphonium hydrogensulfate, triphenyl(propyl-3-sulfonyl)phosphonium tolu-
enesulfonate, L-prolinium sulfate, and L-prolinium nitrate are effective catalysts in
terms of reaction time and yield of obtained product relative to other reported catalysts.
In green organic synthesis, catalyst recovery is more important. Thus, the
reusability of the ILs as catalyst was studied in the synthesis of chromeno
123

H. R. Shaterian, M. Aghakhanizadeh
O
O
O
H
H
H
HSO4
N
N
N
HSO4
H2PO4
H
CH3
CH3
[NMP][H2PO4]
[NMP][HSO4]
[Hnhp][HSO4]
SO3H
SO3
O
O S O
H
SO3H
HO3S
H3C
p
p
HO3S
SO3H
Triphenyl(propyl-3-sulphonyl)phosphonium
toluenesulfonate
(4-Sulfobutyl)tris(4-sulfophenyl)phosphonium
hydrogensulfate
O
HO
O
N
OH
O
N
HO
O
N
O
S
O
H
H
H
H
H
H
O
NO3
[
L-Pro2][SO4]
[L-Pro][NO3]
Fig. 1 Structure of [Hnmp][HSO4], [NMP][HSO4], [NMP][H2PO4], (4-sulfobutyl)tris(4-sulfophenyl)
phosphonium hydrogensulfate, triphenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate, [L-Pro2][SO4],
and [L-Pro][NO3]
Table 1 Optimization of the amount of acidic ILs: 2-pyrrolidonium hydrogensulfate ([Hnmp][HSO4],
A), N-methyl-2-pyrrolidonium hydrogensulfate ([NMP][HSO4], B), N-methyl-2-pyrrolidonium dihydro-
genphosphate ([NMP][H2PO4], C), (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensulfate (D),
triphenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate (E), L-prolinium sulfate ([L-Pro2][SO4], F),
and L-prolinium nitrate ([L-Pro][NO3], G) as catalysts for preparation of chromeno[2,3-d]pyrimidine
derivatives
Entry Catalyst (mol%) Time (min)
Yield (%)a
A
B
C
D
E
F
G
A
B
C
D
E
F
G
1
2
3
4
5
a
–
5
120 120 120 120 120 120 120
–
–
–
–
–
–
–
11
8
10
9
14
11
9
10
8
12
10
9
10
8
15 87 90 93 87 88 91 89
12 89 92 92 89 90 92 87
10
15
20
6
6
7
7
8
6
91 91 94 90 90 94 90
90 93 95 93 93 95 91
5
4
7
4
7
5
Yields refer to isolated pure products. Based on the reaction of salicylaldehyde (2 mmol), malononitrile
(1 mmol), and morpholine at room temperature under solvent-free conditions
[2,3-d]pyrimidine derivatives. After completion of the reaction, ethanol (5 mL) and
water (5 mL) were added to the reaction mixture. The IL was dissolved in ethanol
and water, and filtered for separation of the crude solid product. The separated
product was washed twice with ethanol (29 5 mL) and water (29 5 mL).
123

Mild preparation[2,3-d]pyrimidines catalyzed by Brønsted acidic ILs
Table 2 Preparation of chromeno[2,3-d]pyrimidine derivatives
Entry
Salicylaldehydes
Secondary
amines
Product
Time (min) / Yield (%) a
M.p. /
M.p. [ref]
(°C)
A
B
C
D
E
F
G
CHO
Me
Me
1
2
4a
4b
10/88
9/89
13/92
8/89
10/88
9/90
14/86
181-183 /
177-179 [18]
N
H
OH
CHO
O
11/87
10/90
14/93
10/87
12/88
10/91
15/89
197-199 /
196-197 [19]
OH
N
H
CHO
OH
3
4
5
4c
4d
4e
12/84
9/89
9/90
11/91
7/93
9/89
15/90
12/87
14/90
12/88
10/89
12/88
10/84
8/90
7/87
8/89
8/88
8/86
12/90
11/87
14/85
167-179 /
168-170 [18]
N
H
Br
Br
CHO
OH
Me
Me
200-201 /
196-198 [18]
N
H
CHO
OH
O
216-218 /
219[20]
N
H
Br
Cl
CHO
OH
6
7
4f
10/87
11/88
8/88
11/89
12/84
11/86
13/85
9/89
8/90
7/87
9/89
15/88
15/86
225 /
226 [20]
N
H
O
CHO
OH
4g
10/91
249-251 /
250 [20]
N
H
Cl
CHO
215-216 /
216 [20]
8
9
4h
4i
12/84
9/86
10/87
8/85
13/86
12/88
10/87
9/89
8/88
10/91
10/88
16/89
14/90
OH
CHO
OH
N
H
O
MeO
12/90
231 /
231 [20]
N
H
MeO
CHO
OH
10
11
4j
10/84
17/81
12/89
15/80
10/87
16/82
9/90
11/89
14/86
8/87
12/84
15/82
194-196 /
195 [20]
N
H
CHO
OH
4k
13/84
11/83
180-182 /
181-183 [18]
N
H
OMe
a
Yields refer to isolated pure products. Based on the reaction of salicylaldehyde (2 mmol), malono-
nitrile (1 mmol), and secondary amine at room temperature under solvent-free conditions
To recover the ILs, the aqueous phase containing the ILs was evaporated, and the
remaining viscous liquid was washed with ether (10 mL) and dried under reduced
pressure. The recovered ILs were tested to study their catalytic activity in
subsequent runs without adding fresh catalyst. The ILs were tested for five runs. It
was seen that the ILs displayed very good catalyst reusability without any
considerable loss of activity (Fig. 2).
123

H. R. Shaterian, M. Aghakhanizadeh
Table 3 Comparison of the results of 2-pyrrolidonium hydrogensulfate, N-methyl-2-pyrrolidonium hy-
drogensulfate, N-methyl-2-pyrrolidonium dihydrogenphosphate, (4-sulfobutyl)tris(4-sulfophenyl)phos-
phonium hydrogensulfate, triphenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate, L-prolinium sulfate,
andL-proliniumnitratewithothercatalystsreportedinliteratureforsynthesisofchromeno[2,3-d]pyrimidine
derivatives
Entry Catalyst
Conditions
Time (min) Yield (%)a Ref.
1
2
3
LiClO4 (20 mol%)
EtOH/r.t.
1,440
20
95
76
78
92
87
90
93
87
[18]
[Bmim]BF4 (5 mol%)
Piperidine (20 mol%)
r.t.
[19]
100 °C
660
6
[20]
MW (180 W), 100 °C
Solvent-free, r.t.
Solvent-free, r.t.
Solvent-free, r.t.
Solvent-free, r.t.
[20]
4
5
6
7
[Hnhp][HSO4] (5 mol%)
[NMP][HSO4] (5 mol%)
[NMP][H2PO4] (5 mol%)
11
This work
This work
This work
This work
10
14
(4-Sulfobutyl)tris(4-
sulfophenyl)
10
phosphonium
hydrogensulfate
(5 mol%)
8
Triphenyl(propyl-3-sulfonyl)
phosphonium
Solvent-free, r.t.
12
88
This work
toluenesulfonate
(5 mol%)
9
[L-Pro2][SO4] (5 mol%)
[L-Pro][NO3] (5 mol%)
Solvent-free, r.t.
Solvent-free, r.t.
10
15
91
89
This work
This work
10
a
Yields refer to isolated pure products. Based on the reaction of salicylaldehyde (2 mmol), malononitrile
(1 mmol), and secondary amine at room temperature under solvent-free conditions
Experimental
Chemicals and materials
All reagents were purchased from Merck and Aldrich and used without further
purification. All yields refer to isolated products after purification. 2-Pyrrolido-
nium hydrogensulfate [Hnmp][HSO4] [12], N-methyl-2-pyrrolidonium hydrogen-
sulfate [NMP][HSO4] [13], N-methyl-2-pyrrolidonium dihydrogenphosphate
[NMP][H2PO4] [14], (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensul-
fate [15], triphenyl(propyl-3-sulfonyl)phosphonium toluenesulfonate [16], L-pro-
linium sulfate [L-Pro2][SO4], and L-prolinium nitrate [L-Pro][NO3] [17] were
prepared according to literature procedure. Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker Avance DPX 500-MHz instrument, being
measured in CDCl3 relative to tetramethylsilane (TMS, 0.00 ppm). Melting points
were determined in open capillaries with a BUCHI 510 melting point apparatus.
Thin-layer chromatography (TLC) was performed on silica-gel Polygram SIL
G/UV 254 plates.
123

Mild preparation[2,3-d]pyrimidines catalyzed by Brønsted acidic ILs
Fig. 2 Reusability of acidic ILs as catalyst in preparation of chromeno[2,3-d]pyrimidine derivatives
General procedure for synthesis of chromeno[2,3-d]pyrimidine derivatives (4)
A stirred mixture of salicylaldehydes (1) (2 mmol), malononitrile (2) (1 mmol),
secondary amine (3) (1 mmol), and 2-pyrrolidonium hydrogensulfate (0.009 g,
5 mol%, 0.05 mmol) or N-methyl-2-pyrrolidonium hydrogensulfate (0.0098 g,
5 mol%, 0.05 mmol) or N-methyl-2-pyrrolidonium dihydrogenphosphate (0.0098 g,
5 mol%, 0.05 mmol) or (4-sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogensul-
fate (0.036 g, 5 mol%, 0.05 mmol) or triphenyl(propyl-3-sulfonyl)phosphonium
toluenesulfonate (0.026 g, 5 mol%, 0.05 mmol) or L-prolinium sulfate (0.016 g,
5 mol%, 0.05 mmol) or L-prolinium nitrate (0.009 g, 5 mol%, 0.05 mmol) was reacted
at room temperature for the appropriate times. After completion of the reaction as
indicated by TLC, ethanol (5 mL) and water (5 mL) were added, and the mixture was
stirred to dissolve the IL in solvents. The solid product was filtered and washed with
water and ethanol to afford pure product. To recover the ILs, after isolation of insoluble
products, the aqueous phase containing the ILs was evaporated, and the remaining
viscous liquid was washed with ether (10 mL) and dried under reduced pressure.
All known products have been reported in the literature and were characterized
by comparing their melting point and IR and NMR spectra with authentic samples
[18–20]. We selected spectroscopic data (1H NMR, 13C NMR, IR) for two known
compounds as below:
2-(4-(Piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol
(4c) M.p.
168–170 °C; 1H NMR (CDCl3, 500 MHz): d = 1.77–1.81 (6H, m), 3.45–3.47
(4H, m), 3.93 (2H, s), 6.94–6.97, 7.00–7.02, 7.11–7.14, 7.21–7.31, 7.36–7.40,
8.44–8.46 (8H, 6m, aromatic), 13.50 (1H, brs, OH) ppm; 13C NMR (CDCl3,
125 MHz): d = 24.8, 26.1, 26.4, 49.9, 97.9, 117.5, 117.9, 119.1, 119.2, 119.9,
123

H. R. Shaterian, M. Aghakhanizadeh
124.8, 128.6, 128.9, 129.6, 130.2, 133.2, 151.0, 160.8, 162.3, 165.6 ppm; IR (KBr,
cm-1): 3043, 1622, 1605, 1257, 1151, 1110.
4-Bromo-2-(7-bromo-4-(morpholin-4-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phe-
nol (4e) M.p. 216–218 °C; 1H NMR (CDCl3, 500 MHz): d = 3.41–3.43,
3.81–3.83 (8H, 2t, J = 4.55 Hz), 3.90 (2H, s, CH2), 6.75–6.77, 6.97–6.99,
7.28–7.30, 7.31–7.33, 8.36–8.37 (6H, 5m, aromatic), 12.95 (1H, brs, OH) ppm;
13C NMR (CDCl3, 125 MHz): d = 25.6, 48.8, 66.8, 97.8, 111.0, 117.2, 118.6,
118.9, 119.2, 119.9, 120.2, 121.5, 131.4, 131.5, 135.8, 149.6, 159.6, 160.9, 163.9
(aromatic) ppm; IR (KBr, cm-1): 3046, 1618, 1603, 1216, 1176, 1106, 1018.
Conclusions
We present a rapid and highly efficient method for green synthesis of chromeno[2,3-
d]pyrimidine derivatives using reusable Brønsted acidic ILs as catalysts at room
temperature under solvent-free conditions. We show that a number of ILs with
different core, central atom (P or N), acidic functional groups, and counterions act
well to perform the reaction. With such successful results, this convenient and
efficient protocol should provide a superior alternative to existing methods because
of its fast and clean reaction and high yield. Furthermore, the simple workup
procedure makes the presented method useful and important for synthesis of
chromeno[2,3-d]pyrimidine derivatives. This methodology offers significant
improvements such as simplicity in operation, and green aspects by avoiding
expensive or corrosive catalysts.
Acknowledgments We are grateful to the University of Sistan and Baluchestan Research Council for
partial support of this research.
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