An efficient and environmentally benign protocol for the pseudo four-component synthesis of benzopyranopyrimidines via condensation of salicylic aldehydes, malononitrile and various amines catalyzed by ZrOCl
2
·8H
2
O as an inexpensive and eco-friendly catalyst with high catalytic activity under solvent-free conditions is reported. This protocol provides a new and improved method for obtaining benzopyranopyrimidines in terms of good yields, simple experimental procedure and short reaction time.
INTRODUCTION
The development of new methods for solvent-free organic synthesis involving multicomponent reactions is an important and attractive area of synthetic research.
1
2
Organic reactions should be fast and facile and the target products should be easily separated and purified in high yields without the isolation of any intermediate.
3
From this point of view, solvent-free multicomponent reactions
4
find application as appealing methods to achieve these goals. Solventfree multicomponent reactions offer a wide range of possibilities for the efficient construction of highly complex molecules in a single step, thus avoiding complicated purification operations and allowing savings of both solvents and reagents.
5
6
Functionalized nitrogen-heterocycles play a prominent role in medicinal chemistry and they have been intensively used as scaffolds for drug development. In this context fused pyrimidine derivatives are of particular interest because of their pharmacological profile.
7
Some pyridopyrimidines are known as analgetics
8
and CNS depressants,
9
while pyranopyrimidines exhibits antifungal and antibacterial activity.
10
Several benzopyrano[2,3-
d
]pyrimidines were tested for their cytotoxic activity against a panel of cancer cell lines, and a number were shown to cause significant perturbation in cell cycle kinetics.
11
The use of zirconium(IV) salts as an efficient Lewis acid for various transformations, has been well documented in the literature, because of their easy availability, moisture stability and low toxicity.
12
−
14
Among the various types of Zr(IV) salts, particularly, ZrOCl
2
·8H
2
O has advantages of moisture stability, readily availability and easy handling.
13
Also, the low toxicity of ZrOCl
2
·8H
2
O is evident from their LD50 [LD50 (ZrOCl
2
·8H
2
O, oral rat) = 3500 mg/kg].
14
Therefore, the application of ZrOCl
2
·8H
2
O in organic synthesis is of renewed interest.
As part of our research aimed at developing new methods for the preparation of fused pyrimidine derivatives,
15
−
17
recently, for the first time we have reported synthesis of benzopyrano[2,3-
d
]pyrimidines via pseudo four-component reaction of salicylic aldehyde, malononitrile and amine in the presence of LiClO
4
in EtOH at room temperature for 24 h.
18
Very recently, this multicomponent protocol has been developed by ionic liquid, [Bmim]BF
4
.
19
Due to unique advantages of ZrOCl
2
·8H
2
O, the aim of our research described here was to develop the pseudo fourcomponent synthesis of benzopyrano[2,3-
d
]pyrimidines employing ZrOCl
2
·8H
2
O as an efficient and mild Lewis acid catalyst under solvent-free conditions (
1
).
EXPERIMENTAL
- General Procedure
A mixture of salicylic aldehydes (2 mmol), malononitrile (1 mmol), amines (1 mmol) and ZrOCl
2
·8H
2
O (30 mol%) was stirred at room temperature for 15 h (the progress of the reaction was monitored by TLC). After completion, the reaction mixture was washed with H
2
O (5 ml) and EtOH (5 ml) to afford pure product
4
.
All the products are known and were fully characterized by a comparison with authentic samples (melting point) and IR spectra.
18
2-(4-Morpholino-5
H
-chromeno[2,3-
d
]pyrimidin-2- yl)phenol (4c): White powder (90%); mp 196˗198 ℃. IR (KBr) (
νmax
/cm
˗1
): 3442.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H 3.45 (4H, s, CH
2
), 3.77 (4H, s, CH
2
), 3.88 (2H, s, CH
2
- Ar), 6.84˗7.24 (7H, m, H-Ar), 8.18 (1H, bs, H-Ar), 12.99 (1H, s, OH).
13
C NMR (75 MHz, DMSO-
d
6
):
δ
C
25.1, 48.5, 66.4, 97.8, 116.7, 117.5, 118.5, 119.1, 120.1, 124.9, 128.5, 129.0, 129.4, 133.2, 150.1, 160.2, 160.9, 163.4, 164.3. MS (EI, 70 eV) m/z (%): 361 (M
+
).
3-Methoxy-2-(6-methoxy-4-(piperidin-1-yl)-5H-chromeno[ 2,3-d]pyrimidin-2-yl)phenol (4d):
White powder (91%); mp 195˗197 ℃. IR (KBr) (
νmax
/cm
˗1
): 3442.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
1.69 (6H, s, CH
2
), 3.12 (4H, bs, CH
2
), 3.76˗3.88 (8H, m, 2OCH
3
and CH
2
-Ar), 6.53˗6.58 (2H, m, H-Ar), 7.71˗7.80 (2H, m, H-Ar), 7.17˗7.26 (2H, m, H-Ar), 10.93 (1H, s, OH).
13
C NMR (75 MHz, DMSO-
d
6
):
δ
C
20.6, 24.4, 26.1, 49.4, 56.5, 56.7, 96.6, 104.2, 106.8, 109.1, 109.5, 110.0, 114.2, 128.6, 130.9, 151.4, 157.6, 158.7, 159.9, 160.7, 156.6. MS (EI, 70 eV) m/z (%): 419 (M
+
).
3-Methoxy-2-(6-methoxy-4-morpholino-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4e):
White powder (88%); mp 191˗193 ℃. IR (KBr) (
νmax
/cm
˗1
): 3437.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
3.42 (4H, s, 2CH
2
), 3.67˗3.73 (7H, m, 2CH
2
and OCH
3
), 3.79˗3.84 (5H, m, OCH
3
and CH
2
-Ar), 6.52 (2H, d,
3
J
HH
= 7.0 Hz, H-Ar), 6.74 (2H, m,
3
J
HH
= 8.0 Hz, H-Ar), 7.14˗7.26 (2H, m, H-Ar), 10.15 (1H, s, OH).
13
C NMR (75 MHz, DMSO-
d
6
):
δ
C
20.4, 48.7, 56.1, 56.3, 66.5, 56.0, 97.4, 102.8, 106.4, 108.9, 109.0, 109.3, 115.5, 128.8, 130.4, 151.1, 157.2, 157.3, 158.8, 160.8, 164.0, 165.5. MS (EI, 70 eV) m/z (%): 421 (M
+
).
4-Bromo-2-(7-bromo-4-(piperidin-1-yl)-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4g):
White powder (81%); mp 187˗189 ℃. IR (KBr) (
νmax
/cm
˗1
): 3442.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
1.67 (6H, s, CH
2
), 3.41 (4H, s, CH
2
), 3.88 (2H, s, CH
2
-Ar), 6.81˗7.5 (5H, m, H-Ar), 8.19 (1H, bs, H-Ar), 13.2 (1H, bs, OH). MS (EI, 70 eV) m/z (%): 514 (M
+
). Due to very low solubility of the product 4h, we unable report the
13
C NMR data for this product.
4-Bromo-2-(7-bromo-4-morpholino-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4h):
White powder (85%);mp 198˗200 ℃. IR (KBr) (
νmax
/cm
˗1
): 3416.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
3.47(4H, s, CH
2
), 3.78 (4H, s, CH
2
), 3.97 (2H, s, CH
2
-Ar), 6.84˗6.87 (1H, m, H-Ar), 7.12-7.15 (1H, m, H-Ar), 7.42˗7.48 (2H, m, H-Ar), 7.54 (1H, bs, H-Ar), 13.07 (1H, bs, OH). MS (EI, 70 eV) m/z (%): 519 (M
+
), 474 (38), 353 (30), 127 (90), 86 (100). Due to very low solubility of the product 4i, we unable report the
13
C NMR data for this product.
2-(4-(Dimethylamino)-8-methoxy-5H-chromeno[2,3- d]pyrimidin-2-yl)-5-methoxyphenol (4i):
White powder (77%); mp 174˗176 ℃. IR (KBr) (
νmax
/cm
˗1
): 3421.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
3.19 (6H, s, CH
3
), 3.77 (6H, s, CH
3
), 4.08 (2H, s, CH
2
-Ar), 6.43˗6.44 (1H, m, H-Ar), 6.50˗6.53 (1H, m, H-Ar), 6.71˗6.77 (2H, m, HAr), 7.2 (1H, d,
3
J
HH
= 8.0 Hz, H-Ar), 8.14 (1H, d,
3
J
HH
= 8.0 Hz, H-Ar), 13.53 (1H, s, OH). MS (EI, 70 eV) m/z (%): 379 (M
+
). Due to very low solubility of the product 4j, we unable report the
13
C NMR data for this product.
5-Methoxy-2-(8-methoxy-4-(piperidin-1-yl)-5H-chromeno[ 2,3-d]pyrimidin-2-yl)phenol (4j):
White powder (79%); mp 168˗170 ℃. IR (KBr) (
νmax
/cm
˗1
): 3400.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
1.65 (6H, s, CH
2
), 3.28 (2H, s, CH
2
), 3.28 (2H, s, CH
2
), 3.74 (6H, s, OCH
3
), 3.78 (2H, s, CH
2
-Ar), 6.39˗6.48 (2H, m, H-Ar), 6.66˗6.71 (2H, m, H-Ar), 7.51 (1H, d,
3
J
HH
= 6 Hz, H-Ar), 8.11 (1H, d,
3
J
HH
= 6 Hz, H-Ar), 13.33 (1H, s, OH).
13
C NMR (75 MHz, DMSO-
d
6
):
δ
C
24.3, 24.5, 25.9, 49.1, 55.6, 55.8, 96.9, 101.5, 101.9, 106.7, 111.2, 111.7, 111.9, 129.8, 130.2, 150.9, 159.4, 160.9, 162.0, 163.4, 164.7. MS (EI, 70 eV) m/z (%): 419 (M
+
).
5-Methoxy-2-(8-methoxy-4-morpholino-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4k):
White powder (80%); mp 224˗226 ℃. IR (KBr) (
νmax
/cm
˗1
): 3442.
1
H NMR (300 MHz, DMSO-
d
6
):
δ
H
3.45 (4H, s, CH
2
), 3.75 (10H, m, 2CH
2
and 2OCH
3
), 3.87 (2H, s, CH
2
-Ar), 6.42˗6.51 (2H, m, H-Ar), 6.7˗6.76 (2H, m, H-Ar), 7.19˗7.22 (1H, m, HAr), 8.11˗8.14 (1H, m, H-Ar), 13.21 (1H, s, OH).
13
C NMR (75 MHz, DMSO-
d
6
):
δ
C 24.5, 48.5, 55.7, 55.8, 66.4, 97.2, 101.5, 101.9, 106.9, 111.4, 111.6, 111.8, 129.9, 130.3, 150.7, 159.5, 160.9, 161.9, 163.5, 164.4. MS (EI, 70 eV) m/z (%): 421 (M
+
).
RESULTS AND DISCUSSION
Initially, the reaction of 2-hydroxybenzaldehyde (
1a
, 2 mmol), malononitrile (
2
, 1 mmol) and dimethylamine (
3a
, 1 mmol) as a simple model substrate in the presence of ZrOCl
2
·8H
2
O in different solvents and under solvent-free conditions at room temprature was investigated to optimize the reaction conditions. It was found that the reaction under solvent-free conditions after 15 h resulted in higher isolated yield (
1
). Similarly, the molar ratio of ZrOCl
2
·8H
2
O was studied with the optimum amount being 30 mol% (entry 6). When this reaction was carried out without ZrOCl
2
·8H
2
O the yield of the expected product was trace (entry 9).
Screening of the reaction conditions
Screening of the reaction conditions
Using the optimized conditions, the generality of this reaction was examined using several types of salicylic aldehydes
1a−d
and amines
3a−c
. In all cases, the reactions gave the corresponding products in good isolated yield (
2
). These reactions proceeded very cleanly under mild conditions at room temperature, and no side reactions were observed.
Another advantage of this approach could be related to the reusability of catalyst. We found that the catalyst could be separated from the reaction mixture simply by washing with water and reused after washing with CH
2
Cl
2
and dried at 60 ℃. The reusability of the catalyst was checked by the reaction of salicylaldehyde, malononotrile and dimethyl amine under optimized reaction conditions. The results show that the catalyst can be used effectively three times without any loss of its activity (
2
, entry 1). Therefore, the recyclability of catalyst makes the process economically and potentially viable for commercial applications.
A possible mechanism for the formation of
4
is proposed in
2
. It is reasonable to assume that product
4
results from initial Knoevenagel condensation reaction of salicylic aldehyde
1
and malonontrile
2
followed by subsequent Pinner reaction
(5−6)
. Next, the cyano group of intermediate
6
can be attacked by the amine
3
to produce intermediate
7
. Finally, amine
7
reacts with another molecule of salicylic aldehyde
1
followed by proton transfer to afford the product 4 (
2
).
Synthesis of benzopyrano[2,3-d]pyrimidines4
aIsolated yield after recycling of catalyst
CONCLUSION
In conclusion, we have demonstrated that ZrOCl
2
·8H
2
O can be used as green and reusable catalyst for efficient synthesis of (5
H
-benzopyrano[2,3-
d
]pyrimidin-2-yl)phenols under solvent-free conditions. Moreover, the cheapness, easy availability of the reagent, easy and clean workup makes this method attractive for organic chemist.
Acknowledgements
We are grateful for financial support from the Research Council of Shahid Beheshti University. And the publication cost of this paper was supported by the Korean Chemical Society.
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