Facile one-pot synthesis of pyrido[2,3-d]pyrimidine derivatives over ZrO2 nanoparticles catalyst

Article abstract of DOI:10.1016/j.cclet.2012.01.001

An efficient synthesis of hexahydropyrido[2,3-d]pyrimidinetrione derivatives is achieved via tandem Knoevenagel-Michael addition of aromatic aldehydes, methylcyanoacetate and 4(6)-aminouracil in solvent-free conditions in the presence of 10 mol% of ZrO

Full text of DOI:10.1016/j.cclet.2012.01.001

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 257–260
www.elsevier.com/locate/cclet
Facile one-pot synthesis of pyrido[2,3-d]pyrimidine
derivatives over ZrO2 nanoparticles catalyst
b
Shahrzad Abdolmohammadi a, , Maryam Afsharpour
*
a Department of Chemistry, East Tehran Branch, Islamic Azad University, PO Box 33955-163, Tehran, Iran
b Nano Science and Technology Research Center, University of Tehran, Tehran, Iran
Received 23 August 2011
Available online 24 January 2012
Abstract
An efficient synthesis of hexahydropyrido[2,3-d]pyrimidinetrione derivatives is achieved via tandem Knoevenagel–Michael
addition of aromatic aldehydes, methylcyanoacetate and 4(6)-aminouracil in solvent-free conditions in the presence of 10 mol% of
ZrO2 nanoparticles (ZrO2 NPs) as a heterogenous catalyst. The procedure is formed in high yields, short reaction time and an
environmentally friendly specificity.
# 2012 Shahrzad Abdolmohammadi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Pyrido[2,3-d]pyrimidines; Solvent-free; Tandem Knoevenagel–Michael addition; ZrO2 nanoparticles
Pyridopyrimidine and its derivatives have been studied for over a century because of a variety of chemical and
biological significance. They have been reported as antibacterial [1], antiasthmatic, antiallergic [2], antifolate [3],
tyrosine kinase [4], antimicroibial [5], calcium channel antagonists [6], anti-inflammatory and analgesic [7],
antihypertensive [8], antileishmanial [9], tuberculostatic [10], anticonvulsants [11], diuretic and potassium-sparing
[12], antiaggressive [13] activities. Various synthetic approaches have been reported for the synthesis of
hexahydropyrido[2,3-d]pyrimidinetrione derivatives, such as traditional thermal methods using KF/Al2O3 [14], or
TEBAC [15] as catalyst. However, there is always the need for better methods.
In the last few years the application of metal oxide nanoparticles as an efficient catalyst have proved to be useful in
several scientific and technological areas due to the activation of adsorbed compounds and reaction rate enhancement,
easier wok-up, reusability of the catalyst and the environmentally friendly reaction conditions [16,17]. Currently,
application of these nanocatalysts in organic and inorganic reactions has emerged as a rapidly growing field [18–21].
These facts encouraged us to explore other clean method using ZrO2 nanoparticles (ZrO2 NPs) commercially available
with an average size of 15 nm, for the synthesis of an important class of the pyrido-pyrimidinetrione derivatives 4(a–g)
at 70 8C in solvent-free conditions (Scheme 1 and Table 1). Although, this is the first report of using Lewis acid catalyst
for the synthesis of these biologically active compounds, compared with previous methods [14,15], this method has the
advantages of high yields, mild reaction conditions, short reaction time, easy work-up, inexpensive reagents and
environmentally friendly procedure.
In continuation of our previous works on the development of novel and efficient catalytic methods for the synthesis
of heterocyclic compounds [22–24], herein has been reported a novel and highly efficient solvent-free protocol for the
* Corresponding author.
E-mail addresses: abdolmohamadi_sh@yahoo.com, sabdolmohamadi@qdiau.ac.ir (S. Abdolmohammadi).
1001-8417/$ – see front matter # 2012 Shahrzad Abdolmohammadi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.01.001

258
S. Abdolmohammadi, M. Afsharpour / Chinese Chemical Letters 23 (2012) 257–260
O
R
O
CN
O
O
CN
HN
HN
ZrO2 NPs (10 mol%)
Solvent-free, 70 0C
+
+
Ar
H
O
N
H
3
NH2
O
N
H
N
H
CO2CH3
2
1
4
Scheme 1. Synthesis of hexahydropyrido[2,3-d]pyrimidine derivatives in solvent-free conditions.
Table 1
Synthesis of hexahydropyrido[2,3-d]pyrimidines 4(a–g) in solvent-free conditions using ZrO2 NPs as catalyst.
Product
Ar
mp (8C)
Yielda (%)
4a
4b
4c
4d
4e
4f
4-BrC6H4
>300
>300
>300
>300
>300
>300
>300
97
90
92
93
94
93
96
2-ClC6H4
3-ClC6H4
2,4-Cl2C6H3
4-HOC6H4
4-CH3OC6H4
4-CH3C6H4
4g
a
Yields refer to pure isolated products characterized by IR, 1H NMR spectroscopy, mass spectrometry and elemental analysis.
synthesis of pyrido[d]pyrimidine derivatives 4 via a three-component reaction of aromatic aldehydes,
methylcyanoacetate and 4(6)-aminouracil in the presence of ZrO2 NPs as an efficient, inexpensive, moisture stable,
commercially available and environmentally benign catalyst. We also tried to use this procedure for aliphatic
aldehydes but unfortunately the yields were low because of the low boiling points of aldehydes so they vaporize fast.
As shown in Table 2, the reaction of 4-hydroxybenzaldehyde, 2 and 3 as a model was examined under various
reaction conditions. After 1 h with 5, 10 and 15 mol% of ZrO2 NPs, yields of 67, 94 and 95%, respectively, were
obtained. To show that ZrO2 NPs is an efficient catalyst, we tried the reaction in the absence of ZrO2 NPs, but the
reaction time increased, meanwhile the yield decreased mainly (Table 2, entries 1–4).
The effect of the temperature was studied by carrying out the model reaction in the presence of ZrO2 NPs
(10 mol%) at 70 8C and at 90 8C in solvent-free conditions. It was observed that the yield was not increased as the
reaction temperature was raised (Table 2, entries 3 and 5).
ZrO2 bulk also was evaluated for the model reaction. Clearly, the reaction time using ZrO2 NPs has been reduced by
ten times with higher yield than ZrO2 bulk (Table 2, entries 3 and 6).
Investigation of the effect of solvents showed that the best results were obtained in solvent-free conditions (Table 2,
entries 3 and 7–9).
Although it is not clear how ZrO2 acts as a catalyst for the reaction, on the basis of the surface of metal oxides
exhibit both Lewis acid and Lewis base character [25], the proposed mechanism for the ZrO2 catalyzed one-pot
reaction of aromatic aldehydes, methylcyanoacetate and 4(6)-aminouracil is shown in Scheme 2. It is suggested that,
ZrO2 NPs are coordinated to the oxygen of the aromatic aldehyde 1 and active it for nucleophilic attack [26] by
Table 2
Optimization of the ZrO2 NPs catalyzed model reaction of 4-hydroxybenzaldehyde, methylcyanoacetate and 4(6)-aminouracil for the synthesis of
product 4e.
Entry
Catalyst (mol%)
Solvent
Temp (8C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
No catalyst
None
70
70
6
1
28
67
94
95
94
35
42
48
68
ZrO2 NPs (5%)
ZrO2 NPs (10%)
ZrO2 NPs (15%)
ZrO2 NPs (10%)
ZrO2 bulk (10%)
ZrO2 NPs (10%)
ZrO2 NPs (10%)
ZrO2 NPs (10%)
None
None
70
1
None
70
1
None
90
1
None
70
10
5
CH2Cl2
DMF
70
100
80
5
EtOH/H2O
10
a
Isolated yield.

S. Abdolmohammadi, M. Afsharpour / Chinese Chemical Letters 23 (2012) 257–260
Zr
259
O
O
O
H
HC
Ar
CO2CH3
CN
H
O
CO2CH3
O
Zr
O
+
Ar
H
H
O
H
CN
2
1
Ar
CO2CH3
CN
H
+
ZrO2 NPs
H2O
ZrO2 NPs
Ar
CO2CH3
CN
H
5
O
Zr
CN
O
O
H
CO2CH3
Ar
HN
HN
HN
O
N
H
NH2
H
3
O
N
H
O
O
ZrO2 NPs
O
H
O
CN
Ar
MeO
NH
H
HN
CN
Ar
H
HN
Aromatization
CN
Ar
Cyclization
HN
HN
HN
H
H
O
N
H
O
O
N
H
O
O
N
H
O
4
6
7
Scheme 2. The proposed mechanism for the synthesis of hexahydropyrido[d]pyrimidines in solvent-free conditions catalyzed by ZrO2 NPs (10%).
methylcyanoacetate 2 to produce alkene 5, via a Knoevenagel condensation. On the other hand ZrO2 NPs also
facilitate the Michael addition between alkene 5 and 4(6)-aminouracil 3, by coordination assistance to generate the
Michael adduct 6. Cyclization of 6 gives 4 after aromatization of intermediate 7.
In order to demonstrate the ZrO2 can be catalyses both of two steps of the proposed mechanism, we tried the
reaction into two separate steps. In the absence of ZrO2, the alkene formation is occurred in a long reaction time and in
a very low yield. Also when we used preformed alkene 5 in the reaction with 4(6)-aminouracil 3, it shows that there
was no reaction in the absence of catalyst.
The structure of compounds 4(a–g) were deduced from their 1H NMR and IR spectral data and also by elemental
analysis. Spectroscopic data have been given in general procedure section.
In summary, We have demonstrated that ZrO2 NPs efficiently catalyzes the one-pot three-component synthesis of
2,4,7-trioxo-5-aryl-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles in high yields.
1. General procedure for preparation of compounds 4a–g
A mixture of aromatic aldehyde 1 (1 mmol), methylcyanoacetate (2, 1.2 mmol), 4(6)-aminouracil (3, 1 mmol) and
ZrO2 NPs (12.3 mg, 10 mol%) was stirred at 70 8C for 1 h. The progress of the reaction was monitored with TLC in 1:1
ethanol–ethyl acetate as TLC solvent. Upon completion of the reaction, DMF (5 mL) was added to the reaction
mixture, and ZrO2 NPs was removed by filtration. The organic solution was then poured into cold water (20 mL),
filtered and washed with aqueous ethanol to give the pure product.

260
S. Abdolmohammadi, M. Afsharpour / Chinese Chemical Letters 23 (2012) 257–260
2,4,7-Trioxo-5-(4-bromophenyl)-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles (4a): pale yellow
solid; mp > 300 8C. 1H NMR (DMSO-d6): d 7.12 (d, 2H, HAr, J = 8.4 Hz), 7.49 (d, 2H, HAr, J = 8.4 Hz), 10.10 (s, 1H,
NH), 10.14 (s, 1H, NH), 10.33 (s, 1H, NH). IR (KBr): nmax 3NH 3135 br, CN 2217, 3CO 1653, 1575, 1533 cmꢀ1. Anal.
Calcd. for C14H7BrN4O3 (359.14): C, 46.82; H, 1.96; N, 15.60. Found: C, 46.91; H, 1.85; N, 15.52.
2,4,7-Trioxo-5-(2-chlorophenyl)-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles (4b): pale yellow
solid; mp > 300 8C. 1H NMR (DMSO-d6): d 7.29 (m, 1H, HAr), 7.41 (m, 1H, HAr), 7.53 (m, 1H, HAr), 10.12 (s, 1H,
NH), 10.18 (s, 1H, NH), 10.29 (s, 1H, NH). IR (KBr): nmax 3NH 3133 br, CN 2221, 3CO 1695, 1573, 1513 cmꢀ1. Anal.
Calcd. for C14H7ClN4O3 (314.69): C, 53.43; H, 2.24; N, 17.80. Found: C, 53.35; H, 2.28; N, 17.62.
2,4,7-Trioxo-5-(2,4-dichlorophenyl)-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles (4d): pale yel-
1
low solid; mp > 300 8C. H NMR (DMSO-d6): d 7.29 (d, 1H, HAr, J = 8.0 Hz), 7.38 (dd, 1H, HAr, J = 8.0 Hz,
J0 = 2.0 Hz), 7.60 (d, 1H, HAr, J = 2.0 Hz), 10.07 (s, 1H, NH), 10.16 (s, 1H, NH), 10.24 (s, 1H, NH). IR (KBr): nmax
3NH 3394 br, 3042, CN 2161, 3CO 1718, 1565, 1480 cmꢀ1. Anal. Calcd. for C14H6Cl2N4O3 (349.13): C, 48.16; H,
1.73; N, 16.05. Found: C, 48.19; H, 1.85; N, 15.92.
2,4,7-Trioxo-5-(4-hydroxyphenyl)-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles (4e): pale yellow
solid; mp > 300 8C. 1H NMR (DMSO-d6): d 6.96 (d, 2H, HAr, J = 8.4 Hz), 7.24 (d, 2H, HAr, J = 8.4 Hz), 9.63 (s, 1H,
OH), 10.05 (s, 1H, NH), 10.14 (s, 1H, NH), 10.38 (s, 1H, NH). IR (KBr): nmax 3NH 3335, 3157 br, CN 2211, 3CO 1707,
1643, 1522 cmꢀ1. Anal. Calcd. for C14H8N4O4 (296.24): C, 56.76; H, 2.72; N, 18.91. Found: C, 56.56; H, 2.53; N, 18.78.
2,4,7-Trioxo-5-(4-methoxyphenyl)-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles (4f): pale yel-
low solid; mp > 300 8C. 1H NMR (DMSO-d6): d 3.80 (s, 3H, OCH3), 6.90 (d, 2H, HAr, J = 8.0 Hz), 7.12 (d, 2H, HAr,
J = 8.0 Hz), 10.03 (s, 1H, NH), 10.11 (s, 1H, NH), 10.34 (s, 1H, NH). IR (KBr): nmax 3NH 3390, 3128, 2955, CN 2221,
3CO 1720, 1645, 1603 cmꢀ1. Anal. Calcd. for C15H10N4O4 (310.27): C, 58.07; H, 3.25; N, 18.06. Found: C, 58.19; H,
3.15; N, 18.22.
2,4,7-Trioxo-5-(4-methylphenyl)-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbonitriles (4g): pale yellow
1
solid; mp > 300 8C. H NMR (DMSO-d6): d 2.41 (s, 3H, CH3), 7.22 (d, 2H, HAr, J = 8.0 Hz), 7.32 (d, 2H, HAr,
J = 8.0 Hz), 10.04 (s, 1H, NH), 10.10 (s, 1H, NH), 10.33 (s, 1H, NH). IR (KBr): nmax 3NH 3152 br, 3024, CN 2220,
3CO 1656, 1542, 1513 cmꢀ1. Anal. Calcd. for C15H10N4O3 (294.27): C, 61.22; H, 3.43; N, 19.04. Found: C, 61.39; H,
3.25; N, 19.21.
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