ZnO nanoparticles-catalyzed cyclocondensation reaction of arylmethylidenepyruvic acids with 6-aminouracils

Article abstract of DOI:10.2174/1386207311316010005

A new, efficient, and solvent-free cyclocondensation reaction of arylmethylidenepyruvic acids with 6- aminouracils is presented that uses a catalytic amount of ZnO nanoparticles (ZnO Nps) as a recyclable catalyst at 70 °C. This protocol has the advantages

Full text of DOI:10.2174/1386207311316010005

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32
Combinatorial Chemistry & High Throughput Screening, 2013, 16, 32-36
ZnO
Nanoparticles-Catalyzed
Cyclocondensation
Reaction
of
Arylmethylidenepyruvic Acids with 6-Aminouracils
Shahrzad Abdolmohammadi*
Department of Chemistry, Faculty of Science, East Tehran Branch, Islamic Azad University, P.O. Box 33955-163,
Tehran, Iran
Abstract: A new, efficient, and solvent-free cyclocondensation reaction of arylmethylidenepyruvic acids with 6-
aminouracils is presented that uses a catalytic amount of ZnO nanoparticles (ZnO Nps) as a recyclable catalyst at 70 ˚C.
This protocol has the advantages of high yields (91-98%), easy work-up, very short reaction time (2 h), and using
environmentally friendly procedure.
G
O
O
O
R
R
OH
N
N
ZnO Nanoparticles (10 mol%)
Solvent-free, 70 0C
+
O
CO2H
O
NH2
N
O
G
N
R
N
R
H
Keywords: Cyclocondensation, heterogeneous catalyst, solvent-free, ZnO nanoparticles.
INTRODUCTION
In general, several similar applications of ZnO NPs as an
effective catalyst in green synthetic organic chemistry have
been already highlighted in the literatures [19-26]. However,
the investigation of this nanoscale as heterogeneous catalyst
has been rare. In this regard, we envisaged the application of
readily available and non-toxic ZnO NPs as catalyst in
cyclocondensation reaction of arylmethylidenepyruvic acids
1 with 6-aminouracils 2, to afford 5-aryl-1,3-dimethyl-2,4-
dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-carboxy-
lic acids 3 in a very efficient manner (Scheme 1). Solvent-
free reactions employing heterogeneous catalysts play a
significant role in the greening approach to organic products.
Although we have previously reported the preparation of
these compounds in this way by traditional thermal method
in aqueous media [27], it has been our interest to examine
this reaction in the presence of ZnO NPs as a new efficient
catalyst in solvent-free conditions. This method provides a
noteworthy improvement over previous method as ZnO is
not toxic or expensive, work-up being simply reduced to
filtration followed by treatment with cold water.
In recent years, inorganic solid oxides have attracted a
great deal of interest in the laboratory and industry due to the
activation of adsorbed compounds, enhancement of reaction
rate, simplicity of operation, reusability of the catalyst, and
their use of availability at low cost [1, 2]. Currently,
application of these metal oxides in organic and inorganic
reactions has emerged as a rapidly growing field. A number
of inorganic oxides such as SiO2, Al2O3, etc. have commonly
been used for surface organic chemistry [3-6]. In particular,
Zinc oxide (ZnO) is a very interesting metal oxide as it has
desirable properties such as being inexpensive, non-toxic,
moisture stable, reusable, and commercially available.
Heterocycles containing nitrogen atom in their skeleton,
are abundant in nature and exhibit various important
chemical and biological activities. Among them
pyridopyridines are of interest because they constitute an
important class of natural and non-natural products, many of
which have different biological activities such as
antibacterial [7], antifolate [8], tyrosine-kinase [9],
antimicrobial [10], calcium-channel-antagonist [11], anti-
inflammatory and analgesic [12], antihypertensive [13],
antileishmanial [14], tuberculostatic [15], anticonvulsant
[16], diuretic and potassium-sparing [17], and antiaggressive
[18] activities.
RESULT AND DISCUSSION
With the aim to develop new simple and efficient
processes for the preparation of biologically active
heterocyclic compounds, we have explored a novel approach
to 5-aryl-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyri-
do[2,3-d]pyrimidine-7-carboxylic acids 3, involving
a
conjugate addition/cyclization reaction of arylmethylid-
enepyruvic acids 1 with 6-aminouracils 2 in the presence of
ZnO NPs as an efficient heterogeneous catalyst. The
conjugate addition of nucleophiles to ꢀ,ꢁ-unsaturated
carbonyl compounds is one of the most powerful methods
*Address correspondence to this author at the Department of Chemistry,
Faculty of Science, East Tehran Branch, Islamic Azad University, P.O. Box
33955-163, Tehran, Iran; Tel: +98-21-3359 4950; Fax: +98-21-3359 4332;
E-mails: abdolmohamadi_sh@yahoo.com, sabdolmohamadi@qdiau.ac.ir
1875-5402/13 $58.00+.00
© 2013 Bentham Science Publishers

Arylmethylidenepyruvic Acids with 6-Aminouracils
Combinatorial Chemistry & High Throughput Screening, 2013, Vol. 16, No. 1 33
O
COH
G
O
OH
OH
O
MeOH/KOH
-H2O
G
O
1
G
O
O
O
R
R
OH
N
N
ZnO Nanoparticles (10 mol%)
Solvent-free, 70 0C
+
O
CO2H
O
NH2
N
H
O
G
N
R
N
R
3
1
2
Scheme 1. Synthesis of hexahydropyrido[2,3-d]pyrimidine derivatives.
for the formation of carbon-carbon bonds [28]. Arylmethyl-
idenepyruvic acid 1, as an attractive ꢀ,ꢁ-unsaturated
carbonyl compound was prepared easily according to the
known procedure [29] by reaction of aromatic aldehyde and
pyruvic acid in an aqueous MeOH solution of KOH (Scheme
In comparison to the same reaction catalyzed by ZnO
bulk, using ZnO NPs reduced the reaction time by tow times,
and increased the product yield (Table 2, entries 3 and 6).
We also examined the effects of solvents in the model
reaction. The reaction proceeded smoothly in acetonitrile or
dimethylformamide, while the good result was given in
solvent-free conditions (Table 2, entries 3, 7 and 8).
1). The subsequent cyclocondensation of
1 with 6-
aminouracils 2 in the presence of ZnO NPs in solvent-free
conditions led to corresponding products 3 (a-f) in high to
excellent yields.
To check for recyclability, the catalyst (ZnO Nps) was
centrifuged from the reaction mixture after adding DMF, and
dried in vacuo. It could then be reused for further catalytic
reactions. In each cycle >85% of the catalyst was easily
recovered. As shown in Table 3, the yields of the product
after two and three reuses of the catalyst were almost same
without loss of catalytic activity.
Table 1. Synthesis of Hexahydropyrido[2,3-d]Pyrimidines
3(a-f) in Solvent-Free Conditions
Product
G
R
Yield (%)a,b
3a
3b
3c
3d
3e
3f
Cl
OCH3
CH3
Cl
H
H
93
94
91
98
93
96
Suggested mechanism for this reaction is patterned in
Scheme 2. According to both Lewis acid and Lewis base
character of ZnO [30], it is reasonable that the high
formation of 3 over ZnO NPs, is due to coordinate assisted
internal cyclization of intermediate 4, which is generated
from the initial Michael addition of 6-aminouracils 2 to
arylmethylidenepyruvic acids 1. Intramolecular cyclization
of 4 gives 3 after dehydration of intermediate 5. On the other
hand, the high surface area-to-volume ratio of ZnO NPs is
mainly responsible for its catalytic properties [31].
H
CH3
CH3
CH3
OCH3
CH3
aYields refer to those of pure isolated products characterized by elemental analyses,
mass spectrometry and by IR, 1H and 13C NMR spectroscopic data.
bIn all cases, reaction time was 2 h stirring at 70 ˚C.
The structures of compounds 3(a-f) were fully
characterized by spectral methods. Spectroscopic data have
been given in general procedure section.
As a starting point of this investigation we used the
reaction of 4-methoxyphenylmethylidenepyruvic acid and 6-
amino-N,N-dimethyluracil as
a model under various
conditions. The results are summarized in Table 2.
MATERIAL AND METHODS
In the absence of ZnO NPs the reaction time was
increased, while the yield was reduced mainly. The best
result was obtained with using 10 mol% of ZnO NPs as
catalyst. (Table 2, entries 1-4).
All chemicals used in this work purchased from Fluka
and used without further purification. Melting points were
determined with Electrothermal 9100 melting point
apparatus and were uncorrected. IR spectra were obtained on
1
an ABB FT-IR (FTLA 2000) spectrometer. H NMR and 13C
It is interesting to note that the yield was not improved as
the reaction temperature was raised (Table 2, entries 3 and 5).
NMR spectra were run on a Bruker DRX-500 AVANCE at

34 Combinatorial Chemistry & High Throughput Screening, 2013, Vol. 16, No. 1
Shahrzad Abdolmohammadi
Table 2. ZnO NPs Catalyzed Synthesis of 5-(4-Methoxyphenyl)-1,3-Dimethyl-2,4-Dioxo-1,2,3,4,5,8-Hexahydropyrido[2,3-
d]Pyrimidine-7-Carboxylic Acid (3e) Through the Reaction of 4-Methoxyphenylmethylidenepyruvic Acid and 6-Amino-
N,N-Dimethyluracil Under Different Conditions
Entry
Catalyst (mol%)
Solvent
Temp (˚C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
No catalyst
none
none
70
70
70
70
90
70
80
100
5
2
2
2
2
4
6
5
63
68
93
95
92
61
54
49
ZnO NPs (5%)
ZnO NPs (10%)
ZnO NPs (15%)
ZnO NPs (10%)
ZnO bulk (10%)
ZnO NPs (10%)
ZnO NPs (10%)
none
none
none
none
CH3CN
DMF
aIsolated yield.
500 and 125 MHz respectively using TMS as internal
standard and DMSO-d6 as solvent. Elemental analyses were
carried out using Heraus CHN rapid analyzer. Mass spectra
data were obtained by using GC-MS Hewlet Packard (EI, 70
eV) instrument.
C14H10ClN3O4 (319.75): C 52.60, H 3.15, N 13.14; found: C
52.50, H 3.10, N 13.08.
5-(4-Methoxyphenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropy-
rido[2,3-d]pyrimidine-7-carboxylic acid (3b): White
powder, yield: 0.284 g (90%), m.p. 315–316˚C. IR (KBr)
(ꢀmax/cm-1): 3344 (NH), 3242 (COOH), 1730 (COOH), 1658
Table 3. Reusing of ZnO NPs for the Synthesis of 3e
1
(NCO), 1617 (NCON) cm-1. H-NMR: ꢀ = 3.70 (s, 3 H,
OCH3), 4.51 (d, 3J = 5.4 Hz, 1 H, H-5), 5.87 (dd, 3J = 5.4 Hz,
Recycles
Yield (%)a
Recovery of Catalyst (%)
3
4J = 1.0 Hz, 1 H, H-6), 6.83 (d, J = 8.6 Hz, 2 H, HAr), 7.12
3
(d, J = 8.6 Hz, 2 H, HAr), 8.10 (s, 1 H, NH), 9.90 (s, 1 H,
1
2
93
91
90
96
89
85
NH), 10.43 (s, 1 H, NH), 13.40 (s, 1 H, COOH) ppm. 13C-
NMR: ꢀ = 36.4 (C-5), 55.1 (OCH3), 84.2 (C-C=O), 113.8
(C-6), 114.7 (2 CH), 125.7 (C-7), 128.5 (2 CH), 138.2 (C),
145.7 (C=O), 149.8 (C-OCH3), 157.9 (N-C-N), 163.0 (C=O),
163.5 (C=O) ppm. Mass: (C14H9N5O2) m/z (%)= 315 (5, M),
313 (49), 297 (9), 269 (100), 207 (41), 163 (82), 108 (92), 77
(25), 43 (16). Anal. calc. for C15H13N3O5 (315.28): C 57.14,
H 4.16, N 13.33; found: C, 57.09; H, 4.13; N, 13.30.
3
aIsolated yield.
GENERAL PROCEDURE
A mixture of arylmethylidenepyruvic acids (1, 1 mmol)
and 6-aminouracils (2, 1 mmol) and ZnO NPs (8.1 mg, 10
mol%) was stirred at 70 ˚C, for 2 h as required to complete
the reaction (monitored by TLC). The solid mass was then
eluted with DMF (5 mL), and the mixture was centrifuged at
2000-3000 rmp, for 5 min to remove the catalyst. The
organic solution was then poured into cold water (20 mL),
filtered and washed with aqueous ethanol to furnish the pure
product.
5-(4-Methylphenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyri-
do[2,3-d]pyrimidine-7-carboxylic acid (3c): White powder,
yield: 0.278 g (93%), m.p. 298–299˚C. IR (KBr) (ꢀmax/cm-1):
3344 (NH), 3245 (COOH), 1729 (COOH), 1659 (NCO),
1
1621 (NCON) cm-1. H-NMR: ꢀ = 2.24 (s, 3 H, CH3), 4.52
3
3
(d, J = 5.4 Hz, 1 H, H-5), 5.85 (d, J = 5.4 Hz, 1 H, H-6),
7.08 (br s, 4 H, HAr), 8.09 (s, 1 H, NH), 9.88 (s, 1 H, NH),
10.41 (s, 1 H, NH), 14.35 (s, 1 H, COOH) ppm. 13C-NMR: ꢀ
= 20.5 (CH3), 36.8 (C-5), 83.9 (C-C=O), 114.5 (C-6), 125.8
(C-7), 127.2 (2 CH), 128.9 (2 CH), 135.3 (C-CH3), 142.9
(C), 145.7 (C=O), 149.7 (N-C-N), 162.9 (C=O), 163.3
(C=O) ppm. Mass: (C14H9N5O2) m/z (%)= 299 (14, M), 297
(56), 252 (100), 208 (21), 164 (22), 91 (15), 77 (9), 43 (6).
Anal. calc. for C15H13N3O4 (299.28): C 60.20, H 4.38, N
14.04; found: C 60.12, H 4.30, N 14.00.
5-(4-Chlorophenyl)-2,4-dioxo-1,2,3,4,5,8-hexahydropyri-
do[2,3-d]pyrimidine-7-carboxylic acid (3a): White powder,
yield: 0.303 g (95%), m.p. 319–320˚C. IR (KBr) (ꢀmax/cm-1):
3344 (NH), 3242 (COOH), 1733 (COOH), 1659 (NCO),
1621 (NCON) cm-1. 1H-NMR: ꢀ = 4.60 (d, 3J = 5.3 Hz, 1 H,
H-5), 5.86 (dd, 3J = 5.3, 4J = 1.2 Hz, 1 H, H-6), 7.24 (d, 3J =
3
8.5 Hz, 2 H, HAr), 7.32 (d, J = 8.5 Hz, 2 H, HAr), 8.15 (s, 1
H, NH), 9.91 (s, 1 H, NH), 10.47 (s, 1 H, NH), 13.43 (s, 1 H,
COOH) ppm. 13C-NMR: ꢀ = 36.9 (C-5), 83.7 (C-C=O),
113.7 (C-6), 126.4 (C-7), 128.2 (2 CH), 129.3 (C-Cl), 131.0
(2 CH), 144.8 3 (C), 145.9 (C=O), 149.7 (N-C-N), 162.9
(C=O), 163.2 (C=O) ppm. Mass: (C14H9N5O2) m/z (%)= 321
(1, M+2), 319 (3, M), 264 (28), 238 (28), 97 (57), 83 (68),
77 (16), 69 (80), 57 (100), 43 (94). Anal. calc. for
5-(4-Chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-he-
xahydropyrido[2,3-d]pyrimidine-7-carboxylic acid (3d):
White powder, yield: 0.316 g (91%), m.p. 236–238˚C. IR
(KBr) (ꢀmax/cm-1): 3358 (NH), 3426 (COOH), 1701 (COOH),
1677 (NCO), 1620 (NCON) cm-1. 1H-NMR: ꢀ = 3.07 (s, 3 H,
NCH3), 3.44 (s, 3 H, NCH3), 4.69 (d, 3J = 5.4 Hz, 1 H, H-5),
3
3
6.00 (d, J = 5.4 Hz, 1 H, H-6), 7.25 (d, J = 8.5 Hz, 2 H,
HAr), 7.33 (d, 3J = 8.5 Hz, 2 H, HAr), 7.63 (s, 1 H, NH), 13.57

Arylmethylidenepyruvic Acids with 6-Aminouracils
Combinatorial Chemistry & High Throughput Screening, 2013, Vol. 16, No. 1 35
O
R
N
O
NH2
N
R
2
G
O
Zn
O
Zn
O
O
O
O
OH
R
OH
N
O
G
O
O
N
R
NH
H
1
O
Zn
O
Zn
O
4
ZnO NPs
G
G
O
O
R
R
-H2O
N
N
OH
CO2H
CO2H
N
H
N
H
O
O
N
R
N
R
3
5
Scheme 2. Suggested mechanism for the synthesis of hexahydropyrido[d]pyrimidines catalyzed by ZnO NPs under solvent-free conditions.
(s, 1 H, COOH) ppm. 13C-NMR: ꢀ = 27.5 (NCH3), 29.1
(NCH3), 37.7 (C-5), 85.1 (C-C=O), 115.1 (C-6), 126.7 (C-7),
128.3 (2 CH), 129.3 (C-Cl), 131.1 (2 CH), 144.7 (C), 145.7
(N-C-N), 150.7 (C=O), 160.8 (C=O), 163.4 (C=O) ppm.
Mass: (C14H9N5O2) m/z (%)= 349 (7, M+2), 347 (22, M),
301 (31), 236 (100), 218 (63), 190 (91), 133 (28), 77 (4), 57
(4). Anal. calc. for C16H14ClN3O4 (347.80): C 55.26, H 4.06,
N 12.08; found: C 55.18, H 4.00, N 12.02.
(C-7), 138.0 (C), 145.4 (N-C-N), 150.7 (C=O), 157.9 (C-
OCH3), 160.8(C=O), 163.5 (C=O) ppm. Mass: (C14H9N5O2)
m/z (%)= 343 (50, M), 297 (100), 236 (83), 218 (70), 190
(99), 133 (32), 77 (12), 57 (6). Anal. calc. for C17H17N3O5
(343.34): C 59.47, H 4.99, N 12.24; found: C 59.40, H 4.93,
N 12.18.
5-(4-Methylphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-he-
xahydropyrido[2,3-d]pyrimidine-7-carboxylic acid (3f):
White powder, yield: 0.307 g (94%), m.p. 248–249˚C. IR
(KBr) (ꢀmax/cm-1): 3423 (NH), 3358 (COOH), 1701 (COOH),
1669 (NCO), 1618 (NCON) cm-1. 1H-NMR: ꢀ = 2.23 (s, 3 H,
CH3), 3.07 (s, 3 H, NCH3), 3.44 (s, 3 H, NCH3), 4.62 (d, 3J =
5.5 Hz, 1 H, H-5), 5.99 (d, 3J = 5.5 Hz, 1 H, H-6), 7.06 (d, 3J
= 8.3 Hz, 2 H, HAr), 7.11 (d, 3J = 8.3 Hz, 2 H, HAr), 7.58 (s, 1
H, NH), 13.50 (s, 1 H, COOH) ppm. 13C-NMR: ꢁ = 20.6
(CH3), 27.5 (NCH3), 29.1 (NCH3), 37.7 (C-5), 85.6 (C-
C=O), 116.0 (C-6), 126.3 (2 CH), 127.3 (C-7), 128.9 (2 CH),
135.5 (C-CH3), 142.9 (C), 145.5 (N-C-N), 150.7 (C=O),
160.8 (C=O), 163.5 (C=O) ppm. Mass: (C14H9N5O2) m/z
5-(4-Methoxyphenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-7-carboxylic acid (3e):
White powder, yield: 0.305 g (89%), m.p. 228–229˚C. IR
(KBr) (ꢀmax/cm-1): 3411 (NH), 3366 (COOH), 1701 (COOH),
1669 (NCO), 1627 (NCON) cm-1. 1H-NMR: ꢀ = 3.07 (s, 3 H,
NCH3), 3.44 (s, 3 H, NCH3), 3.69 (s, 3 H, OCH3), 4.60 (d, 3J
= 5.5 Hz, 1 H, H-5), 5.99 (d, 3J = 5.5 Hz, 1 H, H-6), 6.82 (d,
3
3J = 8.6 Hz, 2 H, HAr), 7.12 (d, J = 8.6 Hz, 2 H, HAr), 7.58
(s, 1 H, NH), 13.50 (s, 1 H, COOH) ppm. 13C-NMR: ꢀ =
27.5 (NCH3), 29.0 (NCH3), 37.2 (C-5), 55.0 (OCH3), 85.7
(C-C=O), 113.7 (C-6), 116.0 (2 CH), 126.2 (2 CH), 128.4

36 Combinatorial Chemistry & High Throughput Screening, 2013, Vol. 16, No. 1
Shahrzad Abdolmohammadi
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C 62.38, H 5.23, N 12.84; found: C 62.30, H 5.20, N 12.79.
[12]
CONCLUSION
In conclusion, Zno Nps are found to catalyze the reaction
of arylmethylidenepyruvic acids and 6-aminouracils
efficiently, affording hexahydropyrido[2,3-d]pyrimidines in
high yields. The great advantages of this environmentally
benign and safe procedure include simple reaction set-up,
very mild reaction conditions, high product yields, short
reaction time, and possibility for reusing the catalyst.
[13]
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J.W.
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[15]
[16]
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
[17]
[18]
[19]
ACKNOWLEDGEMENTS
Shahrzad Abdolmohammadi thanks the Research Council
of East Tehran Branch, Islamic Azad University for financial
support of this work.
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Received: March 12, 2012
Revised: August 14, 2012
Accepted: September 4, 2012