A clean procedure for synthesis of pyrido[d]pyrimidine derivatives under solvent-free conditions catalyzed by zro2 nanoparticles

Article abstract of DOI:10.2174/138620712800194486

A simple one-pot method for the preparation of 7-amino-2,4-dioxo-5-aryl-1, 2,3,4-tetrahydropyrido[2,3- d]pyrimidine-6-carbonitriles 4 from aromatic aldehydes, malononitrile and 4(6)-aminouracil in the presence of ZrO2 nanoparticles (ZrO2 NPs) as an effici

Full text of DOI:10.2174/138620712800194486

Combinatorial Chemistry & High Throughput Screening, 2012, 15, 395-399
395
A Clean Procedure for Synthesis of Pyrido[d]Pyrimidine Derivatives
Under Solvent-Free Conditions Catalyzed by ZrO2 Nanoparticles
Shahrzad Abdolmohammadi*,1 and Saeed Balalaie2
1Department of Chemistry, East Tehran Branch, Islamic Azad University, PO Box 33955-163, Tehran, Iran
2Peptide Chemistry Research Group, K.N. Toosi University of Technology, PO Box 15785-4416, Tehran, Iran
Abstract: A simple one-pot method for the preparation of 7-amino-2,4-dioxo-5-aryl-1,2,3,4-tetrahydropyrido[2,3-
d]pyrimidine-6-carbonitriles 4 from aromatic aldehydes, malononitrile and 4(6)-aminouracil in the presence of ZrO2
nanoparticles (ZrO2 NPs) as an efficient heterogeneous catalyst is described. The procedure has the advantages of high
yields (86-97%), short reaction time (2h) and an environmentally friendly specificity.
O
Ar
O
CN
O
CN
CN
HN
HN
ZrO2 Nanoparticles (10 mol%)
Solvent-free, 60 0C
+
+
Ar
H
O
N
H
NH2
NH2
N
H
N
O
Keywords: Solvent-free, tandem knoevenagel-michael addition, tetrahydropyrido[d]pyrimidine, ZrO2 nanoparticles.
O
Ar
INTRODUCTION
4
5
3
HN
CN
Pyridopyrimidine and its derivatives are of considerable
interest. They possess a wide range of biological properties
such as antibacterial [1], antiasthmatic, antiallergic,
antifolate [2], tyrosine kinase [3], antimicrobial [4], calcium
channel antagonists [5], anti-inflammatory and analgesic [6],
antihypertensive [7], antileishmanial [8], tuberculostatic [9],
anticonvulsants [10], diuretic and potassium-sparing [11],
antiaggressive [12] activities. In this paper, we have
described a very simple procedure for the preparation of 7-
amino-2,4-dioxo-5-aryl-1,2,3,4-tetrahydropyrido[2,3-d]pyri-
midine-6-carbonitrile derivatives 4 (Fig. 1) under solvent-
free conditions.
6
2
N
H
N
NH2
O
7
1
8
4
Fig. (1). Structure of pyrido[d]pyrimidine derivatives.
The method that we present here includes the reaction of
benzaldehyde derivatives 1, malononitrile 2 and 4(6)-
aminouracil 3 in the presence of catalytic amounts of ZrO2
NPs (10 mol%) under solvent-free conditions for 2 hours to
give the corresponding products 4(a-h) in high yields (86-
97%) (Scheme 1).
In recent years, it has been recognized a gradual change
from classical reaction conditions to more environmentally
friendly routes [13]. One of these efficient synthetic methods
is to perform reactions on the surface of solid which holds
significant potential for several reasons such as: (a) higher
reactivity in comparison to usual solution counterpart, (b)
easier isolation of products, (c) easier separation and
recycling of the catalysts, (d) reduction of the waste
generation and (e) selectivity and reactivity of the catalysts
which often are comparable to those of enzymes [14-18].
Several inorganic oxides such as SiO2, Al2O3, etc. have
commonly been used for surface organic chemistry [19].
Thus, in continuation of our previous study on the
development of new facile routes in heterocyclic synthesis,
we considered ZrO2 nanoparticles (ZrO2 NPs) to be an
efficient catalyst for the synthesis of tetrahydropyrido
[d]pyrimidine derivatives as a class of important biologically
RESULT AND DISCUSSION
Following up our previous works on the development of
new and efficient methods for the preparation of heterocyclic
compounds [20], herein, we describe a convenient, simple
and clean procedure to 7-amino-2,4-dioxo-5-aryl-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles 4, under
solvent-free conditions in the presence of ZrO2 NPs as an
efficient, inexpensive, reusable, moisture stable, commer-
cially available and environmentally benign catalyst.
Table 1 shows the results obtained in the reaction of a
series of representative aldehydes with malononitrile and
4(6)-aminouracil. Substituent on the aromatic ring did not
show any electronic effects in terms of yields under these
reaction conditions.
active compounds via a three-component reaction of
aromatic aldehydes, malononitrile and 4(6)-aminouracil.
In order to optimize the reaction conditions, first we used
3-nitrobenzaldehyde, 2 and 3 as a model. The experimental
results are summarized in Table 2. After 2 h with 5, 10 and
15 mol% of ZrO2 NPs, yields of 68, 96 and 96%,
respectively, were obtained. It is important to note that in the
*Address correspondence to this author at the Department of Chemistry,
East Tehran Branch, Islamic Azad University, PO Box 33955-163, Tehran,
Iran; Fax: +98-21-3359 4332;
E-mails: abdolmohamadi_sh@yahoo.com, sabdolmohamadi@qdiau.ac.ir
1875-5402/12 $58.00+.00
© 2012 Bentham Science Publishers

396 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5
Abdolmohammadi and Balalaie
O
Ar
N
O
CN
O
CN
HN
HN
ZrO2 Nanoparticles (10 mol%)
Solvent-free, 60 0C
+
+
Ar
H
O
N
H
NH2
N
H
NH2
CN
O
1
2
3
4
Scheme 1. Synthesis of pyrido[d]pyrimidine derivatives.
absence of ZrO2 NPs the reaction time was increased,
meanwhile the yield decreased (Table 2, entries 1-4).
Although it is not clear how ZrO2 NPs act as catalyst for the
reaction, on the basis of the surface of metal oxides which
exhibit both lewis acid and lewis base character [21], a plausible
mechanism for the ZrO2 catalyzed one-pot reaction of aromatic
aldehydes, malononitrile and 4(6)-aminouracil is outlined in
Scheme 2. It is suggested that, ZrO2 NPs are coordinated to the
oxygen of the aromatic aldehyde 1 and activate it for
nucleophilic attack [22] by malononitrile 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 intermediate 7, which
could be easily oxidized to corresponding aromatization product
4 after tautomerization of intermediate 8.
Table 1. ZrO2 NPs Catalyzed Synthesis of Pyrido[d]
Pyrimidines 4(a-h) in Solvent-Free Condition
Product
Ar
Yield (%)a,b
4a
4b
4c
4d
4e
4f
C6H5
89
91
90
97
86
91
96
97
2-Cl-C6H4
2,4-Cl2-C6H3
3-OH-C6H4
4-OCH3-C6H4
4-CH3-C6H4
3-NO2-C6H4
4-NO2-C6H4
The structure of compounds 4(a-h) were deduced from their
1H NMR, 13C NMR and IR spectral data and their molecular
1
weight confirmed by mass spectrometry. H NMR and 13C
4g
NMR spectroscopy was especially useful to elucidate the
structures of products. The mass spectra of these compounds
showed the expected molecular ion signals, selected
spectroscopic data have been given in general procedure
section.
4h
aYields refer to those of pure isolated products characterized by IR, 1H and 13C NMR
spectroscopic data and mass spectrometry.
bIn all cases, reaction time was 2 h stirring at 60ꢀC.
In comparison to the efficiency of catalytic activity of the
ZrO2 NPs with commercially available ZrO2 bulk, using
ZrO2 NPs, the reaction time was reduced by four times with
higher yield than ZrO2 bulk (Table 2, entries 3 and 5).
In order to demonstrate that ZrO2 can catalyze the 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 increasing of temperature to more than 60ꢀC did not
play an important role in the yield of product (Table 2,
entries 3 and 6).
A comparison of the same reaction in various reaction
media is also presented in Table 2. Using solvents such as
CH2Cl2, DMF and EtOH/H2O were less effective versus
solvent-free conditions (Table 2, entries 3 and 7-9).
MATERIAL AND METHODS
All chemicals used in this work purchased from Fluka and
used without further purification. Melting points were
Table 2. Synthesis of 7-Amino-2,4-Dioxo-5-(3-Nitrophenyl)-1,2,3,4-Tetrahydropyrido[2,3-d]Pyrimidine-6-Carbonitrile (4g) Through the
Reaction of 3-Nitrobenzaldehyde, Malononitrile and 4(6)-Aminouracil Under Different Conditions
Entry
Catalyst (mol%)
Solvent
Temp (ꢀC)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
No catalyst
none
none
60
60
60
60
60
80
70
100
80
6
2
2
2
8
2
5
5
5
38
68
96
96
42
97
45
58
73
ZrO2 NPs (5%)
ZrO2 NPs (10%)
ZrO2 NPs (15%)
ZrO2 bulk (10%)
ZrO2 NPs (10%)
ZrO2 NPs (10%)
ZrO2 NPs (10%)
ZrO2 NPs (10%)
none
none
none
none
CH2Cl2
DMF
EtOH/H2O
aIsolated yield.

Pyrido[d]Pyrimidine Derivatives
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5 397
O
Zr
O
O
H
C
H
Ar
H
CN
CN
O
O
O
Zr
O
CN
+
H
H
Ar
H
CN
Ar
H
CN
CN
2
1
+ H2O
ZrO2 NPs
ZrO2 NPs
Ar
H
CN
CN
5
O
Zr
O
CN
CN
H
O
HN
Ar
HN
HN
H
O
N
H
NH2
O
N
H
O
3
ZrO2 NPs
N
H
CN
Ar
H
NH
HN
H
O
N
H
O
6
Cyclization
NH
NH2
NH2
CN
CN
Ar
CN
HN
HN
N
H
HN
Ar Tautomerization HN
O
Ar
HN
Aromatization
O
N
H
N
H
O
O
N
H
O
O
4
7
8
Scheme 2. Proposed mechanism for the one-pot synthesis of tetrahydropyrido[d]pyrimidines catalyzed by ZrO2 NPs under solvent-free
conditions.
determined with Electrothermal 9100 melting point
apparatus and were uncorrected. IR spectra were obtained on
500 and 125 MHz, respectively using TMS as internal
standard and DMSO-d6 as solvent. Mass spectra data were
obtained by using GC-MS Hewlet Packard (EI, 70 eV)
instrument.
an ABB FT-IR (FTLA 2000) spectrometer. 1H NMR and 13
NMR spectra were run on a Bruker DRX-500 AVANCE at
C

398 Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5
Abdolmohammadi and Balalaie
(C=O), 155.43 (C), 156.57 (C), 158.95 (C-OH), 159.79 (C-
NH2), 160.76 (C=O) ppm. Mass: (C14H9N5O3) m/z (%)= 294
(M-H)+, 266 (M+-CO), 251 (M+- HNCO), 118(C6H4N3)+, 77,
57, 43.
General Procedure
A
mixture of aromatic aldehyde
1
(1 mmol),
malononitrile (2, 1.2 mmol), 4(6)-aminouracil (3, 1 mmol)
and ZrO2 NPs (12.3 mg, 10 mol%) was stirred at 60ꢀC for 2
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.
7-amino-2,4-dioxo-5-(4-methoxyphenyl)-1,2,3,4-tetrahy-
dropyrido[2,3-d]pyrimidine-6-carbonitrile (4e): Brick-red
solid, yield: 0.266 g (86%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1):
3404, 3328 (NH2), 3188, 3150 (2 NH), 2219 (CN), 1700,
1
1645 (2 CO) cm-1. H-NMR: ꢀ = 3.80 (s, 3 H, OCH3), 6.94
(m, 2 H, HAr), 7.19 (m, 2 H, HAr), 7.57 (br s, 2 H, NH2),
10.59 (s, 1 H, NH), 10.73 (s, 1 H, NH) ppm. 13C-NMR: ꢁ =
55.02 (OCH3), 88.80 (C-CN), 98.32 (C), 112.93 (2 CH),
115.67 (2 CH), 128.55 (CꢀN), 129.23 (C), 150.13 (C=O),
155.51 (C), 158.84 (C-O), 159.29 (C), 160.02 (C-NH2),
160.82 (C=O) ppm. Mass: (C15H11N5O3) m/z (%)= 309 (M)+,
265 (M+-HNCO), 121, 77, 57, 43.
7-amino-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydropyrido[2, 3-
d]pyrimidine-6-carbonitrile (4a): White solid, yield: 0.248 g
(89%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1): 3403, 3331 (NH2),
3174 (br, 2 NH), 2224 (CN), 1707, 1643 (2 CO) cm-1. H-
1
NMR: ꢀ = 7.24 (m, 2 H, HAr), 7.40 (m, 3 H, HAr), 7.59 (br s,
2 H, NH2), 10.89 (s, 1 H, NH), 11.44 (s, 1 H, NH) ppm. 13C-
NMR: ꢁ = 88.71 (C-CN), 98.32 (C), 115.51 (CH),
127.53(CꢀN), 127.65 (2 CH), 128.26 (2 CH), 136.76 (C),
150.31 (C=O), 155.57 (C), 159.03 (C), 160.05 (C-NH2),
160.86 (C=O) ppm. Mass: (C14H9N5O2) m/z (%)= 278 (M-
H)+, 235 (M+-HNCO), 208 (M+-C2HNO2), 118 (C6H4N3)+,
77, 57, 43.
7-amino-2,4-dioxo-5-(4-methyphenyl)-1,2,3,4-tetrahydrop-
yrido[2,3-d]pyrimidine-6-carbonitrile (4f): White solid,
yield: 0.267 g (91%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1):
3394, 3281 (NH2), 3167, 3031 (2 NH), 2222 (CN), 1699,
1645 (2 CO) cm-1. 1H-NMR: ꢀ = 2.36 (s, 3 H, CH3), 7.12 (d,
2 H, HAr, J = 8.0 Hz), 7.20 (d, 2 H, HAr, J = 8.0 Hz), 7.60
(br s, 2 H, NH2), 10.89 (s, 1 H, NH), 11.43 (s, 1 H, NH)
ppm. 13C-NMR: ꢁ = 20.88 (CH3), 88.70 (C-CN), 98.26 (C),
115.51 (2 CH), 127.48 (2 CH), 128.11(CꢀN), 133.70 (C),
137.43 (C), 150.12 (C=O), 155.46 (C), 159.06 (C), 159.94
(C-NH2), 160.79 (C=O) ppm. Mass: (C15H11N5O2) m/z (%)=
292 (M-H)+, 249 (M+-HNCO), 77, 57, 43.
3
3
7-amino-2,4-dioxo-5-(2-chlorophenyl)-1,2,3,4-tetrahydro-
pyrido[2,3-d]pyrimidine-6-carbonitrile (4b): White solid,
yield: 0.285 g (91%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1):
3390, 3311 (NH2), 3188, 3091 (2 NH), 2228 (CN), 1699,
1648 (2 CO) cm-1. 1H-NMR: ꢀ = 7.28 (dd, 1 H, HAr, 3J = 7.4,
3
4J = 1.5 Hz), 7.38 (t, 1 H, HAr, J = 7.9 Hz), 7.43 (dt, 1 H,
7-amino-2,4-dioxo-5-(3-nitrophenyl)-1,2,3,4-tetrahydro-
pyrido[2,3-d]pyrimidine-6-carbonitrile (4g): Pale Yellow
solid, yield: 0.311 g (96%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1):
3384, 3321 (NH2), 3172, 3081 (2 NH), 2216 (CN), 1718,
1662 (2 CO) cm-1. 1H-NMR: ꢀ = 7.75 (m, 2 H, HAr), 7.77 (br
s, 2 H, NH2), 8.29 (qd, 1 H, HAr, 3J = 7.0, 4J = 1.1 Hz), 11.00
(s, 1 H, NH), 11.54 (s, 1 H, NH) ppm. 13C-NMR: ꢁ = 88.33
(C-CN), 98.33 (C), 115.19 (CH), 122.79 (CH), 123.13 (CH),
129.40 (CꢀN), 134.43 (CH), 138.36 (C), 147.14 (C), 150.11
(C=O), 155.45 (C), 156.10 (C), 160.19 (C-NH2), 160.76
(C=O) ppm. Mass: (C14H8N6O4) m/z (%)= 324 (M)+, 277
(M+-HNCO), 77, 57, 43.
3
4
3
HAr, J = 7.4, J = 1.5 Hz), 7.51 (d, 1 H, HAr, J = 7.9 Hz,),
7.75 (br s, 2 H, NH2), 10.99 (s, 1 H, NH), 11.55 (s, 1 H, NH)
ppm. 13C-NMR: ꢁ = 88.32 (C-CN), 98.47 (C), 114.78 (CH),
126.90 (CꢀN), 128.76 (CH), 128.95 (CH), 129.91 (CH),
130.49 (C), 135.87 (C-Cl), 150.12 (C=O), 155.38 (C),
155.76 (C), 159.72 (C-NH2), 160.94 (C=O) ppm. Mass:
(C14H8ClN5O2) m/z (%)= 313 (M)+, 278 (M+-Cl), 188
(C8H4N4O2)+, 153, 111, 77, 57, 43.
7-amino-2,4-dioxo-5-(2,4-dichlorophenyl)-1,2,3,4-tetrah-
ydropyrido[2,3-d]pyrimidine-6-carbonitrile (4c): White so-
lid, yield: 0.312 g (90%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1):
3377, 3318 (NH2), 3143, 3068 (2 NH), 2206 (CN), 1699,
7-amino-2,4-dioxo-5-(4-nitrophenyl)-1,2,3,4-tetrahydro-
pyrido[2,3-d]pyrimidine-6-carbonitrile (4h): Brick-red solid,
yield: 0.314 g (97%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-1):
3607, 3534 (NH2), 3297, 3070 (2 NH), 2222 (CN), 1703,
1
3
1648 (2 CO) cm-1. H-NMR: ꢀ = 7.34 (d, 1 H, HAr, J = 8.2
3
Hz), 7.50 (d, 1 H, HAr, J = 8.2 Hz), 7.72 (br s, 1 H, HAr),
7.81 (br s, 2 H, NH2), 11.06 (s, 1 H, NH), 11.58 (s, 1 H, NH)
ppm. 13C-NMR: ꢁ = 88.10 (C-CN), 98.41 (C), 114.68 (CH),
127.21 (CꢀN), 128.38 (C-Cl), 130.33 (CH), 131.73 (CH),
133.69 (C), 134.97 (C-Cl), 150.07 (C=O), 154.61 (C),
155.38 (C), 159.79 (C-NH2), 160.88 (C=O) ppm. Mass:
(C14H7Cl2N5O2) m/z (%)= 348 (M+H)+, 312 (M+-Cl), 277
(M+- C2HNO2), 77, 57, 43.
1
3
1590 (2 CO) cm-1. H-NMR: ꢀ = 7.58 (d, 2 H, HAr, J = 8.6
3
Hz), 7.75 (br s, 2 H, NH2), 8.27 (d, 2 H, HAr, J = 8.6 Hz),
11.00 (s, 1 H, NH), 11.55 (s, 1 H, NH) ppm. 13C-NMR: ꢁ =
87.88 (C-CN), 98.16 (C), 115.06 (2 CH), 122.89 (2 CH),
129.15 (C-CN), 143.96 (C), 147.33 (C), 150.18 (C=O),
155.47 (C), 156.62 (C), 160.13 (C-NH2), 160.76 (C=O) ppm.
Mass: (C14H8N6O4) m/z (%)= 324 (M)+, 277 (M+-HNCO),
77, 57, 43.
7-amino-2,4-dioxo-5-(3-hydroxyphenyl)-1,2,3,4-tetrahyd-
ropyrido[2,3-d]pyrimidine-6-carbonitrile (4d): Brick-red
solid, yield: 0.286 g (97%), m.p.>300ºC. IR (KBr) (ꢀmax/cm-
1): 3391, 3322 (NH2), 3164, 3071 (2 NH), 2237 (CN), 1686,
CONCLUSION
1
1649 (2 CO) cm-1. H-NMR: ꢀ = 6.59 (s, 1 H, HAr), 6.62 (d,
In conclusion, we found a novel method available for the
synthesis of 7-amino-2,4-dioxo-5-aryl-1,2,3,4-tetrahydropy-
rido[2,3-d]pyrimidine-6-carbonitriles, meanwhile the new
method also expands the application of the catalyst of ZrO2
NPs in organic synthesis. Compared with previous methods
for the synthesis of these biologically active compounds
3
1 H, HAr, J = 7.4 Hz), 6.78 (dd, 1 H, HAr, J = 8.0, J = 1.9
3
4
3
Hz), 7.18 (t, 1 H, HAr, J = 8.0 Hz), 7.58 (br s, 2 H, NH2),
9.46 (s, 1 H, OH), 11.06 (s, 2 H, 2NH) ppm. 13C-NMR: ꢁ =
88.53 (C-CN), 98.25 (C), 114.34 (CH), 115.15 (CH), 115.39
(CH), 118.06 (CH), 128.77 (CꢀN), 137.92 (C), 150.19

Pyrido[d]Pyrimidine Derivatives
Combinatorial Chemistry & High Throughput Screening, 2012, Vol. 15, No. 5 399
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[23], this method has the advantages of high yields, mild
reaction conditions, short reaction time, easy work-up,
inexpensive reagents and environmentally friendly
procedure.
[11]
[12]
[13]
[14]
ACKNOWLEDGEMENTS
Shahrzad Abdolmohammadi would like to thank East
Tehran Branch Islamic Azad University for financial
support.
CONFLICT OF INTEREST
Declared none.
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Received: June 21, 2011
Revised: November 9, 2011
Accepted: December 21, 2011