Efficient synthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acids catalyzed by a TiO2/SiO2 nanocomposite in aqueous media at room temperature

Article abstract of DOI:10.1515/znb-2018-0076

A novel and efficient synthesis of eight 5-Aryl-1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-carboxylic acids using a TiO₂/SiO₂ nanocomposite with a molar ratio of 1:1 as a recyclable heterogeneous catalyst i

Full text of DOI:10.1515/znb-2018-0076

Z. Naturforsch. 2018; aop
Sepehr Sadegh-Samiei* and Shahrzad Abdolmohammadi
Efficient synthesis of pyrido[2,3-d]pyrimidine-7-carboxylic
acids catalyzed by a TiO2/SiO2 nanocomposite in aqueous
media at room temperature
https://doi.org/10.1515/znb-2018-0076
significant biological activities. Among the latter are
antibacterial, antifungal [6], anticancer [7], analgesic,
antiviral [8], antitubercular [9], anti-HIV [10], tyrosine
kinase-inhibiting [11], antimalarial [12], anti-inflamma-
tory [13], and diuretic [14] activities. Herein, we wish to
report a successful synthesis of pyrido[2,3-d]pyrimidine-
7-carboxylic acids 4 in aqueous media using a TiO2/SiO2
nanocomposite with a molar ratio of 1:1 as an efficient
heterogeneous catalyst (Scheme 1). This catalytic proto-
col involves a cyclocondensation reaction of 4-substituted
phenylmethylidenepyruvic acids, which are easily pre-
pared according to a known procedure [15], with ammo-
Received April 19, 2018; accepted June 14, 2018
Abstract: A novel and efficient synthesis of eight 5-aryl-
1,3-dimethyl-2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]
pyrimidine-7-carboxylic acids using a TiO2/SiO2 nanocom-
posite with a molar ratio of 1:1 as a recyclable heteroge-
neous catalyst is described. The desired products, five of
which are new, are formed in short reaction times (2–3 h)
with high to excellent yields (94%–98%) under very mod-
erate reaction conditions (room temperature, aqueous
media).
Keywords: 1,3-dimethyl barbituric acid; 4-substituted phe- nium acetate and 1,3-dimethyl barbituric acid. Although
nylmethylidenepyruvic acids; aqueous media; pyrido[2,3- two synthetic routes have been developed previously
d]pyrimidine-7-carboxylic acids; recyclability of catalyst; for the synthesis of these compounds, we consider this
TiO2/SiO2 nanocomposite.
new procedure as an attractive synthetic alternative. The
reported methods use the same starting materials in water
as reaction media under reflux [16], or catalyzed by ZnO
NPs at 70°C under solvent-free conditions [17]. Our efforts
were aimed at the use of the catalytic abilities of TiO2/SiO2
nanocomposites in water under less harsh conditions for
the synthesis of the compounds mentioned previously.
1 Introduction
Metal nanoparticles (NPs), especially metal oxide NPs, are
increasingly considered to be an efficient and promising
family of novel heterogeneous catalysts. They were shown
to have notable advantages such as high catalytic activ-
ity, good reusability, improved selectivity, and generally 2 Results and discussion
a broad range of applications in various organic transfor-
mations [1]. Among them, TiO2 NPs have been prepared A green and efficient preparation of 5-aryl-1,3-dimethyl-
with different particle sizes and crystalline modifications, 2,4-dioxo-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimi-
and used as heterogeneous catalysts for various organic dine-7-carboxylic acid 4 was developed through the
reactions [2–4]. Moreover, the catalytic activity of TiO2 NPs condensation of 4-substituted phenylmethylidenepyruvic
was significantly improved after covering them with silica acids 1, ammonium acetate 2, and 1,3-dimethyl barbituric
shells. TiO2/SiO2 nanocomposites are important for their acid 3, in the presence of a catalytic amount of TiO2/SiO2
unique properties such as electronic properties and large nanocomposite (15 mol%) at room temperature in water
specific surface area, and can be used effectively in syn- (Scheme 1).
thetic organic chemistry [5].
TiO2/SiO2 nanocomposite in the molar ratio of 1:1 was
Pyrimidine derivatives constitute a privileged class prepared using a literature procedure [18]. The X-ray
of heterocycles because of their synthetic versatility and powder diffraction (XRD) pattern of the nanocomposite
showed the existence of anatase-TiO2 in an amorphous
silica matrix. The transmission electron microscopy (TEM)
*Corresponding author: Sepehr Sadegh-Samiei, Department of
image of the nanocomposite showed that all composites
Chemistry, East Tehran Branch, Islamic Azad University, P.O. Box
have a grainy structure with nanoparticle sizes of 5–9 nm.
18735-138, Tehran, Iran, e-mail: sepehr.samiei@gmail.com
The chemical composition of as-prepared nanocomposite
Shahrzad Abdolmohammadi: Young Researchers and Elite Club,
East Tehran Branch, Islamic Azad University, P.O. Box 18735-138,
Tehran, Iran
was determined by X-ray fluorescence (XRF) technique
and the results showed that the composite consists of
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2ꢀ ꢀS. Sadegh-Samiei and S. Abdolmohammadi: Efficient synthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acids
R
O
TiO2/SiO2 nanocomposite
(15 mol%)
O
N
O
OH
N
N
NH4OAc
+
+
O
H2O, r. t.
O
N
O
O
HOOC
N
R
H
1
2
3
4
1a, 4a R = H, 1b, 4b R = Br, 1c, 4c R = Cl, 1d, 4d R = F, 1e, 4e R = OH, 1f, 4f R = OCH3,
1g, 4g R = CH3, 1h, 4h R = NO2
Scheme 1:ꢀSynthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acids (4a–h) using TiO2/SiO2 nanocomposites as catalyst.
55% TiO2 and 45% SiO2 (the molar ratio of TiO2 to SiO2 in nanocomposite with two commercial nanopowders, TiO2
the composite was approximately 1:1). Both XRD and TEM NPs (10–30 nm, anatase-TiO2), and SiO2 NPs (20 nm, non-
images of the as-synthesized nanocomposite have been porous), it was observed that the use of 20 mol% of the
presented in a previously published article [19].
TiO2 NPs and the SiO2 NPs alone produced the desired
In the present work, optimized reaction conditions product 4a in 77% and 64% yields, respectively (entries
were obtained in a model system using phenylmethylide- 5 and 6).
nepyruvic acid (1a; Rꢁ=ꢁH), ammonium acetate (2), and
In further tests, it was found that heating under reflux
1,3-dimethyl barbituric acid (3) to afford the correspond- in H2O did not improve the yield and the reaction time in
ing product (4a; Rꢁ=ꢁH) under various reaction conditions the presence of the catalyst (entries 3 and 7). Finally, it
including different amounts of TiO2/SiO2 nanocompos- was found that the best product yields were obtained in
ite as catalyst (Scheme 1 and Table 1). In the absence of aqueous media (entries 3 and 8–10).
catalyst, 74% of the product was obtained after 5 h in
The generality of the method was corroborated using
refluxing H2O (entry 1). The optimization of the cata- several 4-substituted phenylmethylidenepyruvic acids
lyst loading showed that 15 mol% of catalyst was suf- under optimized conditions (Table 2). The isolated com-
ficient to effectively catalyze the reaction (entries 2–4). pounds (4a–h) were characterized by infrared (IR), proton
When comparing the catalytic efficiency of the TiO2/SiO2 nuclear magnetic resonance (1H NMR) and carbon-13
Table 1:ꢀSynthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acid (4a;
Table 2:ꢀSynthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acids
Rꢁ=ꢁH) under different conditions (Scheme 1).a
(4; Rꢁ=ꢁvarious) from 4-substituted phenylmethylidenepyruvic acids
(1; Rꢁ=ꢁvarious), ammonium acetate (2), 1,3-dimethyl barbituric acid
Entry Nanocatalyst
Solvent Temperature Time Yield
(3), and a TiO2/SiO2 nanocomposite as catalyst (Scheme 1).a
(°C)
(h) (%)b,c
Product
R
Yield (%)b Time (h)
m. p. (°C)
1
2
No catalyst
H2O
Reflux
r. t.
5
4
3
3
5
6
2
3
3
3
74
82
96
TiO2/SiO2 (10%)a H2O
TiO2/SiO2 (15%)a H2O
TiO2/SiO2 (20%)a H2O
Nano-TiO2 (20%) H2O
Nano-SiO2 (20%) H2O
TiO2/SiO2 (15%)a H2O
TiO2/SiO2 (15%)a EtOH
TiO2/SiO2 (15%)a CH3CN
TiO2/SiO2 (15%)a CH2Cl2
Observed
Literature
3
r. t.
4
r. t.
95 4a
77 4b
64 4c
96 4d
86 4e
75 4f
71 4g
4h
H
95
98
96
96
94
94
96
97
3
2
221–223
251–253
–
–
5
r. t.
Br
6
r. t.
Cl
2.5 237–239 236–238 [16]
7
Reflux
r. t.
F
3
3
245–247
254–256
–
–
8
OH
OCH3
CH3
NO2
9
r. t.
r. t.
2.5 226–228 228–229 [16]
2.5 248–250 248–249 [16]
2
10
239–241
–
aAccording to the molar ratio of the TiO2 to the SiO2 in the TiO2/SiO2
composite (1:1), the catalyst loadings in mol% with respect to TiO2
were calculated to be 14, 21, and 28 mg for 10, 15, and 20 mol% of
the catalyst, respectively; breaction conditions: a mixture of phe-
nylmethylidenepyruvic acid (1a; Rꢁ=ꢁH) (1 mmol), ammonium acetate
2 (1.2 mmol), 1,3-dimethyl barbituric acid 3 (1 mmol), and TiO2/
SiO2 nanocomposite in 3 mL of solvent was stirred at the indicated
temperatures and times; cisolated yield.
aReaction conditions: a mixture of 4-substituted phenylmethyl-
idenepyruvic acids (1; Rꢁ=ꢁvarious) (1 mmol), ammonium acetate 2
(1.2 mmol), 1,3-dimethyl barbituric acid 3 (1 mmol), and TiO2/SiO2
nanocomposite (15 mol%; 21 mg) in 3 mL of water was stirred at
room temperature for the indicated times; byields refer to those of
pure isolated products that were characterized by IR, 1H, and 13
NMR spectral data and by elemental analyses.
C
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ꢂ3
S. Sadegh-Samiei and S. Abdolmohammadi: Efficient synthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acidsꢂ
O
OH
O
R
1
R
O
O
N
N
+
NH4OAc
O
N
O
N
O
H2N
N
O
O
H
O
N
2
3
5
O
O
H2N
6
TiO2/SiO2
nanocomposite
R
R
O
H2O
O
N
N
N
HOOC
HO
N
O
HOOC
N
N
H
O
H
4
7
Scheme 2:ꢀThe proposed mechanism for the formation of 4.
nuclear magnetic resonance (13C NMR) data and also by
elemental analyses.
4 Experimental section
A mechanism for the catalytic behavior of TiO2/SiO2
nanocomposite is provided in Scheme 2. This catalytic
cycle is preceded by the reaction of 1,3-dimethyl barbitu-
ric acid (3) with ammonium acetate (2) to generate enami-
none (5). Then, nanocatalyst participate in the subsequent
Michael addition of 5 to phenylmethylidenepyruvic acid 1
to produce intermediate 6. Further intermolecular cycliza-
tion of 6 affords the product 4 after dehydration.
The recyclability of the catalyst was explored using a
simple procedure described in the Experimental section
and reused up to four times for the synthesis of 4a with
a moderate decrease in catalytic activity (product yields:
95%, 93%, 91%, and 90%, respectively).
4.1 Materials and methods
All chemicals used in this work were purchased from
Merck and Fluka in high purity (provided by Kimiaexir
Chemical Company, Tehran, Iran). Melting points were
determined with an Electrothermal 9100 apparatus (East
Tehran Branch, Islamic Azad University, Tehran, Iran).
FT-IR spectra were obtained using a Bruker Equinox 55
Golden Gate Micro-ATR spectrometer (Chemistry and
Chemical Engineering Research Center of Iran, Tehran,
1
Iran). H NMR and 13C NMR spectra were recorded on a
Bruker DRX-300 AVANCE at 300 and 75 MHz, respectively,
using tetramethylsilane as an internal standard and deu-
terated dimethylsulfoxide as a solvent (Sharif University
of Technology, Tehran, Iran). Elemental analyses were
carried out using a Foss-Heraeus CHN-O-Rapid analyzer
(Polymer and Petrochemical Institute, Tehran, Iran).
3 Conclusion
We found that TiO2/SiO2 nanocomposite successfully The TEM image of the catalyst was obtained on a Philips
catalyzes the cyclocondensation reaction of 4-substituted EM208 transmission electron microscope under accelera-
phenylmethylidenepyruvic acids, ammonium acetate, tion (Nuclear Science and Technology Research Institute
and 1,3-dimethyl barbituric acid to afford pyrido[2,3-d] AEOI, Tehran, Iran). Powder XRD data were determined
pyrimidine-7-carboxylic acids in aqueous media. Using on a Philips, X’Pert diffractometer using CuKα radiation
the inexpensive, recyclable, and nontoxic catalyst mild (λꢀ=ꢀ1.54 Å) (Nuclear Science and Technology Research
reaction conditions, high yields and short reaction times Institute AEOI). The composition analysis of the catalyst
at room temperature are the advantages of this protocol.
was carried out by XRF spectroscopy using an Oxford
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4ꢀ ꢀS. Sadegh-Samiei and S. Abdolmohammadi: Efficient synthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acids
ED 2000 equipment (Nuclear Science and Technology (1H, d, Jꢀ=ꢀ5.0 Hz, H-5), 5.99 (1H, d, Jꢀ=ꢀ5.0 Hz, H-6), 7.49
Research Institute AEOI).
(3H, m, HAr), 7.59 (1H, s, NH), 7.70 (2H, m, HAr), 13.51 (1H, s,
COOH) ppm. – 13C NMR: δꢀ=ꢀ26.9, 29.2, 37.4, 87.0, 116.2, 122.3,
123.8, 126.8, 129.1, 140.3, 146.7, 151.4, 160.2, 164.3 ppm.
– IR (KBr): νmaxꢀ=ꢀ3339, 3220, 2956, 2858, 1708, 1650,
1621 cm−1. – Analysis calcd. for C16H15N3O4 (313.31): C 61.34,
H 4.83, N 13.41; found C 61.23, H 5.03, N 13.27%.
4.2 General procedure for the preparation
of the TiO2/SiO2 nanocomposite
catalyst [18]
Titanium tetrachloride (2 mL) was added dropwise into
deionized water (200 mL) in an ice-water bath with strong
magnetic stirring. After the hydrolysis was completed, the
released HCl was neutralized by adding dilute NH4OH to
adjust the pH to 7. The produced solid was filtered and
washed with distilled water. The precipitate was dispersed
into a 0.3 m HNO3 aqueous solution (200 mL) to remove all
the chloride ions. The mixture was then refluxed under
strong stirring at 70°C for 16 h, as the titania sol was pre-
pared. Tetraethylorthosilicate (25 mL) was added dropwise
into the above sol and stirred at 70°C for approximately
0.5 h. Finally, the TiO2/SiO2 nanocomposite powder was
filtered and washed with distilled water and then dried in
air at ambient temperature.
4.4.2 5-(4-Bromophenyl)-1,3-dimethyl-2,4-dioxo-
1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-
carboxylic acid (4b)
1
White solid; yield: 0.38 g (98%), m. p. 251°C–253°C. – H
NMR: δꢀ=ꢀ3.06 (3H, s, NCH3), 3.44 (3H, s, NCH3), 4.65 (1H,
d, Jꢀ=ꢀ5.4 Hz, H-5), 6.01 (1H, d, Jꢀ=ꢀ5.4 Hz, H-6), 7.24 (2H, d,
Jꢀ=ꢀ8.1 Hz, HAr), 7.61 (1H, s, NH), 8.40 (2H, d, Jꢀ=ꢀ8.1 Hz, HAr),
13.49 (1H, s, COOH) ppm. – 13C NMR: δꢀ=ꢀ27.6, 29.1, 37.6,
86.5, 116.4, 126.7, 127.3, 128.2, 133.8, 139.5, 147.1, 151.2, 159.8,
163.1 ppm. – IR (KBr): νmaxꢀ=ꢀ3340, 3294, 2963, 2860, 1711,
1663, 1564 cm−1. – Analysis calcd. for C16H14BrN3O4 (392.21):
C 49.00, H 3.60, N 10.71; found C 49.14, H 3.51, N 10.81%.
4.3 General procedure for the synthesis
of compounds 4a–k
4.4.3 1,3-Dimethyl-2,4-dioxo-5-(4-fluorophenyl)-
1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-
carboxylic acid (4d)
A mixture of 4-substituted phenylmethylidenepyru-
vic acids 1 (1 mmol), ammonium acetate (2, 1.2 mmol),
1,3-dimethyl barbituric acid (3, 1 mmol), and TiO2/SiO2 White solid; yield: 0.382 g (96%), m. p. 245°C–247°C. – 1H
nanocomposite (21 mg, 15 mol%) in H2O (3 mL) was stirred NMR: δꢀ=ꢀ3.02 (3H, s, NCH3), 3.43 (3H, s, NCH3), 4.60 (1H,
at room temperature for 3 h. After completion of the reac- d, Jꢀ=ꢀ5.4 Hz, H-5), 5.97 (1H, d, Jꢀ=ꢀ5.4 Hz, H-6), 7.31 (4H,
13
tion [as monitored by thin layer chromatography in ethyl m, HAr), 7.58 (1H, s, NH), 13.38 (1H, s, COOH) ppm. – C
acetate-n-hexane (2:1) as thin layer chromatography NMR: δꢀ=ꢀ26.5, 29.3, 38.1, 88.0, 116.1, 117.7, 126.1, 127.7, 141.9,
solvent], the reaction mixture was filtered and the solid 146.5, 151.5, 157.0, 158.7, 162.8 ppm. – IR (KBr): νmaxꢀ=ꢀ3339,
mass was diluted with dimethylformamide (2 mL). The 3251, 2960, 2848, 1709, 1660, 1618 cm−1. – Analysis calcd.
resulting mixture was centrifuged at 2000–3000 rpm for for C16H14FN3O4 (331.30): C 58.01, H 4.26, N 12.88; found C
5 min to remove the TiO2/SiO2 nanocatalyst for reusing 58.31, H 4.40, N 12.65%.
after drying at 80°C for several hours in vacuo. The organic
solution was poured into ice-cold water (5 mL), filtered,
and washed with aqueous ethanol to afford the pure prod- 4.4.4 1,3-Dimethyl-2,4-dioxo-5-(4-hydroxyphenyl)-
ucts 4.
1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-
carboxylic acid (4e)
1
4.4 Spectroscopic and physical data
White solid; yield: 0.31 g (94%), m. p. 254°C–256°C. – H
NMR: δꢀ=ꢀ3.05 (3H, s, NCH3), 3.40 (3H, s, NCH3), 4.595 (1H,
d, Jꢀ=ꢀ5.2 Hz, H-5), 6.03 (1H, d, Jꢀ=ꢀ5.2 Hz, H-6), 6.98 (2H,
d, Jꢀ=ꢀ8.3 Hz, HAr), 7.22 (2H, d, Jꢀ=ꢀ8.3 Hz, HAr), 7.60 (1H, s,
NH), 9.17 (1H, s, OH), 13.46 (1H, s, COOH) ppm. – 13C NMR:
δꢀ=ꢀ27.3, 29.5, 37.6, 86.9, 115.9, 128.0, 130.4, 136.5, 140.6, 145.8,
4.4.1 1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4,5,8-
hexahydropyrido[2,3-d]pyrimidine-7-carboxylic
acid (4a)
White solid; yield: 0.30 g (96%), m. p. 221°C–223°C. – 148.3, 151.2, 160.0, 164.1 ppm. – IR (KBr): νmaxꢀ=ꢀ3464, 3336,
1H NMR: δꢀ=ꢀ3.05 (3H, s, NCH3), 3.45 (3H, s, NCH3), 4.61 3260, 2964, 2853, 1714, 1659, 1631 cm−1. – Analysis calcd. for
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S. Sadegh-Samiei and S. Abdolmohammadi: Efficient synthesis of pyrido[2,3-d]pyrimidine-7-carboxylic acidsꢂ ꢂ5
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1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-7-
carboxylic acid (4h)
1
White solid; yield: 0.35 g (98%), m. p. 239°C–241°C. – H
NMR: δꢀ=ꢀ3.07 (3H, s, NCH3), 3.44 (3H, s, NCH3), 4.63 (1H,
d, Jꢀ=ꢀ5.5 Hz, H-5), 5.99 (1H, d, Jꢀ=ꢀ5.5 Hz, H-6), 7.42 (2H, d,
Jꢀ=ꢀ8.6 Hz, HAr), 7.60 (1H, s, NH), 8.03 (2H, d, Jꢀ=ꢀ8.6 Hz, HAr),
13.54 (1H, s, COOH) ppm. – 13C NMR: δꢀ=ꢀ27.4, 29.3, 37.8, 88.1,
115.5, 124.1, 126.4, 126.8, 142.5, 144.0, 148.2, 150.8, 159.6,
164.0 ppm. – IR (KBr): νmaxꢀ=ꢀ3338, 3246, 2955, 2852, 1709,
1657, 1618 cm−1. – Analysis calcd. for C16H14N4O6 (358.31):
C 53.63, H 3.94, N 15.64; found C 53.46, H 3.84, N 15.49%.
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5 Supporting information
Copies of the NMR spectra of 4a, 4b, and 4h are given
as Supporting Information available online (https://doi.
org/10.1515/znb-2018-0076).
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Graphical synopsis
R
Sepehr Sadegh-Samiei and
Shahrzad Abdolmohammadi
TiO2/SiO2 nanocomposite
15 mol%
O
N
O
N
O
Efficient synthesis of pyrido[2,3-d]
pyrimidine-7-carboxylic acids catalyzed
by a TiO2/SiO2 nanocomposite in aqueous
media at room temperature
OH
N
NH4OAc
+
+
O
H2O, r. t.
O
O
N
O
HOOC
N
R
H
https://doi.org/10.1515/znb-2018-0076
Z. Naturforsch. 2018; x(x)b: xxx–xxx
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