Enviro-economic, ultrasound-assisted one-pot, three-component synthesis of pyrido[2,3-d]pyrimidines in aqueous medium

Article abstract of DOI:10.1515/znb-2012-0309

Tetra-n-butyl ammonium bromide (TBAB) was found to be an efficient phase-transfer catalyst for the synthesis of pyrido[2,3-d]pyrimidines by one-pot reaction of 6-aminouracils, aromatic aldehydes, and malononitrile or ethyl cyanoacetate in water under ultr

Full text of DOI:10.1515/znb-2012-0309

Enviro-economic, Ultrasound-assisted One-pot, Three-component
Synthesis of Pyrido[2,3-d]pyrimidines in Aqueous Medium
Essam M. Hussein
Department of Chemistry, Faculty of Science, Assiut University, Assiut 71516, Egypt
Reprint requests to Dr. Essam M. Hussein. Fax: 0020882342708.
E-mail: essam.hussein78@yahoo.com
Z. Naturforsch. 2012, 67b, 231 – 237; received February 18, 2012
Tetra-n-butyl ammonium bromide (TBAB) was found to be an efficient phase-transfer catalyst for
the synthesis of pyrido[2,3-d]pyrimidines by one-pot reaction of 6-aminouracils, aromatic aldehydes,
and malononitrile or ethyl cyanoacetate in water under ultrasonic irradiation. The advantages of this
method are the use of an inexpensive and readily available catalyst, short reaction time, easy work-up,
improved yields, and the use of water as a solvent that is environmentally benign.
Key words: Ultrasound, Uracil, Pyrido[2,3-d]pyrimidine, Tetra-n-Butyl Ammonium Bromide
Introduction
literature, however, they usually require harsh condi-
tions [14], long reaction times [15, 16] and complex
synthetic pathways [5]. So, new routes for the synthe-
sis of these molecules have attracted considerable at-
tention as a rapid entry for the formation of these hete-
rocycles [17 – 19]. Ultrasonication, based on cavitation
effects leading to mass transfer improvement, is an im-
portant technique that is widely used in organic synthe-
sis and has a profound impact on the way chemists ap-
proach organic and parallel syntheses. Reduction in re-
action times, improved yields and suppression of side
products, relative to traditional thermal heating, are
benefits of this technology [20, 21].
As a consequence of our interest in the synthesis of
N-heterocycles in aqueous medium [22, 23], we inves-
tigated a three-component reaction of 6-aminouracils
1a, b, aromatic aldehydes 2a – h, and malononitrile (3)
or ethyl cyanoacetate (4) in water under ultrasonic ir-
radiation to afford a series of pyrido[2,3-d]pyrimid-
ine derivatives (5a – u) instead of the corresponding
1,4-dihydropyrido[2,3-d]pyrimidine derivatives 6 via
spontaneous aromatization (Scheme 1).
Multi-step reactions usually produce large amounts
of waste, principally due to a series of complex isola-
tion procedures which often involve toxic, hazardous
and expensive solvents after each step. Thus, multi-
component reactions (MCRs), in which multiple re-
actions are performed in one synthetic operation have
been used extensively to form carbon-carbon bonds
in synthetic chemistry [1, 2]. Such reactions offer a
wide range of possibilities for the efficient construc-
tion of highly complex molecules in a single proce-
dural step, thus avoiding the complicated purification
operations and allowing savings of both solvents and
reagents. On the other hand, polyfunctionalized hete-
rocycles play considerable roles in the drug discovery
process, and analysis of drugs shows that most of them
consits of polyfunctionalized heterocycles [3]. There-
fore, research on the multi-components synthesis of
polyfunctionalized heterocyclic compounds is an in-
teresting challenge. Pyrido[2,3-d]pyrimidines are bio-
logically interesting molecules that have established
utility in the pharmaceutical and the agrochemical in-
dustries. Compounds with these ring systems have di-
verse pharmacological activity such as antitumor [4, 5],
cardiotonic [6, 7], hepatoprotective [6], antihyperten-
Results and Discussion
In our initial study, the evaluation of various addi-
sive [6], antibronchitic [8], antifungal [9], antibacte- tives was carried out for the synthesis of pyrido[2,3-
rial [10], and antifolate activity [11]. Therefore, these d]pyrimidine derivatives in aqueous medium under
fused heterocycles have been extensively investigated, ultrasonic irradiation. A mixture of 6-amino-2-thio-
and their preparation is well documented [12, 13]. As uracil (1a), 4-methoxybenzaldehyde (2a) and malo-
a result, a number of reports have appeared in the nonitrile (3) as a simple model substrate in the pres-
c
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Essam M. Hussein · Synthesis of Pyrido[2,3-d]pyrimidines
Table 1. Optimization of the condition for the reaction de- Table 2. Solvent effects on the reaction of 6-amino-2-thio-
pricted in Scheme 1a.
uracil (1a), 4-methoxybenzaldehyde (2a), and malononitrile
(3) in the presence of TBAB (15 mol-%) at 70 ◦C.
Entry
Additiveb
Temp. (◦C)
Time (min)
360
240
180
120
90
Yield (%)c
Entry
Solventa
CH3OH
C2H5OH
DMF
DMSO
THF
Time (min)
180
Yield (%)b
1
2
3
–
70
70
70
70
70
70
r. t.
40
60
80
90
trace
30
36
55
72
95
60
70
81
95
95
K2CO3
PTSA
SDS
1
2
3
4
5
6
78
73
71
120
180
180
360
360
50
4
5
6
7
8
9
10
11
TEBA
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
65
50
120
90
50
50
trace
trace
95
CH3CN
H2O
7
a
5 mL of solvent was used; b isolated yield of pure 5a.
50
Table 3. Synthesis of pyrido[2,3-d]pyrimidines 5a – u in
aqueous medium under ultrasonic irradiation.
a
The reaction was carried out with 6-amino-2-thiouracil (1a),
4-methoxybenzaldehyde (2a) and malononitrile (3) in water;
Entry Product
X
Ar
Ewg
Time (min) Yield (%)
the amount of each additive was 15 mol-%; c isolated yield of 5a.
b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
S
S
S
S
S
S
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
4-MeOC6H4 CN
4-NO2C6H4 CN
50
65
60
70
60
75
75
80
70
95
90
99
60
80
80
95
90
80
90
95
99
95
96
94
92
93
90
95
91
79
85
84
71
89
86
81
86
75
89
92
81
79
4-ClC6H4
4-BrC6H4
CN
CN
4-HOC6H4 CN
Ph
3-pyridyl
2-furyl
CN
CN
CN
4-MeOC6H4 CO2Et
4-NO2C6H4 CO2Et
4-ClC6H4
3-pyridyl
CO2Et
CO2Et
4-MeOC6H4 CN
4-NO2C6H4 CN
4-ClC6H4
3-pyridyl
2-furyl
CN
CN
CN
4-MeOC6H4 CO2Et
4-NO2C6H4 CO2Et
Scheme 1. Synthesis of 5a.
5t
5u
4-ClC6H4
3-pyridyl
CO2Et
CO2Et
ence of a catalytic amount of TBAB (◦15 mol-%) as
phase transfer catalyst in water at 70 C was inves-
tigated to establish the feasibility of the strategy and was obtained when TBAB was used which provided a
to optimize the reaction conditions (Scheme 1). The yield of 95 %.
procedure was simple and easy to operate. It was re-
ported [24, 25] that 1,4-dihydro-pyrido[2,3-d]pyrimid-
ine-2,4-dionederivatives were unstable in air and could
easily be oxidized to the corresponding aromatization
products.
We examined this reaction in the absence and pres-
ence of several other additives. When the reaction
was carried out without any additives, only a trace
amount of the product resulted (Table 1, entry 1).
Bases or acids such as K2CO3 or p-toluene sulfonic
To study the effect of the amount of the cata-
lyst, the reactions were carried out with different
amounts of TBAB ranging from 10 to 20 mol-%. It
was found that when increasing the amount of TBAB
from 10 to 15, and 20 mol-%, the yields increased
from 81 to 95 and 88 %, respectively. Thus 15 mol-%
TBAB in water is sufficient to push this reaction for-
ward. Larger amounts of TBAB did not improve the
yields.
To optimize the reaction temperature, the reactions
acid (PTSA) can push the reaction yield (Table 1, en- were carried out at different temperatures ranging from
tries 2, 3). When surfactants, such as sodium dode- r. t. to 90 ◦C. It was found that the yield was improved
cyl sulfate (SDS), triethyl benzyl ammonium chloride and the reaction time was shortened when the temper-
(TEBA) and n-tetrabutyl ammonium bromide (TBAB) ature was increased to 70 ◦C. No significant change in
were used in this reaction, the yields of the products yield was observed when the temperature was further
were improved (Table 1, entries 4 – 6). The best result increased to 80 and 90 ◦C (Table 1, entries 6 – 11).
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Essam M. Hussein · Synthesis of Pyrido[2,3-d]pyrimidines
Scheme 2. Synthesis of pyrido[2,3-d]pyrimidines 5a – u.
233
at 3310, 3220 cm−1 for NH2 and 2210 cm−1 for CN
were observed in the IR spectrum. The 1H NMR spec-
trum showed the absence of the methine proton of
the uracil and the presence of a singlet signal at δ =
6.36 ppm for the NH2 group and two singlet signals at
δ = 12.49, 13.10 ppm for two NH protons.
According to the structure of 5a – u a sequential
Knoevenagel condensation, Michael addition, and in-
tramolecular cyclization followed by the aromatization
may take place during the formation of the products. A
possible mechanism is shown in Scheme 3.
In conclusion, an enviro-economic, ultrasound-
assisted one-pot, and efficient three-component syn-
thesis of pyrido[2,3-d]pyrimidines in aqueous medium
has been developed. Prominent among the advantages
of this new method are operational simplicity, good
yields in short reaction times and easy work-up pro-
cedures.
Experimental Section
The time required for the completion of each reaction was
monitored by TLC. All melting points are uncorrected and
were measured on a Gallenkamp apparatus. The IR spectra
were recorded on a Shimadzu 470 IR spectrometer (KBr).
The 1H NMR spectra were measured on a Varian EM-390
(90 MHz). The 13C NMR spectra were obtained on a Var-
ian EM-200 (100 MHz) spectrometer with TMS as internal
standard and [D6]DMSO as solvent. Mass spectra were de-
termined on a Jeol JMS-600 spectrometer. Elemental analy-
ses (C, H, N, and S) were performed on an elemental anal-
ysis system Vario EL V2.3. The results were found to be in
good agreement with the calculated values. Ultrasonication
R
ꢀ
was performed in an Elma D-7700 (Singen, Germany) ul-
trasound cleaner with a frequency of 35 kHz. The reaction
flasks were immersed in the cleaner in such a way that the
surface of the reactants was slightly lower than the water in
the cleaner, and the temperature of the water bath was con-
trolled by an electronic temperature control system.
Compounds 1a, b were prepared according to the method
described in the literature [26]. Compounds 2a – h, 3 and 4
are commercially available.
Scheme 3. Possible mechanism for the formation of pyrido-
[2,3-d]pyrimidines.
Furthermore, different solvents were screened in the
model reaction. It was found that the reaction in water
led to high yields after 50 min (Table 2).
Under the optimized reaction conditions, a series of
pyrido[2,3-d]pyrimidine derivatives (5a – u) were syn-
thesized (Scheme 2, Table 3).
As shown in Table 3, it was found that this method is
successful with a variety of substrates. 6-Aminouracils
(1a, b) and different aromatic aldehydes (2a – h) were
used in this protocol, and also the reaction with malo-
nonitrile (3) or ethyl cyanoacetate (4) led to the desired
products.
Amino-1,2,3,4-tetrahydro-5-(4-methoxyphenyl)-4-oxo-2-
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5a)
A mixture of 6-amino-2-thiouracil (1a) (0.143 g, 1 mmol),
4-methoxybenzaldehyde (2a) (0.136 g, 1 mmol), malononi-
trile (3) (0.066 g, 1 mmol), and TBAB (0.048 g, 15 mol-%) in
water (5 mL) was sonicated at 70 ◦C for 50 min (TLC). After
completion of the reaction, the reaction mixture was filtered
and the precipitate washed with water and ethanol to afford
The structure of the obtained compounds was as-
certained by spectroscopic data and elemental analy-
sis. Taking 5b as the example, sharp absorption bands the pure product 5a.
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Yellow crystals; m. p. > 300 ◦C. – IR (KBr): ν =
Essam M. Hussein · Synthesis of Pyrido[2,3-d]pyrimidines
◦
Pale-yellow crystals; m. p. > 300 C. – IR (KBr): ν =
3410 (NH), 3300, 3200 (NH2), 2200 (CN), 1680 (C=O), 3410 (NH), 3350, 3200 (NH2), 3100 (OH), 2210 (CN), 1690
1630 cm−1 (C=N). – 1H NMR: δ = 3.91 (s, 3H, CH3), 6.43 (C=O), 1640 cm−1 (C=N). – 1H NMR: δ = 6.37 (s, 2H,
(s, 2H, NH2), 7.20 (d, 2H, H-Ar), 8.00 (d, 2H, H-Ar), 11.52 NH2), 6.91 (d, 2H, H-Ar), 7.90 (d, 2H, H-Ar), 8.21 (s, 1H,
(s, 1H, NH), 11.59 (s, 1H, NH). – MS ((+)-FAB): m/z (%) = OH), 11.67 (s, 1H, NH), 11.91 (s, 1H, NH). – MS ((+)-FAB):
325.40 (9) [M]+. – C15H11N5O2S (325.35): calcd. C 55.38, m/z (%) = 311.57 (8) [M]+. – C14H11N5O2S (311.32):
H 3.41, N 21.53, S 9.86; found C 55.16, H 3.25, N 21.38, calcd. C 54.01, H 2.91, N 22.50, S 10.3; found C 53.88,
S 9.61.
H 2.75, N 22.31, S 10.18.
7-Amino-1,2,3,4-tetrahydro-5-(4-nitrophenyl)-4-oxo-2-
7-Amino-1,2,3,4-tetrahydro-5-phenyl-4-oxo-2-thioxopyrido-
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5b)
[2,3-d]pyrimidine-6-carbonitrile (5f)
From 1a, 2b and 3.
From 1a, 2f and 3.
◦
Pale-yellow crystals; m. p. > 300 C. – IR (KBr): ν =
Yellow crystals; m. p. > 300 ◦C. – IR (KBr): ν =
3410 (NH), 3310, 3220 (NH2), 2210 (CN), 1680 (C=O), 3400 (NH), 3300, 3200 (NH2), 2200 (CN), 1680 (C=O),
1635 cm−1 (C=N). – 1H NMR: δ = 6.36 (s, 2H, NH2), 8.15 1630 cm−1 (C=N). – 1H NMR: δ = 6.30 (s, 2H, NH2),
(d, 2H, H-Ar), 8.40 (d, 2H, H-Ar), 12.49 (s, 1H, NH), 13.10 7.55 (m, 3H, H-Ar), 7.85 (m, 2H, H-Ar), 11.75 (s, 1H, NH),
(s, 1H, NH). – 13C NMR: δ = 90.2, 108.2, 114.2, 115.1, 11.85 (s, 1H, NH). – 13C NMR: δ = 59.7, 84.3, 117.1, 125.2,
116.6, 122.8, 129.1, 133.3, 152.2, 154.4, 160.5, 161.7, 163.9, 126.4, 127.1, 128.3, 128.9, 144.3, 151.3, 152.1, 164.8, 165.3,
174.6. – MS ((+)-FAB): m/z (%) = 342.00 (16) [M]+. – 178.8. – MS ((+)-FAB): m/z (%) = 295.05 (16) [M]+. –
C14H8N6O3S (340.33): calcd. C 49.41, H 2.37, N 24.69, C14H9N5OS (295.33): calcd. C 56.94, H 3.07, N 23.71,
S 9.42; found C 49.30, H 2.15, N 24.51, S 9.25.
S 10.86; found C 56.88, H 3.00, N 23.51, S 10.69.
7-Amino-1,2,3,4-tetrahydro-5-(4-chlorophenyl)-4-oxo-2-
7-Amino-1,2,3,4-tetrahydro-5-(3-pyridyl)-4-oxo-2-
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5c)
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5g)
From 1a, 2c and 3.
From 1a, 2g and 3.
Yellow-crystals; m. p. > 300 ◦C. – IR (KBr): ν =
3400 (NH), 3310, 3220 (NH2), 2210 (CN), 1685 (C=O),
◦
Pale-yellow crystals; m. p. > 300 C. – IR (KBr): ν =
3410 (NH), 3300, 3195 (NH2), 2210 (CN), 1685 (C=O),
1640 cm−1 (C=N). – 1H NMR: δ = 6.45 (s, 2H, NH2), 7.73 1635 cm−1 (C=N). – 1H NMR: δ = 6.40 (s, 2H, NH2), 7.50 –
(d, 2H, H-Ar), 8.00 (d, 2H, H-Ar), 11.54 (s, 1H, NH), 11.62 7.80 (m, 4H, H-Ar), 11.82 (s, 1H, NH), 11.86 (s, 1H, NH). –
13C NMR: δ = 91.3, 105,2, 117.3, 130.4, 131.1, 134.5, 141.1,
(s, 1H, NH). – 13C NMR: δ = 88.8, 114.1, 115.1, 116.7,
123.1, 129.6, 133.8, 144.5, 152.2, 154.8, 161.1, 161.9, 164.3, 144.3, 152.1, 156.2, 161.1, 164.8, 173.8. – MS ((+)-FAB):
174.7. – MS ((+)-FAB): m/z (%) = 329.88 (19) [M]+. – m/z (%) = 296.02 (20) [M]+. – C13H8N6OS (296.31): calcd.
C 52.70, H 2.72, N 28.36, S 10.82; found C 52.60, H 2.55,
C14H8ClN5OS (329.76): calcd. C 50.99, H 2.45, N 21.24,
S 9.72, Cl 10.75; found C 50.84, H 2.33, N 21.09, S 9.62, N 28.15, S 10.69.
Cl 10.60.
7-Amino-1,2,3,4-tetrahydro-5-(2-furyl)-4-oxo-2-
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5h)
7-Amino-1,2,3,4-tetrahydro-5-(4-bromophenyl)-4-oxo-2-
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5d)
From 1a, 2h and 3.
Pale-brown crystals; m. p. > 300 C. – IR (KBr): ν =
◦
From 1a, 2d and 3.
Pale-yellow crystals; m. p. > 300 C. – IR (KBr): ν =
◦
3400 (NH), 3300, 3200 (NH2), 2220 (CN), 1685 (C=O),
1630 cm−1 (C=N). – 1H NMR: δ = 6.42 (s, 2H, NH2), 6.90 –
7.85 (m, 3H, H-Ar), 11.82 (s, 1H, NH), 11.90 (s, 1H, NH). –
MS ((+)-FAB): m/z (%) = 285.05 (11) [M]+. – C12H7N5O2S
(285.28): calcd. C 50.52, H 2.47, N 24.55, S 11.24; found
C 50.33, H 2.35, N 24.40, S 11.12.
3410 (NH), 3300, 3200 (NH2), 2205 (CN), 1680 (C=O),
1630 cm−1 (C=N). – 1H NMR: δ = 6.31 (s, 2H, NH2),
7.49 (d, 2H, H-Ar), 7.78 (d, 2H, H-Ar), 11.60 (s, 1H, NH),
11.70 (s, 1H, NH). – MS ((+)-FAB): m/z (%) = 376.22
(10) [M+2]+, 374.91 (11) [M]+. – C14H8BrN5OS (374.22):
calcd. C 44.93, H 2.15, N 18.71, S 8.57, Br 21.35; found
C 44.75, H 2.11, N 18.57, S 8.46, Br 21.20.
Ethyl 7-amino-1,2,3,4-tetrahydro-4-oxo-5-(4-methoxyphen-
yl)-2-thioxopyrido[2,3-d] pyrimidine-6-carboxylate (5i)
7-Amino-1,2,3,4-tetrahydro-5-(4-hydroxyphenyl)-4-oxo-2-
thioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5e)
From 1a, 2a and 4.
Pale-yellow crystals; m. p. 201 – 202 ◦C. – IR (KBr):
From 1a, 2e and 3.
ν = 3422, 3315 (NH2), 3200 (NH), 1720 (C=O),
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235
1
1640 cm−1(C=N). – H NMR: δ = 1.35 (t, 3H, CH3), 3.90 1640 cm−1 (C=N). – 1H NMR: δ = 3.95 (s, 3H, CH3), 6.24
(s, 3H, CH3), 4.33 (q, 2H, CH2), 6.44 (s, 2H, NH2), 7.00 (s, 2H, NH2), 7.18 (d, 2H, H-Ar), 8.00 (d, 2H, H-Ar), 10.10
(d, 2H, H-Ar), 8.00 (d, 2H, H-Ar), 11.91 (s, 1H, NH), 12.15 (s, 1H, NH), 10.20 (s, 1H, NH). – 13C NMR: δ = 54.6, 115.1,
(s, 1H, NH). – 13C NMR: δ = 14.6, 50.3, 62.8, 91.9, 107.2, 115.6, 116.2, 124.2, 132.4, 133.5, 134.5, 134.6, 149.1, 153.6,
115.5, 123.7, 124.8, 127.2, 132.1, 137.1, 149.6, 152.5, 154.2, 159.0, 160.5, 164.4, 165.1. – MS ((+)-FAB): m/z (%) =
161.6, 170.4, 174.5. – MS ((+)-FAB): m/z (%) = 372.21 (10) 309.96 (7) [M]+. – C15H11N5O3 (309.28): calcd. C 58.25,
[M]+. – C17H16N4O4S (372.40): calcd. C 54.83, H 4.33, H 3.58, N 22.64; found C 58.10, H 3.42, N 22.45.
N 15.04, S 8.61; found C 54.65, H 4.21, N 14.89, S 8.48.
7-Amino-1,2,3,4-tetrahydro-5-(4-nitrophenyl)-2,4-
Ethyl 7-amino-1,2,3,4-tetrahydro-4-oxo-5-(4-nitrophenyl)- dioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5n)
2-thioxopyrido[2,3-d]pyrimidine-6-carboxylate (5j)
From 1b, 2b and 3.
Yellow crystals; m. p. > 300 ◦C. – IR (KBr): ν =
From 1a, 2b and 4.
◦
Bright-yellow crystals; m. p. 226 – 228 C. – IR (KBr): 3410 (NH), 3300, 3200 (NH2), 2205 (CN), 1705 (C=O),
ν = 3330, 3290 (NH2), 3100 (NH), 1715 (C=O), 1640 cm−1 1640 cm−1 (C=N). – 1H NMR: δ = 6.90 (s, 2H, NH2), 7.87
(C=N). – 1H NMR: δ = 1.40 (t, 3H, CH3), 4.45 (q, 2H, CH2), (d, 2H, H-Ar), 8.32 (d, 2H, H-Ar), 10.60 (s, 1H, NH), 10.75
6.45 (s, 2H, NH2), 7.70 (d, 2H, H-Ar), 8.40 (d, 2H, H-Ar), (s, 1H, NH). – MS ((+)-FAB): m/z (%) = 324.00 (10) [M]+. –
11.69 (s, 1H, NH), 12.04 (s, 1H, NH). – MS ((+)-FAB): m/z C14H10N6O4 (324.25): calcd. C 51.86, H 2.49, N 25.92;
(%) = 387.10 (13) [M]+. – C16H13N5O5S (387.37): calcd. found C 51.76, H 2.29, N 25.75.
C 49.61, H 3.38, N 18.08, S 8.28; found C 49.50, H 3.10,
N 17.91, S 8.20.
7-Amino-1,2,3,4-tetrahydro-5-(4-chlorophenyl)-2,4-
dioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5o)
Ethyl 7-amino-1,2,3,4-tetrahydro-4-oxo-5-(4-chlorophenyl)-
2-thioxopyrido[2,3-d] pyrimidine-6-carboxylate (5k)
From 1b, 2c and 3.
Pale-yellow crystals; m. p. > 300 C. – IR (KBr): ν =
◦
From 1a, 2c and 4.
3400, 3310 (NH2), 3200 (NH), 2205 (CN), 1705 (C=O),
Pale-yellow crystals; m. p. 211 – 212 ◦C. – IR (KBr): ν = 1640 cm−1 (C=N). – 1H NMR: δ = 6.15 (s, 2H, NH2), 7.50
3350, 3250 (NH2), 3100 (NH), 1715 (C=O), 1635 cm−1 (d, 2H, H-Ar), 7.86 (d, 2H, H-Ar), 10.44 (s, 1H, NH), 10.70
(C=N). – 1H NMR: δ = 1.32 (t, 3H, CH3), 4.31 (q, 2H, CH2), (s, 1H, NH). – 13C NMR: δ = 80.5, 114.1, 115.1, 116.7,
6.40 (s, 2H, NH2), 7.60 (d, 2H, H-Ar), 8.01 (d, 2H, H-Ar), 123.3, 129.9, 133.7, 136.2, 154.8, 157.1, 161.1, 161.9, 163.9,
12.45 (s, 1H, NH), 12.61 (s, 1H, NH). – 13C NMR: δ = 13.7, 165.1. – MS ((+)-FAB): m/z (%) = 313.25 (12) [M]+. –
65.7, 93.1, 106.6, 114.7, 123.2, 124.1, 126.3, 130.6, 137.2, C14H8ClN5O2 (313.70): calcd. C 53.60, H 2.57, N 22.33,
149.7, 150.1, 152.0, 161.6, 170.4, 174.6. – FAB MS: m/z Cl 11.30; found C 53.42, H 2.49, N 22.20, Cl 11.20.
(%) = 376.58 (19) [M]+. – C16H13ClN4O3S (376.82): calcd.
C 51.00, H 3.48, N 14.87, S 8.51, Cl 9.41; found C 50.89,
7-Amino-1,2,3,4-tetrahydro-5-(3-pyridyl)-2,4-dioxopyrido-
H 3.30, N 14.70, S 8.40, Cl 9.22.
[2,3-d]pyrimidine-6-carbonitrile (5p)
From 1b, 2g and 3.
Ethyl 7-amino-1,2,3,4-tetrahydro-4-oxo-5-(3-pyridyl)-2-thi-
oxopyrido[2,3-d]pyrimidine-6-carboxylate (5l)
Yellow crystals; m. p. > 300 ◦C. – IR (KBr): ν =
3400, 3300 (NH2), 3200 (NH2), 2205 (CN), 1700 (C=O),
1630 cm−1 (C=N). – 1H NMR: δ = 6.20 (s, 2H, NH2), 7.20–
From 1a, 2g and 4.
Yellow crystals; m. p. 215 – 216 ◦C. – IR (KBr): ν = 3400, 8.00 (m, 4H, H-Ar), 10.45 (s, 1H, NH), 10.52 (s, 1H, NH). –
3300 (NH2), 3150 (NH), 1720 (C=O), 1640 cm−1 (C=N). – MS ((+)-FAB): m/z (%) = 280.00 (10) [M]+. – C13H8N6O2
1H NMR: δ = 1.20 (t, 3H, CH3), 4.51 (q, 2H, CH2), 6.30 (s, (280.24): calcd. C 55.72, H 2.88, N 29.99; found C 55.53,
2H, NH2), 7.30–7.85 (m, 4H, H-Ar), 9.82 (s, 1H, NH), 9.95 H 2.80, N 29.70.
(s, 1H, NH). – MS ((+)-FAB): m/z (%) = 343.05 (16) [M]+. –
C15H15N5O3S (343.36): calcd. C 52.47, H 3.82, N 20.40,
S 9.34; found C 52.30, H 3.75, N 20.25, S 9.22.
7-Amino-1,2,3,4-tetrahydro-5-(2-furyl)-2,4-dioxopyrido-
[2,3-d]pyrimidine-6-carbonitrile (5q)
From 1b, 2h and 3.
7-Amino-1,2,3,4-tetrahydro-5-(4-methoxyphenyl)-2,4-
dioxopyrido[2,3-d]pyrimidine-6-carbonitrile (5m)
Yellow crystals; m. p. > 300 ◦C. – IR (KBr): ν =
3350 (NH), 3200, 3150 (NH2), 2210 (CN), 1705 (C=O),
1640 cm−1 (C=N). – 1H NMR: δ = 6.30 (s, 2H, NH2), 6.66 –
From 1b, 2a and 3.
◦
Pale-yellow crystals; m. p. > 300 C. – IR (KBr): ν = 7.50 (m, 3H, H-Ar), 10.24 (s, 1H, NH), 10.60 (s, 1H, NH). –
3410, 3400 (NH2), 3190 (NH), 2205 (CN), 1700 (C=O), MS ((+)-FAB): m/z (%) = 269.05 (11) [M]+. – C12H7N5O3
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Essam M. Hussein · Synthesis of Pyrido[2,3-d]pyrimidines
(269.22): calcd. C 53.54, H 2.62, N 26.01; found C 53.40, Ethyl 7-amino-1,2,3,4-tetrahydro-5-(4-chlorophenyl)-2,4-di-
H 2.50, N 25.90.
oxopyrido[2,3-d]pyrimidine-6-carboxylate (5t)
From 1b, 2c and 4.
Pale-yellow crystals; m. p. 205 – 207 ◦C. – IR (KBr): ν =
3350, 3200 (NH2), 3100 (NH), 1715 (C=O), 1630 cm−1
(C=N). – 1H NMR: δ = 1.30 (t, 3H, CH3), 4.30 (q, 2H, CH2),
6.65 (s, 2H, NH2), 7.12 (d, 2H, H-Ar), 8.00 (d, 2H, H-Ar),
10.35 (s, 1H, NH), 10.60 (s, 1H, NH). – 13C NMR: δ = 14.1,
65.5, 93.2, 106.5, 114.9, 122.6, 124.1, 126.3, 130.6, 137.2,
149.7, 152.0, 156.4, 161.3, 163.4, 165.2. – MS ((+)-FAB):
m/z (%) = 360.95 (6) [M]+. – C16H13ClN4O4 (360.75):
calcd. C 53.27, H 3.63, N 15.53, Cl 9.83; found C 53.19,
H 3.45, N 15.40, Cl 9.70.
Ethyl 7-amino-1,2,3,4-tetrahydro-5-(4-methoxyphenyl)-2,4-
dioxopyrido[2,3-d]pyrimidine-6-carboxylate (5r)
From 1b, 2a and 4.
Pale-yellow crystals; m. p. 196 – 198 ◦C. – IR (KBr): ν =
3400, 3300 (NH2), 3200 (NH), 1715 (C=O), 1640 cm−1
(C=N). – 1H NMR: δ = 1.34 (t, 3H, CH3), 3.85 (s, 3H, CH3),
4.30 (q, 2H, CH2), 6.77 (s, 2H, NH2), 7.00 (d, 2H, H-Ar),
8.10 (d, 2H, H-Ar), 10.70 (s, 1H, NH), 10.85 (s, 1H, NH). –
13C NMR: δ = 14.2, 50.4, 63.1, 92.2, 107.6, 115.6, 123.8,
124.5, 127.2, 132.1, 137.3, 149.7, 152.5, 155.2, 161.6, 163.3,
164.8. – MS ((+)-FAB): m/z (%) = 356.00 (10) [M]+. –
C17H16N4O5 (356.33): calcd. C 57.30, H 4.53, N 15.72;
found C 57.15, H 4.45, N 15.60.
Ethyl 7-amino-1,2,3,4-tetrahydro-5-(3-pyridyl)-2,4-dioxo-
pyrido[2,3-d]pyrimidine-6-carboxylate (5u)
From 1b, 2g and 4.
Yellow crystals; m. p. 210 – 211 ◦C. – IR (KBr): ν =
3400, 3300 (NH2), 3150 (NH), 1715 (C=O), 1640 (C=N). –
1H NMR: δ = 1.25 (t, 3H, CH3), 4.59 (q, 2H, CH2), 7.49
(s, 2H, NH2), 7.50–8.00 (m, 4H, H-Ar), 11.10 (s, 1H, NH),
11.21 (s, 1H, NH). – MS ((+)-FAB): m/z (%) = 327.00
(7) [M]+. – C15H13N5O4 (327.29): calcd. C 55.05, H 4.00,
N 21.40; found C 54.85, H 3.81, N 21.29.
Ethyl 7-amino-1,2,3,4-tetrahydro-5-(4-nitrophenyl)-2,4-di-
oxopyrido[2,3-d]pyrimidine-6-carboxylate (5s)
From 1b, 2b and 4.
Yellow crystals; m. p. 220 – 221 ◦C. – IR (KBr): ν =
3350, 3250 (NH2), 3100 (NH), 1715 (C=O), 1640 (C=N). –
1H NMR: δ = 1.32 (t, 3H, CH3), 4.35 (q, 2H, CH2), 6.76
(s, 2H, NH2), 7.39 (d, 2H, H-Ar), 8.30 (d, 2H, H-Ar), 10.71
(s, 1H, NH), 10.90 (s, 1H, NH). – MS ((+)-FAB): m/z (%) =
371.00 (12) [M]+. – C16H13N5O6 (371.30): calcd. C 51.76,
H 3.53, N 18.86; Found C 51.65, H 3.39, N 18.75.
Acknowledgement
The author is thankful to Assiut University and Faculty of
Science (Assiut, Egypt) for providing financial assistance to
carry out this work.
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