A simple protocol for the green synthesis of a new series of pyrimido[4,5b][1,6]naphthyridines in the presence of silver nanoparticles (AgNPs)

Article abstract of DOI:10.24820/ark.5550190.p010.705

Eight polyfunctionalized pyrimidonaphthyridine derivatives has been synthesized, in 79-92% yields, via the one-pot, three-component reaction of aryl glyoxal monohydrates, 6-aminouracil and 4-hydroxyquinolin-2(1H)-one in H₂O/EtOH in the presence of AgNPs under mild conditions. In this work colloidal AgNPs acts as an efficient, economical, green nanocatalyst, leading to a simple method of preparation.

Full text of DOI:10.24820/ark.5550190.p010.705

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Arkivoc 2018, part vii, 0-0
A simple protocol for the green synthesis of a new series of pyrimido[4,5-
b][1,6]naphthyridines in the presence of silver nanoparticles (AgNPs)
a
a
b
a
Ahmad Poursattar Marjani, * Jabbar Khalafy, Fatemeh Majidi Arlan, and Elham Eyni
aDepartment of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia, Iran
Research Department of Analytical Chemistry, Iranian Academic Center for Education, Culture and Research,
P. O. Box 57155-397, Urmia, Iran
b
Email: a.poursattar@gmail.com; a.poursattar@urmia.ac.ir
Received 07-30-2018
Accepted 10-15-2018
Published on line 12-07-2018
Abstract
Eight polyfunctionalized pyrimidonaphthyridine derivatives has been synthesized, in 79-92% yields, via the
one-pot, three-component reaction of aryl glyoxal monohydrates, 6-aminouracil and 4-hydroxyquinolin-2(1H)-
one in H O/EtOH in the presence of AgNPs under mild conditions. In this work colloidal AgNPs acts as an
2
efficient, economical, green nanocatalyst, leading to a simple method of preparation.
Keywords: Aryl glyoxal hydrates, 6-aminouracil, AgNPs, 4-hydroxyquinolin-2(1H)-one, pyrimidonaphthyridines
DOI: https://doi.org/10.24820/ark.5550190.p010.705
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Introduction
Nitrogen-containing fused heterocycles have stimulated the interest of chemists because of their wide range
1
2
3,4
5,6
of biological, medicinal and therapeutic properties, such as anti-cancer, anti-HIV anti-microbial, anti-
7
8
tumor and anti-bacterial. As such, their synthesis via the combination various hetero scaffolds is of interest
in medicinal chemistry and developing more fused nitrogen-containing ring systems is worthwhile.
Both pyrimidine and 1,6-naphthyridine scaffolds are important structural motifs in chemistry, so preparing
pyrimidonaphthyridine derivatives, in which these scaffolds are merged, could, tentatively, provide
compounds that exhibit simultaneously the biological properties of each moiety.9,10
11
The green synthesis of silver nanoparticles (AgNPs) using Ferula latisecta leaf extracts has been reported.
Ghahremanzadeh et al. reported a one-pot, three component synthesis of spiro- furo- pyrido- pyridimidine-
indolines using highly active magnetically reusable nano catalysts in water.12
As part of our on-going work on the synthesis of fused heterocycles by one-pot multicomponent
reactions,13-21 we report herein, a one-pot, three component approach for accessing fused pyrimido-
naphthyridines by reaction of aryl glyoxals, 6-aminouracil and 4-hydroxyquinolin-2(1H)-one in the presence of
AgNPs under mild conditions in high yields.
Results and Discussion
The reaction of 4-methylphenyl glyoxal monohydrate (1e), 6-aminouracil (2) and 4-hydroxyquinolin-2(1H)-one
(3) was chosen as a trial reaction (Table 1). The reaction mixture was stirred using various catalysts and two
disparate green solvent systems. A solid precipitate separated out in 50-92% yields, which was characterized
by its spectral data to be the desired substituted pyrimido[4,5-b][1,6]naphthyridine (4e).
The highest yield (91%) was achieved when the reaction was performed using 10 ppm of AgNPs as a
nanocatalyst in H O/EtOH (1:1) after 3 h of reaction time (Table 1, entry 6). To investigate the effect of catalyst
2
amount, the reaction was repeated in the presence of various amounts of AgNPs. Increasing the amount of
catalyst did not affect the reaction yield significantly.
To find the most appropriate solvent for this reaction, the reaction was then repeated using various green
solvent systems such as H
2
O, EtOH, EtOH/H
2
O (1:1), EtOH/H
2
O (1:2), and AcOH (Table 1); EtOH/H O (1:1) was
2
the best choice of solvent for this reaction. Acidic catalysts such as p-TSA and L-proline provided lower yields
(
Table 1). The aryl glyoxal monohydrates 1a-h were obtained by oxidation of similar acetophenones 5a-h with
22
SeO by literature methods (Scheme 1).
2
R = H, 4-Cl, 4-Br, 4-F, 4-Me, 4-MeO, 3-MeO-4-OH, 3,4-(MeO)
2
Scheme 1. The preparation of aryl glyoxal monohydrates 1a-h.
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Table 1. Optimization of the reaction conditions
Entry
Solvent
Temp.
Catalyst
(mol %)
Time
(h)
7
7
6
6
3
3
3
Yield 4e
(%)
52
o
(
C)
1
2
3
4
5
6
7
8
9
2
EtOH/H O (1:1)
Reflux
Reflux
Reflux
Reflux
60
60
60
60
60
L-proline (20 mol%)
L-proline (20 mol%)
p-TSA (20 mol%)
p-TSA (20 mol%)
AgNPs (5 ppm)
AgNPs (10 ppm)
AgNPs (20 ppm)
AgNPs (10 ppm)
AgNPs (10 ppm)
L-proline (20 mol%)
L-proline (20 mol%)
EtOH
EtOH
58
57
50
74
91
92
91
-
EtOH/H
2
O (1:1)
O (1:1)
EtOH/H
2
EtOH/H
2
O (1:1)
O (1:1)
O (2:1)
EtOH/H
EtOH/H
2
2
2
H
2
O
24
10
10
1
1
0
1
AcOH
AcOH
70
Reflux
79
70
The AgNPs was prepared via minor modifications of the literature method.23,24 The SEM image and EDX
spectrum of the nanocatalyst used are shown in Figures 1 and 2, respectively.
Figure 1. SEM images of AgNPs.
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Figure 2. EDX spectrum of AgNPs.
The one-pot, three-component reaction of aryl glyoxal monohydrates 1a-h, 6-aminouracil (2) and 4-
hydroxyquinolin-2(1H)-one (3) in the presence of AgNPs (10 ppm) in H O/EtOH (1:1) afforded the desired
pyrimido[4,5-b][1,6]naphthyridines 4a-h in high yields (Table 2). The substituted pyrimido[4,5-
2
1
13
b][1,6]naphthyridines 4a-h were characterized using FT-IR, H and C NMR spectral data and microanalysis.
1
In the H NMR spectra of products 4a-h, the characteristic broad singlets at around δ
H
10.33-11.78,
ascribed to the NH groups, was present in all new products. In the 13C NMR spectra, signals located around δ
59.8-173.3 were attributed to the three different carbonyl groups. In the FT-IR (KBr) spectra, the
characteristic absorptions bands at 3302-3438 and 1649-1718 cm could be assigned to the vibrations of NH
and different carbonyl groups, respectively.
C
1
-1
Table 2. The synthesis of pyrimido[4,5-b][1,6]naphthyridines 4a-h.
Yields
Entry
Ar
Time (min)
(
%)
1
2
3
4
5
6
7
8
Ph
300
240
270
240
180
150
180
210
4a (79)
4b (88)
4c (82)
4d (87)
4e (91)
4f (92)
4g (89)
4h (90)
4-BrC
4-ClC
4-FC
4-Tol
4-MeOC
6 4
H
6
H
4
6 4
H
6
H
4
3-MeO-4-HOC
3,4-(MeO)
6 3
H
2
C
H
6 3
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The proposed mechanism of this reaction involves the initial condensation of aryl glyoxals with 4-
hydroxyquinolin-2(1H)-one to give an intermediate that reacts with 6-aminouracil to form the expected
products through intramolecular condensation and further oxidation (Scheme 2).
Scheme 2. The proposed mechanism for synthesis of compounds 4a-h in the presence of nanocatalyst.
Conclusions
We have developed a one-pot, three-component synthesis of pyrimido[4,5-b][1,6]naphthyridine derivatives in
the presence of AgNPs as a nanocatalyst. This protocol has the advantages of using a green solvent system, a
low nanocatalyst loading (10 ppm), high yields and a simple work up procedure.
Experimental Section
1
General. Melting points were measured on a Philip Harris C4954718 apparatus and are uncorrected. H and
13
C NMR spectra were recorded on a Bruker Avance AQS 300 MHz spectrometer at 300 and 75.5 MHz,
respectively. Chemical shifts were measured in DMSO-d
6
using TMS as the internal standard. Fourier
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Transform Infrared (FTIR) spectra were recorded on a Thermo-Nicolet Nexus 670-FT-IR instrument. Elemental
analyses were performed using a Leco Analyzer 932. The scanning electron microscopy (SEM) image of
nanoparticles was obtained from Philips XL30. The EDX analysis of nanoparticles was obtained using the BAL-
TEC SCDOOS apparatus.
Preparation of AgNPs as nanocatalyst. A solution of glucose (1% w/v) (1 mL) and a solution of sodium citrate
-
3
-3
(
1×10 M) (2 mL) were added to a solution of silver nitrate (1×10 M) (1 mL). The resulting solution was
o
23,24
heated at 60 C for an hour when the color of the mixture changed from pale yellow to orange.
work the colloidal form of AgNPs we used, but freeze-dried nanoparticals were also satisfactory.25
In this
General procedure for synthesis of new pyrimido[4,5-b][1,6]naphthyridines 4a-h. The aryl glyoxal
monohydrate (1 mmol) was dissolved in H O/EtOH (1:1) (6 mL), then 6-aminouracil (1 mmol), 4-
2
hydroxyquinolin-2(1H)-one (1 mmol) and AgNPs (10 ppm) were added to the reaction mixture. The reaction
mixture was heated at 60 °C for different periods of time according to Table 2. Thin layer chromatography
(TLC), was used to determine the reaction completion using (EtOAc/hexane, 2:3) as eluent. The obtained
precipitate was filtered and then rinsed with distilled water. The products, recrystallized from EtOH, were
obtained as pale yellow to brown powders, in yields of 79-92%.
7
-Benzoylbenzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4a). Yield 79% (303 mg),
o
-1
light brown powder, mp 347 C (dec). IR (KBr, νmax, cm ): 3357, 3190, 3001, 2872, 1718, 1643, 1608, 1510,
1
1
1
7
462, 1428, 1279, 1215, 1146, 819, 765. H NMR (300 MHz, DMSO-d
6
): δ
O exchanged, NH), 7.78 (1H, d, J 8.1 Hz, Ar), 7.47 (1H, dd, J
H
11.69 (1H, s, D O exchanged, NH),
2
1.26 (1H, s, D
.5, 7.5 Hz, Ar), 7.39 (2H, d, J 7.5 Hz, Ar), 7.30-7.21 (3H, m, Ar), 7.13 (2H, dd, J 7.5, 7.5 Hz, Ar). C NMR (75.5
): δ 163.3, 159.9, 159.8, 158.9, 151.5, 143.2, 140.5, 138.8, 138.7, 132.6, 132.5, 130.0, 129.6,
29.5, 128.5, 127.7, 127.5, 125.7, 125.4, 122.3. Anal. calcd for C21 : C, 65.62; H, 3.15; N, 14.58. Found:
requires: M = 384.0859.
-(4-Bromobenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4b). Yield 88%
2
O exchanged, NH), 10.38 (1H, s, D
2
13
MHz, DMSO-d
1
6
C
H
H
12
N
4 4
O
4 4
O
+
C, 65.44; H, 3.02; N, 14.69%. HRMS: Found: m/z 384.0871 [M] . C21
7
12
N
o
-1
(406 mg), pale yellow powder, mp 337 C (dec). IR (KBr, νmax, cm ): 3434, 3166, 3029, 2879, 1692, 1612, 1493,
1
1
447, 1256, 1129, 1007. H NMR (300 MHz, DMSO-d
6
): δ
O exchanged, NH), 7.78 (1H, d, J 7.8 Hz, Ar), 7.53-7.40 (3H, m, Ar), 7.37 (1H, d,
J 8.4 Hz, Ar), 7.29 (2H, d, J 8.1 Hz, Ar), 7.14 (1H, dd, J 7.8, 7.8 Hz, Ar). 13C NMR (75.5 MHz, DMSO-d
): δ 163.5,
63.2, 160.0, 159.0, 152.8, 151.6, 150.9, 140.7, 140.5, 138.8, 132.6, 131.9, 131.8, 130.7, 130.4, 129.4, 127.4,
H
11.78 (1H, s, D
2
O exchanged, NH), 11.28 (1H, s, D O
2
exchanged, NH), 10.37 (1H, s, D
2
6
C
1
1
27.3, 119.9. Anal. calcd for C21
H
11BrN
4
O
4
: C, 54.45; H, 2.39; N, 12.09. Found: C, 54.27; H, 2.22; N, 12.26%.
+
+
HRMS: Found: m/z 463.9956 [M+2] , 461.9951 [M] . C21
H11BrN
4
O requires: M = 463.9943, 461.9964.
4
7
-(4-Chlorobenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4c). Yield 82%
o
-1
(343 mg), light brown powder, mp 340 C (dec). IR (KBr, νmax, cm ): 3438, 3181, 3087, 2892, 1709, 1609, 1501,
1
1440, 1249, 1137, 1097, 1011. H NMR (300 MHz, DMSO-d
): δ
6 H
11.73 (1H, s, D
2
O exchanged, NH), 11.28 (1H,
s, D
Ar), 7.42 (2H, dd, J 8.1, 8.1 Hz, Ar), 7.26 (1H, d, J 8.7 Hz, Ar), 7.20-7.01 (3H, m, Ar). C NMR (75.5 MHz, DMSO-
2
O exchanged, NH), 10.40 (1H, s, D
2
O exchanged, NH), 7.78 (1H, d, J 8.1 Hz, Ar), 7.50 (1H, dd, J 8.1, 8.1 Hz,
13
d
1
1
7
6
): δ 166.2, 163.3, 159.9, 159.0, 151.6, 140.4, 138.7, 129.2, 129.1, 127.8, 127.7, 124.6, 122.3, 116.6, 116.3,
C
16.2, 116.1, 115.6, 114.8. Anal. calcd for C21
3.24%. HRMS: Found: m/z 420.0447 [M+2] , 418.0472 [M] . C21
H
11ClN
4
O
4
: C, 60.23; H, 2.65; N, 13.38. Found: C, 60.09; H, 2.78; N,
+
+
H
11ClN
4
O requires: M = 420.0439, 418.0469.
4
-(4-Fluorobenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4d). Yield 87%
o
-1
(350 mg), brown powder, mp 339 C (dec). IR (KBr, νmax, cm ): 3302, 3150, 3037, 2890, 1680, 1509, 1439,
1
1239, 1152, 1019. H NMR (300 MHz, DMSO-d
6
): δ
H
11.66 (1H, s, D
2
O exchanged, NH), 11.29 (1H, s, D O
2
2
exchanged, NH), 10.42 (1H, s, D O exchanged, NH), 7.78 (1H, d, J 8.7 Hz, Ar), 7.53-7.30 (6H, m, Ar), 7.15 (1H,
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Poursattar Marjani, A. et al.
dd, J 7.8, 7.8 Hz, Ar). 13C NMR (75.5 MHz, DMSO-d
): δ
163.6, 163.2, 159.9, 159.8, 152.8, 151.6, 150.9, 140.6,
6
C
1
40.5, 138.8, 131.6, 131.1, 129.7, 129.3, 129.1, 127.9, 127.5, 127.4, 124.7. Anal. calcd for C21
H
11FN
4
O : C,
4
+
62.69; H, 2.76; N, 13.93. Found: C, 62.40; H, 2.65; N, 14.19%. HRMS: Found: m/z 402.0770 [M] . C21
H11FN
O
4 4
requires: M = 402.0764.
-(4-Methylbenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4e). Yield 91%
7
o
-1
(362 mg), pale orange powder, mp 333 C (dec). IR (KBr, νmax, cm ): 3420, 3175, 3034, 1709, 1672, 1636, 1503,
1
1
s, D
436, 1399, 1241, 1140, 1018. H NMR (300 MHz, DMSO-d
6
): δ
O exchanged, NH), 7.78 (1H, d, J 7.5 Hz, Ar), 7.47 (1H, dd, J 7.5, 7.5 Hz,
Ar), 7.35 (2H, d, J 7.8 Hz, Ar), 7.12-7.33 (1H, m, Ar), 7.11 (1H, dd, J 7.2, 7.2 Hz, Ar), 7.05 (2H, d, J 7.5 Hz, Ar),
H
11.61 (1H, s, D
2
O exchanged, NH), 11.24 (1H,
2
O exchanged, NH), 10.36 (1H, s, D
2
13
2
1
6
.26 (3H, s, CH
3
). C NMR (75.5 MHz, DMSO-d
6
): δ 173.3, 163.6, 160.0, 158.8, 152.7, 151.6, 150.9, 140.3,
C
40.2, 138.8, 136.1, 135.9, 130.0, 129.8, 128.7, 127.5, 127.4, 125.6, 125.5, 18.6. Anal. calcd for C22
6.33; H, 3.54; N, 14.06. Found: C, 66.19; H, 3.40; N, 14.28%. HRMS: Found: m/z 398.1003 [M] . C22
H
14
N
H
4
O : C,
4
+
14
N
O
4 4
requires: M = 398.1015.
-(4-Methoxybenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4f). Yield 92%
7
o
-1
(381 mg), pale yellow powder, mp 335 C (dec). IR (KBr, νmax, cm ): 3410, 3183, 3069, 2857, 1685, 1634, 1517,
1
1448, 1244, 1190, 1131, 1020. H NMR (300 MHz, DMSO-d
6
): δ
H
11.58 (1H, s, D
2
O exchanged, NH), 11.25 (1H,
s, D
Ar), 7.40-7.20 (3H, m, Ar), 7.12 (1H, dd, J 7.8, 7.8 Hz, Ar), 6.83 (2H, d, J 8.1 Hz, Ar), 3.73 (3H, s, OCH
75.5 MHz, DMSO-d ): δ 163.7, 163.4, 160.0, 152.7, 151.6, 151.0, 140.2, 140.0, 139.0, 128.9, 128.5, 127.0,
25.2, 122.3, 122.2, 115.7, 115.6, 107.0, 100.5, 27.5. Anal. calcd for C22 : C, 66.77; H, 3.41; N, 13.52.
requires: M = 414.0964.
-(4-Hydroxy-3-methoxybenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4g).
2
O exchanged, NH), 10.33 (1H, s, D
2
O exchanged, NH), 7.78 (1H, d, J 7.5 Hz, Ar), 7.44 (1H, dd, J 8.4, 8.4 Hz,
13
3
). C NMR
(
6
C
1
H
H
14
N
4 5
O
4 5
O
+
Found: C, 66.52; H, 3.39; N, 13.68%. HRMS: Found: m/z 414.0989 [M] . C22
14
N
7
o
-1
Yield 89% (383 mg), brown powder, mp 297 C (dec). IR (KBr, νmax, cm ): 3348, 3188, 2996, 2877, 1710, 1638,
1
1
511, 1436, 1277, 1217, 1148, 1022, 816, 770. H NMR (300 MHz, DMSO-d
6
): δ
O exchanged, NH), 8.94 (1H, s, D
.83-7.78 (1H, m, Ar), 7.47-7.32 (1H, m, Ar), 7.31-7.25 (1H, m, Ar), 7.13-7.00 (2H, m, Ar), 6.71 (1H, d, J 7.2 Hz,
H
11.47 (1H, s, D
2
O exchanged,
NH), 11.27 (1H, s, D
7
2
O exchanged, NH), 10.33 (1H, s, D
2
2
O exchanged, OH),
1
3
Ar), 6.70 (1H, d, J 7.5 Hz, Ar), 3.52 (3H, s, OCH
3
). C NMR (75.5 MHz, DMSO-d
54.1, 151.6, 150.3, 147.5, 145.8, 140.0, 138.7, 129.7, 128.9, 123.9, 122.2, 122.1, 120.6, 115.6, 114.2, 114.1,
12.1, 16.3. Anal. calcd for C21
6
): δ 166.2, 163.5, 159.9, 158.9,
C
1
1
H
12
N
N
4
O
O
5
: C, 63.00; H, 3.02; N, 13.99. Found: C, 62.85; H, 2.92; N, 14.14%. HRMS:
requires: M = 430.0913.
+
Found: m/z 430.0934 [M] . C21
H
12
4
5
7
9
1
-(3,4-Dimethoxybenzoyl)benzo[h]pyrimido[4,5-b][1,6]naphthyridine-6,8,10(5H,9H,11H)-trione (4h). Yield
0% (400 mg), brown powder, mp 361 C (dec). IR (KBr, νmax, cm ): 3368, 3208, 2933, 2857, 1649, 1512, 1455,
o
-1
1
250, 1219, 1148, 1020. H NMR (300 MHz, DMSO-d
6
): δ
O exchanged, NH), 7.78 (1H, d, J 7.5 Hz, Ar), 7.47 (1H, dd, J 7.8, 7.8 Hz, Ar),
.26 (1H, d, J 7.8 Hz, Ar), 7.13 (1H, dd, J 7.2, 7.2 Hz, Ar), 7.04 (1H, s, Ar), 6.94 (1H, d, J 7.5 Hz, Ar), 6.62 (1H, d, J
H
11.55 (1H, s, D
2
O exchanged, NH), 11.29 (1H, s, D O
2
exchanged, NH), 10.36 (1H, s, D
2
7
8
1
1
13
.7 Hz, Ar), 3.67 (3H, s, CH
3
), 3.53 (3H, s, CH
3
). C NMR (75.5 MHz, DMSO-d
6
): δ 167.9, 163.5, 162.3, 159.8,
C
51.4, 148.6, 148.0, 144.2, 139.7, 138.3, 130.3, 128.5, 125.1, 125.0, 124.5, 124.4, 119.3, 118.5, 116.2, 115.4,
13.4, 25.2, 21.7. Anal. calcd for C23
H
H
16
N
4
O
4 6
O
6
: C, 62.16; H, 3.63; N, 12.61. Found: C, 61.99; H, 3.53; N, 12.80%.
requires: M = 444.1070.
+
HRMS: Found: m/z 444.1061 [M] . C23
16
N
Acknowledgements
The authors gratefully acknowledge financial support from Urmia University.
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