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)

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(1 H )- one in H 2 O/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.


Introduction
Nitrogen-containing fused heterocycles have stimulated the interest of chemists because of their wide range of biological, medicinal and therapeutic properties, 1 such as anti-cancer, 2 anti-HIV 3,4 anti-microbial, 5,6 antitumor 7 and anti-bacterial. 8As 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. 9,10he green synthesis of silver nanoparticles (AgNPs) using Ferula latisecta leaf extracts has been reported. 11hahremanzadeh et al. reported a one-pot, three component synthesis of spiro-furo-pyrido-pyridimidineindolines using highly active magnetically reusable nano catalysts in water. 12s part of our on-going work on the synthesis of fused heterocycles by one-pot multicomponent reactions, [13][14][15][16][17][18][19][20][21] we report herein, a one-pot, three component approach for accessing fused pyrimidonaphthyridines by reaction of aryl glyoxals, 6-aminouracil and 4-hydroxyquinolin-2(1H)-one in the presence of AgNPs under mild conditions in high yields.
The highest yield (91%) was achieved when the reaction was performed using 10 ppm of AgNPs as a nanocatalyst in H 2 O/EtOH (1:1) after 3 h of reaction time (Table 1, entry 6).To investigate the effect of catalyst 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 2 O (1:1) was 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 SeO 2 by literature methods 22  The AgNPs was prepared via minor modifications of the literature method. 23,24The SEM image and EDX spectrum of the nanocatalyst used are shown in Figures 1 and 2, respectively.2).The substituted pyrimido[4,5b] [1,6]naphthyridines 4a-h were characterized using FT-IR, 1 H and 13 C NMR spectral data and microanalysis.
In the 1 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 13 C NMR spectra, signals located around δ C 159.8-173.3were attributed to the three different carbonyl groups.In the FT-IR (KBr) spectra, the characteristic absorptions bands at 3302-3438 and 1649-1718 cm -1 could be assigned to the vibrations of NH and different carbonyl groups, respectively.The proposed mechanism of this reaction involves the initial condensation of aryl glyoxals with 4hydroxyquinolin-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
General.Melting points were measured on a Philip Harris C4954718 apparatus and are uncorrected. 1H 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 (1×10 -3 M) (2 mL) were added to a solution of silver nitrate (1×10 -3 M) (1 mL).The resulting solution was heated at 60 o C for an hour when the color of the mixture changed from pale yellow to orange. 23,24In this work the colloidal form of AgNPs we used, but freeze-dried nanoparticals were also satisfactory. 25eneral procedure for synthesis of new pyrimido[4,5-b][1,6]naphthyridines 4a-h.The aryl glyoxal monohydrate (1 mmol) was dissolved in H 2 O/EtOH (1:1) (6 mL), then 6-aminouracil (1 mmol), 4hydroxyquinolin-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%.