Magnetic nanoparticles-supported tungstic acid (MNP ...

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Cite this: RSC Adv., 2015, 5, 2223

Magnetic nanoparticles-supported tungstic acid (MNP-TA): an efficient magnetic recyclable catalyst for the one-pot synthesis of spirooxindoles in water Ali Khalafi-Nezhad,* Masoumeh Divar and Farhad Panahi* This paper reports the preparation, characterization and catalytic application of a novel, magnetically separable catalyst consisting of tungstic acid supported on silica coated magnetic nanoparticles. To obtain this new catalyst system, first, (3-chloropropyl)triethoxysilane was reacted with silica coated magnetic nanoparticles to generate a 3-chloropropyl magnetic nanoparticle (3-CPMNP) substrate. Subsequently, the addition of sodium tungstate to 3-CPMNP resulted in the stabilization of tungstic acid species on the surface of the magnetic nanoparticles (MNP-TA). The synthesized catalyst was characterized using some different microscopic and spectroscopic techniques such as X-ray powder diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and FTIR spectroscopy. The catalyst nanoparticles were obtained with near spherical morphology and an average size of
45 nm. The W content of the catalyst was determined by ICP analysis to be 82.5 ppm (82.5 mg L1), which was equal to 8.25% w/w (0.45 mmol g1). The catalyst was successfully used for the

Received 23rd October 2014 Accepted 19th November 2014

one-pot synthesis of spirooxindoles via the multicomponent reaction of isatins and dicarbonyl compounds in water, which was used as a green solvent. The results revealed that this new catalyst

DOI: 10.1039/c4ra12976h

showed high catalytic activity in this protocol and that it can be reused at least 5 times without any

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change in its catalytic activity.

Introduction Designing a green reaction that complies with all or a set of twelve principles of green chemistry has been extensively studied in recent years.1,2 The use of water as a green solvent for organic reactions is a good choice as it follows one of the most important principles of green chemistry (the h principle).1–4 According to the green chemistry principles, the heterogeneous catalysis discipline is innovative because it has become an essential part of sustainability.5,6 Moreover, in multicomponent approaches, complex products are synthesized from readily available starting materials in a single step process.7,8 From this point of view, multicomponent reactions (MCRs) have emerged as green and powerful tools in organic synthesis. Thus, heterogeneously catalyzed MCRs and the use of environmentally benign solvents and reagents are particularly attractive because they incorporate many of the green chemistry principles (Fig. 1).9,10 In recent years, there has been a signicant increase in interest in the synthesis of spirooxindole derivatives because of the widespread biological activity related to them.11–20 On the other hand, a large number of pyrimidine derivatives consist of Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran. E-mail: khala@chem.susc.ac.ir; [email protected]; Fax: +98 711 2280926; Tel: +98-7116137163

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barbituric acid and 2-amino-uracil have attracted great interest for their biological activities and applications in medicine and therapeutics. In this situation, the production of this signicant ring system combined with spirooxindole remains an issue of current interest.21–23 Although different methods for the synthesis of diverse spirooxindole derivatives have been developed, there is still a need for adaptable, straightforward, and environmentally friendly processes to obtain these types of compounds.9–32 Tungstic acid (TA) is known as an efficient catalyst in organic synthesis.33–35 Moreover, this solid acid has been made even greener by immobilization of TA onto solid supports. In fact, the immobilization of TA on silica has been employed in previous studies.36–38 However, when the homogeneous catalyst is

Fig. 1 Heterogeneously catalyzed MCRs in water is known as a green process.

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Fig. 2 Effect of size of support on reactivity of a heterogeneous catalyst, difficulty in separation of nanocatalysts from reaction mixture and role of magnetic nanoparticles as supports.

supported, a reduction in the reactant diffusion rate to the surface of catalyst is observed. As a result of this phenomenon, the reactivity and selectivity of the supported catalysts decreases frequently in comparison with the homogeneous counterparts.39 It is reasonable to assume that by decreasing the size of the support, reactivity can be increased. Undoubtedly, nanoparticles are reasonable potential candidate supports because of their nanometer size range;40 moreover, the dispersibility of nanoparticles in solution is high, resulting in the formation of emulsions, which further increases the diffusion rate. These factors lead to the easy access of reactants in solution to the active sites on the surface of nanocatalysts.41,42 However, when the size of support is decreased to the nanometer scale, a new problem emerges, i.e. catalyst recovery, because a simple ltration method cannot overcome the big obstacle of catalyst separation from the reaction media. This is where the use of magnetic nanoparticles (MNPs) as a support has been introduced. Thus, considerable effort has been focused on magnetically recyclable supports, and studies have shown that by the use of MNPs as supports, both reactivity and reusability (catalyst can be separated from reaction condition using an external magnetic eld) of catalyst are improved (Fig. 2).43,44 Thus, by immobilization of TA on MNPs, it is possible to prepare a highly efficient solid acid for application in organic reactions. In this study, the application of the MNP-TA catalyst was investigated for the one-pot synthesis of spirooxindoles in water.

Paper

Scheme 1

Synthetic route for the preparation of the MNP-TA catalyst.

sodium tungstate (Na2WO4), followed by acidication of the obtained material, which leads to the formation of MNP-TA catalyst. The TEM images of the MNP-TA catalyst (Fig. 3) show that nanoparticles of the catalyst with near spherical morphology are assembled with relatively good monodispersity. The SEM images of the MNP-TA catalyst (Fig. 4) show that the catalyst particles possess near spherical morphology with relatively good monodispersity. In this study, the average diameter of the MNPs was estimated to be
45 nm. The histogram shown in Fig. 5 was proposed according to the results obtained from the TEM and SEM images, and it revealed the size distributions of the MNP-TA nanoparticles. The XRD pattern of the MNP-TA catalyst also shows that we have MNPs in the structure of the catalyst (Fig. 6). The peak in 2q ¼ 18.5 corresponded to the SiO2 shell. The peaks indexed as (220), (311), (400), (422), (511), and (440) are the planes of the Fe3O4 nanoparticles.48,49 According to Fig. 6, a

Results and discussion Catalyst preparation and characterization The synthetic pathway for the synthesis of magnetic nanoparticles-supported tungstic acid (MNP-TA) catalyst is shown in Scheme 1. As shown in Scheme 1, MNs were prepared by coprecipitation method using a procedure reported in the literature.45 Then, the synthesized MNs were coated by silica using a sol–gel process to obtain core–shell MNPs (Fe3O4@SiO2).46 The synthesized Fe3O4@SiO2 was reacted with (3-chloropropyl)triethoxysilane to obtain 3-chloropropyl magnetic nanoparticles (3CPMNP) substrate.47 The obtained 3-CPMNP was treated with

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Fig. 3

TEM images of four different positions of the MNP-TA catalyst.

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about 39 nm. This value is in good agreement with data obtained from the TEM image. In some cases, it has been reported that the result provided by this equation overestimates the crystallite size of nanoparticles.51 The EDX spectrum of NMP-TA catalyst (Fig. 7) represented the presence of the expected elements of Fe, Si, O, W and C in the structure of the catalyst. A comparison of the FT-IR spectra of Fe3O4@SiO2, Na2WO4 and MNP-TA catalyst is shown in Fig. 8. FT-IR

Fig. 4 SEM image of the MNP-TA catalyst.

Fig. 7 EDX analysis of the MNP-TA catalyst.

Fig. 5 Histogram representing the size distribution of synthesized the MNP-TA catalyst.

Fig. 6

XRD pattern of the MNP-TA catalyst.

sharp peak of Fe3O4 is observed at
2q ¼ 35.8 . The size of the catalyst particles was determined from X-ray line broadening using the Debye–Scherrer formula,50 which is D ¼ 0.9 L/b cos(q), where D is the average crystalline size, L is the X-ray wavelength, b is the angular line width at half-maximum intensity, and q is ˚ and b ¼ 0.257 mm, and the Bragg angle. For q ¼ 18 , L ¼ 1.06 A the average size of the catalyst nanoparticles is estimated to be

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Fig. 8 Comparison of FT-IR spectra of Fe3O4@SiO2, Na2WO4$2H2O and MNP-TA catalyst.

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spectroscopy was used as for further characterization of the NMP-TA catalyst. Comparison between the FT-IR spectra of Fe3O4@SiO2, Na2WO4 and MNP-TA catalyst reveals some absorption bands, which conrm the presence of WO4 moieties in the structure of the catalyst. A strong absorption band in the range of 586 cm1 has attributed to Fe–O/Fe–O–Fe bindings of magnetite.52 A broad band around 1118 cm1, corresponding to asymmetric stretching of the Si–O–Si bond, was seen in Fe3O4@SiO2 nanoparticles.53 The abovementioned peaks appeared in the FT-IR of MNP-TSA catalyst. Moreover, peaks at around 624 cm1 can be attributed to the bending vibration of the Si–O–Si bonds,54 whereas the peak at 833 cm1 could be attributed to the stretching vibration of W]O.38 Note that these peaks are observable in the FT-IR spectrum of the catalyst. Furthermore, the absorptions at 1691 and 1465 cm1, appearing in the FTIR spectra of MNP-TA, indicate the presence of the WO4 group. The percentage of tungsten (W) in the catalyst was determined by ICP analysis, which showed 8.25 (%w/w) of tungsten. Thus, 1 gram of catalyst includes 0.45 mmol of W. Since, per one W there is one acidic hydrogen the amount of W approximately equal to amount of proton, 1 gram of catalyst is equal to 0.45 mmol of H+.

Synthesis of spirooxindoles in the presence of MNP-TA catalyst To evaluate catalytic performance, the MNP-TA catalyst was applied in the multicomponent reaction of isatins, 5-amino-1,3dimethyluracil and 2-cyanoacetates for the synthesis of some novel spirooxindoles. Thus, the reaction between isatin (1a), 5-amino-1,3-dimethyluracil (2) and methyl-2-cyanoacetate (3a)

Table 1

was selected as a simple model substrate, and optimization studies are shown in Table 1. In our initial selection, no catalyst was used and compound 4a was not produced even aer 24 h (Table 1, entry 1). We used SiO2 as a catalyst in water, and a trace amount of 4a was isolated (Table 1, entry 2). When Fe3O4@SiO2 was used as a catalyst for this reaction, the isolated yield of product obtained was 10% (Table 1, entry 3). It was seen that the yield of desired product increased to 60% when TA was used as a catalyst (Table 1, entry 4). Interestingly, the yield of product increased to 95% by the use of MNP-TA as a catalyst aer 8 h (Table 1, entry 5). These experiments revealed that the MNP-TA catalyst is more efficient than TA in this reaction. Thus, MNP-TA was found to be an efficient, magnetic, and recyclable catalyst for the one-pot synthesis of spirooxindoles in water. As shown by varying the type of solvent, the yield of the desired product did not change signicantly in comparison with that of water (Table 1, entries 6–8). The yield of product was decreased 35% when the reaction was performed at room temperature (Table 1, entry 9). Moreover, by increasing the amount of catalyst, the yield of product remained unchanged (Table 1, entry 10). Furthermore, as a result of reducing the amount of catalyst, a reduction was observed in the yield of product (Table 1, entries 11–12). These results show that a catalytic amount of MNP-TA is applicable for this reaction. Thus, a simple system, i.e. MNP-TA (0.1 g, 5 mol%), H2O as a solvent, and reux temperature of water, was chosen as the optimized reaction conditions (Table 1, entry 5). To determine the scope of this protocol, various spirooxindoles were synthesized under the optimized conditions, and the results are summarized in Table 2. As shown in Table 2, the reaction between isatin, 5-amino-1,3-dimethyluracil and 2-cyanoacetates proceeded smoothly to furnish the desired products

Optimization of reaction condition between isatin, 5-amino-1,3-dimethyluracil and 2-cyanoacetates in the presence of MNP-TA

catalysta

Entry

Catalyst (mol%)

Solvent

Temp. ( C)

Time (h)

Yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12

— SiO2 (0.05 g) Fe3O4@SiO2 (0.05 g) TA (10) MNP-TA MNP-TA MNP-TA MNP-TA MNP-TA MNP-TA MNP-TA MNP-TA

H2O H2O H2O H2O H2O — EtOH Toluene H2O H2O H2O H2O

Reux Reux Reux Reux Reux 100 Reux 100 r.t. Reux Reux Reux

24 24 24 24 8 12 12 12 24 8 12 12

0 Trace 10 60 93 51 53 44 35 95c 85d 78e

a

Reaction conditions: catalyst: MNP-TA (5.0 mol%) and solvent (5 mL). b Isolated yield. c 0.1 g of SiO2 was used. Catalyst: 7.5 mol%. d Catalyst: 3.0 mol%. e Catalyst: 2.5 mol%.

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Table 2 Products of tree-component coupling reaction catalyzed by MNP-TA catalyst in watera

to excellent yields. The results demonstrate that our environmentally benign catalyst system is one of the most efficient heterogeneous catalyst systems for the one-pot synthesis of spirooxindoles in water. Note that the MNP-TA catalyst is superior to some of the previously reported catalysts in terms of reaction condition and sustainability.11–20 The recyclability of MNP-TA catalyst for this protocol has also been investigated. The results show that the MNP-TA catalyst is recovered by simple external magnetic attraction; moreover, there was no remarkable loss in its catalytic activity aer ve cycles of reusability (Table 3). Aer ve cycles of reusability, we also checked the W content of MNP-TA catalyst using ICP analysis, and the data showed that less than 1% of the stabilized tungstic acid species were removed from the MNP substrate. In one reaction, when the reaction was complete, hot ltration was performed, and ICP analysis indicated that the amount of leached W to be less than 0.3%. The TEM image of the catalyst showed that the morphology and size of the catalyst aer ve cycles of reusability did not change remarkably.

Conclusions

a

Reaction conditions and reagents: isatin (1 mmol), 5-amino-1,3dimethyluracil (1 mmol), 2-cyanoacetate (1 mmol), MNP-TA (0.1 g, 5 mol%), H2O (2 mL), and 80  C.

in good to excellent yields. The generality of this protocol was observed by the application of divers components under optimized conditions. As shown in Table 2, the reaction of both isatin and Nsubstituted analogs gave the corresponding products with good

In this study, magnetic nanoparticle-supported tungstic acid (MNP-TA) was successfully synthesized using the reaction of sodium tungstate with the pre-prepared 3-chloropropyl magnetic nanoparticles (3-CPMNP). The synthetic usefulness of this heterogeneous catalyst for the one-pot synthesis of spirooxindoles in water as a green solvent via the reaction of isatins, 5-amino-1,3-dimethyluracil and 2-cyanoacetates was demonstrated. The target products ranging from 4a–l were obtained in excellent yields and short reaction times. This new catalyst can be easily dispersed in solution to produce a pseudohomogeneous catalyst system to generate a highly reactive catalyst sites. Reusability and easy workup (using external magnetic attraction) were two other advantages of this catalyst system. Moreover, the MNP-TA catalyst provides great promise towards further useful applications in other acid-catalyzed transformations in future.

Experimental General

Reusability of the MNP-TA catalyst in the reaction of isatin, 5amino-1,3-dimethyluracil and methyl-2-cyanoacetate under optimized conditionsa

Table 3

Run

Yield of product (%)

Recovery of catalyst (%)

1 2 3 4 5

93 91 90 89 87

99 98 96.5 96 95

a

Reaction conditions: isatin (1 mmol), 5-amino-1,3-dimethyluracil (1 mmol), 2-cyanoacetate (1 mmol), MNP-TA (0.1 g, 5 mol%), H2O (2 mL), and 80  C.

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Chemicals were purchased from Fluka, Merck and Aldrich chemical companies and used without further purication. The known products were characterized by comparison of their spectral and physical data with those reported in the literature. 1 H (250 MHz) and 13C NMR (62.9 MHz) spectra were recorded on a Bruker Advance spectrometer using CDCl3 and DMSO-d6 solutions with tetramethylsilane (TMS) as an internal standard. X-ray diffraction (XRD, D8 Advance, Bruker, AXS) and FT-IR spectroscopy (Shimadzu, FT-IR 8300 spectrophotometer) were employed for characterization of the MNP-TA catalyst and products. ICP analysis was performed using an inductively coupled plasma (ICP) analyzer (Varian, Vista-Pro). The scanning electron micrograph (SEM) for the MNP-TA catalyst was obtained by SEM instrumentation (SEM, XL-30 FEG SEM,

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Philips, at 20 kV). Transmission electron microscopy (TEM) was performed using a TEM apparatus (Zeiss EM 900, 80 kV) for characterization of the MNP-TA catalyst. Melting points were determined in open capillary tubes in a Barnstead electrothermal 9100 BZ circulating oil melting point apparatus. The reaction monitoring was accomplished by TLC on silica gel PolyGram SILG/UV254 plates. Note that column chromatography was carried out on columns of silica gel 60 (70–230 mesh). Preparation of Fe3O4 nanoparticles Magnetite nanoparticles (MNs) used for this work were synthesized by the co-precipitation method.45 FeCl2$4H2O (2 g) and FeCl3$6H2O (5.2 g) and 0.85 mL HCl were dissolved in 25 mL deionized water under nitrogen gas, and the resulting solution was added dropwise to a 250 mL solution of NaOH (0.1 M) under vigorous mechanical stirring at 80  C for 30 min. The magnetite precipitates were washed with deionized water, and then stored in deionized water at a concentration of 10 g L1. Preparation of Fe3O4@SiO2 nanoparticles Fe3O4@SiO2 nanoparticles were prepared based on the literature46 with some modications: 25 mL of i-PrOH, 20 mL of PEG300, and 10 mL of water, and 2 g of Fe3O4 were added to a mixture of heptanes (125 mL). Then, the mixture was stirred by mechanical stirrer under N2 gas for 30 minutes. 20 mL of tetraethyl orthosilicate (TEOS) was added to the mixture, and then the solution was stirred for 12 h at 30  C. Aer the specied time, 10 mL of ammonia was added, and the solution was stirred continuously for another 12 h. The precipitates were washed with ethanol (3  10 mL) and collected by an external magnetic eld, and the desired product was dried under vacuum overnight. Synthesis of 3-CPMNP To a mixture of water/ethanol (250 mL, 1 : 1), Fe3O4@SiO2 nanoparticles (5.0 g) were added and then sonicated for 30 minutes. Aer that, (3-chloropropyl)triethoxysilane (4 mmol, 0.96 g, 0.96 mL) was added to this solution and again sonicated for 5 h and washed with EtOH (3  5 mL) in order to obtain 3-CPMNP as a dark solid (5.35 g). Preparation of MNP-TA catalyst n-Hexane (10 mL) was added to a mixture of 3-CPMNP (5.0 g) and sodium tungstate (1.47 g, 5 mmol). The reaction mixture was stirred under reux conditions (70  C) for 4 h. Aer completion of the reaction, the reaction mixture was ltered, washed with distilled water, dried, and then stirred in the presence of 0.1 N HCl (40 mL) for an hour. Finally, the mixture was ltered, washed with distilled water, and dried to afford the catalyst (5.5 g). General procedure for the synthesis of spirooxindoles using MNP-TA catalyst 6-Amino-1,3-dimethyluracil (1 mmol) and MNP-TA (0.1 g, 5 mol%) was added successively to a stirred aqueous mixture of

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isatin (1 mmol) and malononitrile (1 mmol) under reux conditions with vigorous stirring. When the reaction was complete (monitored by TLC), the catalyst was separated by an external magnet. The precipitated solid was ltered, washed with water and ethanol, and then puried by recrystallization from ethanol. Methyl-60 -amino-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carboxylate (4a) White crystals (yield: 93%, 0.36 g); m.p. > 300  C. IR (KBr, cm1): 3895, 3178, 3070, 2923, 3360, 1697, 1851, 1674, 1458, 1164, 1126, 1033, 1010, 817, 686, 570. 1H NMR (250 MHz, DMSO-d6/ TMS): d (ppm) ¼ 2.66 (s, 6H, CH3), 3.84 (s, 3H, CH3), 6.81–7.66 (complex, 5 arom. H and NH), 8.81 (brs, 2H, NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 28.8, 29.6, 41.1, 49.4, 52.4, 81.7, 101.9, 114.8, 118.4, 123.5, 132.0, 134.3, 141.0, 153.5, 159.0, 164.5, 167.2, 169.7, 170.2. Anal. calcd for C18H17N5O5: C, 56.39; H, 4.47; N, 18.27; found: C, 56.55; H, 4.38; N, 18.34. Ethyl-60 -amino-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carboxylate (4b) White crystals (yield: 94%, 0.37 g); m.p. > 300  C. IR (KBr, cm1): 3624, 3186, 3121, 1175, 1654, 1486, 684, 580. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 1.21 (t, J ¼ 7.5 Hz, 3H, CH3), 2.66 (s, 6H, CH3), 4.20 (q, J ¼ 5.0 Hz, 2H, CH2), 6.81–7.66 (complex, 7 arom. H and NH2), 8.16 (brs, 1H, NH). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 14.2, 29.6, 32.7, 45.0, 57.4, 86.5, 114.8, 123.5, 127.0, 129.1, 132.0, 134.3, 141.0, 162.0, 164.5, 168.9, 169.9, 173.4. Anal. calcd for C19H19N5O5: C, 57.43; H, 4.82; N, 17.62; found: C, 57.50; H, 4.780; N, 17.72. 60 -Amino-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 -tetrahydro-20 Hspiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 -carbonitrile (4c) White crystals (yield: 90%, 0.31 g); m.p. > 300  C. IR (KBr, cm1): 3629, 3154, 1175, 1654, 1486, 694, 580. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 2.66 (s, 6H, CH3), 6.81–7.66 (complex, 7 arom. H and NH2), 8.55 (brs, 1H, NH). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 28.9, 29.6, 54.1, 57.1, 103.1, 114.8, 117.2, 121.7, 124.8, 127.7, 129.7, 141.0, 152.1, 157.9, 162.5, 165.5, 168.8. Anal. calcd. for C17H14N6O3: C, 58.28; H, 4.03; N, 23.99; found: C, 58.37; H, 4.00; N, 24.05. Methyl-60 -amino-1-butyl-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carboxylate (4d) White crystals (yield: 90%, 0.39 g); m.p. > 300  C. IR (KBr, cm1): 3158, 3078, 2973, 2073, 1876, 1458, 1174, 1019, 820, 688. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 1.21 (t, J ¼ 2.0 Hz, 3H, CH3), 1.55–1.63 (m, 4H, C2H4), 2.62 (s, 6H, CH3), 3.17–3.25 (m, 2H, CH2) 3.81 (s, 3H, CH3), 6.81–7.66 (complex, 7 arom. H and NH and NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm): 14.2, 20.0, 28.8, 29.5, 42.1, 51.1, 81.7, 103.3, 116.0, 123.5, 127.5, 130.0, 132.0, 146.5, 149.4, 160.4, 164.5, 166.7, 169.9; anal.

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calcd for C22H25N5O5: C, 60.13; H, 5.73; N, 15.94; found: C, 60.20; H, 5.65; N, 15.86.

146.5, 151.0, 164.5, 166.7, 169.9. Anal. calcd for C22H23N5O5: C, 60.40; H, 5.30; N, 16.01; found: C, 60.48; H, 5.22; N, 16.08.

Ethyl-60 -amino-1-butyl-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carboxylate (4e)

1-Allyl-60 -amino-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carbonitrile (4i)

White crystals (yield: 88%, 0.4 g); m.p. > 300  C. IR (KBr, cm1): 3178, 3070, 2923, 2083, 1836, 1458, 1164, 1010, 817, 686, 570. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 1.21 (t, J ¼ 2 Hz, 3H, CH3), 1.66–1.77 (complex, 7H, C2H4, CH3), 2.73 (s, 6H, CH3), 4.17–4.25 (m, 2H, CH2) 5.11–5.20 (q, J ¼ 7.25 Hz, 2H, CH2), 6.92– 7.49 (complex, 7 arom. H and NH and NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 11.0, 20.0, 28.8, 29.1, 41.1, 53.6, 61.0, 80.0, 103.3, 118.3, 120.7, 123.5, 127.5, 129.1, 141.0, 160.4, 164.5, 169.9, 171.3, 173.1; anal. calcd for C23H27N5O5: C, 60.92; H, 6.00; N, 15.44; found: C, 60.86; H, 5.92; N, 15.56.

White crystals (yield: 89%, 0.35 g); m.p. > 300  C. IR (KBr, cm1): 3628, 3184, 3121, 1697, 1175, 1654, 1486, 684, 570. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 2.83 (s, 6H, CH3), 5.11 (dd, J ¼ 1.7, 4.8 Hz, 1H, CH2), 5.57 (dd, J ¼ 1.8, 10.3, 1H, CH2), 5.83–5.96 (m, 1H, CH), 7.08–7.48 (complex, 7 arom. H, NH and NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 29.5, 29.6, 47.7, 52.1, 58.2, 103.3, 119.2, 120.7, 123.5, 126.6, 130.0, 144.3, 151.5, 157.9, 161.8, 164.8, 164.5, 166.7. Anal. calcd for C20H18N6O3: C, 61.53; H, 4.05; N, 21.53. Found: C, 61.58; H, 4.00; N, 21.63.

60 -Amino-1-butyl-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carbonitrile (4f) 

White crystals (yield: 95%; 0.38 g); m.p. > 300 C. IR (KBr): 3128, 3070, 2113, 1458, 1164, 1010, 686 cm1. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 1.21 (t, J ¼ 2.0 Hz, 3H, CH3), 1.66– 1.74 (m, 4H, C2H4), 2.84 (s, 6H, CH3), 4.18–4.25 (m, 2H, CH2) 6.81–7.66 (complex, 7 arom. H and NH and NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 13.4, 20.7, 29.3, 30.0, 30.6, 54.0, 55.9, 103.6, 116.7, 122.4, 123.3, 125.3, 128.0, 141.6, 144.6, 151.9, 156.7, 162.4, 169.7. Anal. calcd for C21H22N6O3: C, 62.06; H, 5.46; N, 20.68; found: C, 62.14; H, 5.37; N, 20.75. Methyl-1-allyl-60 -amino-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carboxylate (4g) White crystals (yield: 94%, 0.4 g); m.p. > 300  C. IR (KBr, cm1): 3818, 3749, 3175, 3101, 1766, 1697, 1174, 1654, 1542, 1496, 694, 570. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 2.94 (s, 6H, CH3), 3.49 (s, 3H, CH3), 5.57 (dd, J ¼ 1.8, 4.3 Hz, 1H, CH2), 5.89 (dd, J ¼ 1.3, 10.1 Hz, 1H, CH2), 5.85–5.91 (m, 1H, CH), 6.88–7.48 (complex, 7 arom. H, NH and NH2). 13C NMR (62.5 MHz, DMSOd6): d 28.8, 29.6, 41.1, 49.4, 53.6, 81.7, 103.3, 123.5, 126.6, 127.5, 129.1, 130.0, 146.5, 149.4, 157.0, 160.4, 164.5, 169.9. Anal. calcd for C21H21N5O5: C, 59.57; H, 5.00; N, 16.54; found: C, 60.08; H, 4.93; N, 16.86. Ethyl-1-allyl-60 -amino-10 ,30 -dimethyl-2,20 ,40 -trioxo-10 ,30 ,40 ,50 tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d]pyrimidine]-70 carboxylate (4h) White crystals (yield: 96%, 0.42 g); m.p. > 300  C. IR (KBr, cm1): 3828, 3759, 3185, 3111, 1786, 1697, 1175, 1654, 1542, 1486, 694, 570. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 2.93 (s, 6H, CH3), 4.22 (q, J ¼ 4.2, 2 Hz, 2H, CH2), 5.12 (dd, J ¼ 1.8, 4.6 Hz, 1H, CH2), 5.57 (dd, J ¼ 1.7, 10.1 Hz, 1H, CH2), 5.83–5.96 (m, 1H, CH), 6.91–7.48 (complex, 7 arom. H, NH and NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 14.2, 29.1, 29.6, 49.4, 52.4, 61.9, 80.0, 103.1, 118.3, 120.2, 123.5, 125.5, 129.1, 144.3,

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Methyl-60 -amino-1-(1-ethoxy-1-oxopropan-2-yl)-10 ,30 -dimethyl2,20 ,40 -trioxo-10 ,30 ,40 ,50 -tetrahydro-20 H-spiro[indoline-3,80 pyrido[3,2-d]pyrimidine]-70 -carboxylate (4j) White crystals (yield: 91%, 0.44 g); m.p. > 300  C. IR (KBr, cm1): 3440, 3201, 2954, 1766, 1697, 1651, 1542, 1496, 1427, 1249, 982, 763. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 0.96 (t, J ¼ 7.5 Hz, 3H, CH3), 1.42 (d, J ¼ 7.7 Hz, 3H, CH3), 2.72 (s, 6H, CH3), 3.81 (s, 3H, CH3), 4.18–4.25 (m, 1H, CH), 4.62–4.68 (q, J ¼ 2.5 Hz, 2H, CH2) 6.88–7.61 (complex, 7 arom. H, NH and NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 14.2, 14.9, 29.5, 29.6, 41.1, 51.1, 61.0, 65.3, 81.7, 103.3, 118.3, 120.7, 123.3, 146.5, 149.4, 153.5, 157.9, 164.5, 164.5, 166.7, 168.8, 171.8, 171.8, 173.1. Anal. calcd for C23H25N5O7: C, 57.14; H, 5.21; N, 14.49; found: C, 57.55; H, 5.15; N, 14.62. Ethyl-60 -amino-1-(1-ethoxy-1-oxopropan-2-yl)-10 ,30 -dimethyl2,20 ,40 -trioxo-10 ,30 ,40 ,50 -tetrahydro-20 H-spiro[indoline-3,80 pyrido[3,2-d]pyrimidine]-70 -carboxylate (4k) White crystals (yield: 96%, 0.48 g); m.p. > 300  C. IR (KBr, cm1): 3895, 3178, 3070, 2923, 3360, 1697, 1851, 1674, 1458, 1164, 1126, 1033, 1010, 817, 686, 570. 1H NMR (250 MHz, DMSO-d6/ TMS): d (ppm) ¼ 1.10–1.66 (complex, 9H, CH3), 2.72 (s,6H, CH3), 3.78–4.18 (m, 4H, CH2), 4.62–4.68 (m, 1H, CH), 6.88–7.25 (complex, 5 arom. H and NH), 8.81 (brs, 2H, NH2). 13C NMR (62.5 MHz, DMSO-d6/TMS): d (ppm) ¼ 14.2, 14.9, 29.5, 29.6, 51.1, 61.0, 64.8, 80.0, 103.3, 119.2, 120.7, 123.5, 126.6, 127.5, 132.0, 145.1, 149.4, 151.8, 157.9, 164.5, 168.8, 169.9, 171.5. Anal. calcd. for C24H27N5O7: C, 57.94; H, 5.47; N, 14.08; found: C, 57.98; H, 5.38; N, 14.14. Ethyl-2-(60 -amino-70 -cyano-10 ,30 -dimethyl-2,20 ,40 -trioxo10 ,30 ,40 ,50 -tetrahydro-20 H-spiro[indoline-3,80 -pyrido[3,2-d] pyrimidin]-1-yl)propanoate (4l) White crystals (yield: 92%, 0.41 g); m.p. > 300  C. IR (KBr, cm1): 3128, 3070, 2113, 1458, 1164, 1010, 686. 1H NMR (250 MHz, DMSO-d6/TMS): d (ppm) ¼ 0.96 (t, J ¼ 7.5 Hz, 3H, CH3), 1.42 (d, 3H, J ¼ 7.75 Hz, CH3), 2.66 (s, 6H, CH3), 4.20 (q, J ¼ 5.0 Hz, 2H, CH2), 4.65 (q, J ¼ 2.5 Hz, 1H, CH), 6.88–7.61 (complex, 6 arom. H and NH2), 8.63 (brs, 1H, NH). 13C NMR (62.5 MHz, DMSO-d6/

RSC Adv., 2015, 5, 2223–2230 | 2229

RSC Advances

TMS): d (ppm) ¼ 13.2, 14.2, 29.5, 29.6, 41.1, 53.2, 57.4, 103.3, 118.3, 119.3, 122.2, 123.5, 130.0, 145.0, 146.5, 153.5, 164.5, 169.9, anal. calcd for C22H22N6O5: C, 58.66; H, 4.92; N, 18.66; found: C, 58.76; H, 4.88; N, 18.75.

Acknowledgements We acknowledge Shiraz University partially supporting this study.

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