Magnetic nanoparticles-supported tungstic acid (MNP-TA): an efficient magnetic recyclable catalyst for the one-pot synthesis of spirooxindoles in water

Abstract

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 FT-IR 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 L⁻¹), which was equal to 8.25% w/w (0.45 mmol g⁻¹). The catalyst was successfully used for the 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 showed high catalytic activity in this protocol and that it can be reused at least 5 times without any change in its catalytic activity.

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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 fifth 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

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

In recent years, there has been a significant 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 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 significant 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 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 filtration 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 field) of catalyst are improved (Fig. 2).^43,44

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.

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.

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.

Scheme 1 Synthetic route for the preparation of the MNP-TA catalyst.

As shown in Scheme 1, MNs were prepared by co-precipitation 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 (3-CPMNP) substrate.⁴⁷ The obtained 3-CPMNP was treated with sodium tungstate (Na₂WO₄), followed by acidification 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.

Fig. 3 TEM images of four different positions of the MNP-TA catalyst.

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.

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

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.

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

The XRD pattern of the MNP-TA catalyst also shows that we have MNPs in the structure of the catalyst (Fig. 6).

Fig. 6 XRD pattern of the MNP-TA catalyst.

The peak in 2θ = 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 sharp peak of Fe₃O₄ is observed at ∼2θ = 35.8°. The size of the catalyst particles was determined from X-ray line broadening using the Debye–Scherrer formula,⁵⁰ which is D = 0.9 L/β cos(θ), where D is the average crystalline size, L is the X-ray wavelength, β is the angular line width at half-maximum intensity, and θ is the Bragg angle. For θ = 18°, L = 1.06 Å and β = 0.257 mm, and the average size of the catalyst nanoparticles is estimated to be 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 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 confirm the presence of WO₄ moieties in the structure of the catalyst. A strong absorption band in the range of 586 cm⁻¹ has attributed to Fe–O/Fe–O–Fe bindings of magnetite.⁵² A broad band around 1118 cm⁻¹, 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 cm⁻¹ can be attributed to the bending vibration of the Si–O–Si bonds,⁵⁴ whereas the peak at 833 cm⁻¹ 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 cm⁻¹, appearing in the FTIR spectra of MNP-TA, indicate the presence of the WO₄ group.

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

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

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-1,3-dimethyluracil 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) was selected as a simple model substrate, and optimization studies are shown in Table 1.

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

Entry	Catalyst (mol%)	Solvent	Temp. (°C)	Time (h)	Yield^b (%)
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%.
1	—	H2O	Reflux	24	0
2	SiO2 (0.05 g)	H2O	Reflux	24	Trace
3	Fe3O4@SiO2 (0.05 g)	H2O	Reflux	24	10
4	TA (10)	H2O	Reflux	24	60
5	MNP-TA	H2O	Reflux	8	93
6	MNP-TA	—	100	12	51
7	MNP-TA	EtOH	Reflux	12	53
8	MNP-TA	Toluene	100	12	44
9	MNP-TA	H2O	r.t.	24	35
10	MNP-TA	H2O	Reflux	8	95^c
11	MNP-TA	H2O	Reflux	12	85^d
12	MNP-TA	H2O	Reflux	12	78^e

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In our initial selection, no catalyst was used and compound 4a was not produced even after 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 after 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 significantly 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 reflux 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 in good to excellent yields. The generality of this protocol was observed by the application of divers components under optimized conditions.

Table 2 Products of tree-component coupling reaction catalyzed by MNP-TA catalyst in water^a

a Reaction conditions and reagents: 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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Table 3 Reusability of the MNP-TA catalyst in the reaction of isatin, 5-amino-1,3-dimethyluracil and methyl-2-cyanoacetate under optimized conditions^a

Run	Yield of product (%)	Recovery of catalyst (%)
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.
1	93	99
2	91	98
3	90	96.5
4	89	96
5	87	95

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As shown in Table 2, the reaction of both isatin and N-substituted analogs gave the corresponding products with good 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 after five cycles of reusability (Table 3).

After five 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 filtration 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 after five cycles of reusability did not change remarkably.

Conclusions

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 pseudo-homogeneous 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

Chemicals were purchased from Fluka, Merck and Aldrich chemical companies and used without further purification. The known products were characterized by comparison of their spectral and physical data with those reported in the literature. ¹H (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, 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 electro-thermal 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 L⁻¹.

Preparation of Fe₃O₄@SiO₂ nanoparticles

Fe₃O₄@SiO₂ nanoparticles were prepared based on the literature⁴⁶ with some modifications: 25 mL of i-PrOH, 20 mL of PEG-300, 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. After the specified 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 field, 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. After 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 reflux conditions (70 °C) for 4 h. After completion of the reaction, the reaction mixture was filtered, 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 filtered, 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 isatin (1 mmol) and malononitrile (1 mmol) under reflux conditions with vigorous stirring. When the reaction was complete (monitored by TLC), the catalyst was separated by an external magnet. The precipitated solid was filtered, washed with water and ethanol, and then purified by recrystallization from ethanol.

Methyl-6′-amino-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4a)

White crystals (yield: 93%, 0.36 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3895, 3178, 3070, 2923, 3360, 1697, 1851, 1674, 1458, 1164, 1126, 1033, 1010, 817, 686, 570. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 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): δ (ppm) = 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-6′-amino-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4b)

White crystals (yield: 94%, 0.37 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3624, 3186, 3121, 1175, 1654, 1486, 684, 580. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 1.21 (t, J = 7.5 Hz, 3H, CH₃), 2.66 (s, 6H, CH₃), 4.20 (q, J = 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): δ (ppm) = 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.

6′-Amino-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carbonitrile (4c)

White crystals (yield: 90%, 0.31 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3629, 3154, 1175, 1654, 1486, 694, 580. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 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): δ (ppm) = 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-6′-amino-1-butyl-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4d)

White crystals (yield: 90%, 0.39 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3158, 3078, 2973, 2073, 1876, 1458, 1174, 1019, 820, 688. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 1.21 (t, J = 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): δ (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. calcd for C₂₂H₂₅N₅O₅: C, 60.13; H, 5.73; N, 15.94; found: C, 60.20; H, 5.65; N, 15.86.

Ethyl-6′-amino-1-butyl-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4e)

White crystals (yield: 88%, 0.4 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3178, 3070, 2923, 2083, 1836, 1458, 1164, 1010, 817, 686, 570. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 1.21 (t, J = 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 = 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): δ (ppm) = 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.

6′-Amino-1-butyl-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carbonitrile (4f)

White crystals (yield: 95%; 0.38 g); m.p. > 300 °C. IR (KBr): 3128, 3070, 2113, 1458, 1164, 1010, 686 cm⁻¹. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 1.21 (t, J = 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): δ (ppm) = 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-6′-amino-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4g)

White crystals (yield: 94%, 0.4 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3818, 3749, 3175, 3101, 1766, 1697, 1174, 1654, 1542, 1496, 694, 570. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 2.94 (s, 6H, CH₃), 3.49 (s, 3H, CH₃), 5.57 (dd, J = 1.8, 4.3 Hz, 1H, CH₂), 5.89 (dd, J = 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, DMSO-d6): δ 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-6′-amino-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4h)

White crystals (yield: 96%, 0.42 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3828, 3759, 3185, 3111, 1786, 1697, 1175, 1654, 1542, 1486, 694, 570. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 2.93 (s, 6H, CH₃), 4.22 (q,J = 4.2, 2 Hz, 2H, CH₂), 5.12 (dd, J = 1.8, 4.6 Hz, 1H, CH₂), 5.57 (dd, J = 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): δ (ppm) = 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, 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.

1-Allyl-6′-amino-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carbonitrile (4i)

White crystals (yield: 89%, 0.35 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3628, 3184, 3121, 1697, 1175, 1654, 1486, 684, 570. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 2.83 (s, 6H, CH₃), 5.11 (dd, J = 1.7, 4.8 Hz, 1H, CH₂), 5.57 (dd, J = 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): δ (ppm) = 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.

Methyl-6′-amino-1-(1-ethoxy-1-oxopropan-2-yl)-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4j)

White crystals (yield: 91%, 0.44 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3440, 3201, 2954, 1766, 1697, 1651, 1542, 1496, 1427, 1249, 982, 763. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 0.96 (t, J = 7.5 Hz, 3H, CH₃), 1.42 (d, J = 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 = 2.5 Hz, 2H, CH₂) 6.88–7.61 (complex, 7 arom. H, NH and NH₂). ¹³C NMR (62.5 MHz, DMSO-d₆/TMS): δ (ppm) = 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-6′-amino-1-(1-ethoxy-1-oxopropan-2-yl)-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidine]-7′-carboxylate (4k)

White crystals (yield: 96%, 0.48 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3895, 3178, 3070, 2923, 3360, 1697, 1851, 1674, 1458, 1164, 1126, 1033, 1010, 817, 686, 570. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 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): δ (ppm) = 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-(6′-amino-7′-cyano-1′,3′-dimethyl-2,2′,4′-trioxo-1′,3′,4′,5′-tetrahydro-2′H-spiro[indoline-3,8′-pyrido[3,2-d]pyrimidin]-1-yl)propanoate (4l)

White crystals (yield: 92%, 0.41 g); m.p. > 300 °C. IR (KBr, cm⁻¹): 3128, 3070, 2113, 1458, 1164, 1010, 686. ¹H NMR (250 MHz, DMSO-d₆/TMS): δ (ppm) = 0.96 (t, J = 7.5 Hz, 3H, CH₃), 1.42 (d, 3H, J = 7.75 Hz, CH₃), 2.66 (s, 6H, CH₃), 4.20 (q, J = 5.0 Hz, 2H, CH₂), 4.65 (q, J = 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/TMS): δ (ppm) = 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.

Notes and references

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