An expeditious one-pot synthesis of pyrido[2,3- d ]pyrimidines using Fe 3 O 4 –ZnO–NH 2 –PW 12 O 40 nanocatalyst

Abstract

An efficient protocol for the facile synthesis of a series of pyrido[2,3-d]pyrimidine derivatives has been developed applying Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ nanocatalyst in water. This novel method has the benefits of operational simplicity, green aspects by avoiding toxic solvents and high to excellent yields of products. Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ was synthesized and characterized by Fourier transform infrared, X-ray diffraction, vibrating sample magnetometer, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and transmission electron microscopy analyses. The nanocatalyst is readily isolated and recovered from the reaction mixture by an external magnet.

Introduction

Pyrimidopyrimidine scaffold is a well-known pharmacophore in drug design and synthetic chemistry and has attracted considerable interest in recent years. ¹ Because of these valuable features, the syntheses of various substituted pyridopyrimidine derivatives have been reported using different methods and catalysts, such as reaction of arylaldehyde, 6-aminouracil, and malononitrile in catalyst-free condition using glycerol, ² electrocatalytic synthesis in ethanol, ³ diammonium hydrogen phosphate (DAHP), ⁴ tetrabutyl ammonium bromide (TBAB), ⁵ triethylbenzylammonium chloride (TEBAC), ⁶ sulfonic acid functionalized SBA-15 (SBA-Pr-SO₃H), ⁷ Al-HMS-20, ⁸ and Lewis base surfactant-combined catalyst (LBSC). ⁹

On the other hand, the use of nanomaterials as catalyst supports has considerably increased because of their large surface-to-volume ratio, which makes them efficient catalysts for chemical synthesis. For example, using Au nanocatalyst on modifed bentonite and silica for solvent-free oxidation of cyclohexene with molecular oxygen, ¹⁰ sulfamic acid functionalized nano-titanium dioxide as a heterogeneous nanocatalyst for synthesis of hexahydroquinolines, ¹¹ synthesis of pyrido[2,3-d]pyrimidines catalyzed by nanocrystalline MgO in water, ¹² and ZrO₂ nanoparticles. ¹³ Among different nanoparticles, magnetite (Fe₃O₄) has been the focus of much attention as an interesting alternative to allow separation of the nanocatalyst from the reaction mixture by means of an external magnetic field. For example, microwave-assisted synthesis of pyrido[2,3-d:6,5-d′]dipyrimidine derivatives using CuFe₂O₄ nanoparticles in water, ¹⁴ synthesis of novel bioactive indole-substituted pyrido[2,3-d]pyrimidines using Fe₃O₄@SiO₂-supported ionic liquid nanocatalyst ¹⁵ have been reported.

Herein, in continuation of our interest in using nanocatalysts in organic synthesis.^16,17 the synthesis of Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ (Fe₃O₄·PMO1) as a magnetically separable nanocatalyst for the synthesis of a series of pyrido[2,3-d]pyrimidine derivatives is reported.

Result and discussions

Catalyst characterization

The catalyst was prepared and characterized by Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM) measurements (Supporting Information).

Catalytic studies

In order to investigate the catalytic activity of Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀, we employed the catalyst for the synthesis of substituted pyrido[2,3-d]pyrimidines. To optimize the reaction conditions, the reaction of equimolar amount of benzaldehyde, 6-aminouracil, and malononitrile was selected as a model reaction and then the effect of some variants such as solvent, catalyst, and temperature was investigated. The model reaction was examined in different solvents such as H₂O, CH₃CN, EtOH, dimethylformamide (DMF), toluene, 1,4-dioxane, and dicholoroethane. According to the results, using 20 mg Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ in H₂O at 80 °C proved to be the best condition for this reaction (Table 1). By performing the reaction in the presence of an acid, a base, and a salt, no improvement was achieved (entries 15–17). In order to show the role of catalyst, similar reaction was performed in the absence of the catalyst. However, a trace amount of the product generated even after a prolonged reaction time (entry 18).

Table 1.

Optimization of synthesis of pyrido[2,3-d]pyrimidines using Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ (Fe₃O₄·PMO1) nanoparticles under various conditions ^a .

Entry	Catalyst (mg)	Extra reagent	Temperature (°C)	Solvent	Time (min)	Yield b (%)
1	Fe3O4·PMO1 (5)	−	80	H2O	10	60
2	Fe3O4·PMO1 (10)	−	80	H2O	10	71
3	Fe3O4·PMO1 (15)	−	80	H2O	10	88
4	Fe3O4·PMO1 (20)	−	80	H2O	10	95
5	Fe3O4·PMO1 (25)	−	80	H2O	10	95
6	Fe3O4·PMO1 (20)	−	60	H2O	10	85
7	Fe3O4·PMO1 (20)	−	70	H2O	10	89
8	Fe3O4·PMO1 (20)	−	90	H2O	10	94
9	Fe3O4·PMO1 (20)	−	80	EtOH	10	90
10	Fe3O4·PMO1 (20)	−	80	DMF	10	79
11	Fe3O4·PMO1 (20)	−	80	1,4-Dioxane	20	66
12	Fe3O4·PMO1 (20)	−	80	Dichloroethane	30	56
13	Fe3O4·PMO1 (20)	−	80	Toluene	30	71
14	Fe3O4·PMO1 (20)	−	80	CH3CN	10	86
15	Fe3O4·PMO1 (20)	HCl (0.1 mL)	80	H2O	10	90
16	Fe3O4·PMO1 (20)	NaOH (0.1 mL)	80	H2O	10	95
17	Fe3O4·PMO1 (20)	NaCl (0.1 mL)	80	H2O	10	95
18	−	−	80	H2O	360	20

a

Reaction conditions: benzaldehyde (1 mmol), 6-aminouracil (1 mmol), and malononitrile (1 mmol).

b

Isolated yields.

The effect of various catalysts was also screened on the model reaction. Nano Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ afforded the appropriate reaction time and high yield (Table 2).

Table 2.

Comparison of Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ nanoparticles for the synthesis of pyrido[2,3-d]pyrimidine 4aa with previously reported procedures.

Entry	Catalyst (mol%)	Temp (°C)	Solvent	Time (min)	Yield b (%)	Ref.
1	Nano-MgO (25)	80	H2O	18	95	12
2	ZrO2 NPs (10)	60	−	120	89	13
3	Triethanolamine (TEOA) (20)	80	H2O	150	87	9
4	Al-HMS-20 (25)	r.t.	EtOH	720	91	8
5	SBA-Pr-SO3H (30)	60	−	5	82	7
6	Fe3O4·PMO1 (20 mg)	80	H2O	10	95	This work

a

Reaction conditions: benzaldehyde (1 mmol), 6-aminouracil (1 mmol), and malononitrile (1 mmol).

b

Isolated yields.

Under optimized reaction conditions, several derivatives of pyrido[2,3-d]pyrimidine were synthesized using various aryl aldehydes (Table 3). This novel greener protocol furnished the desired products in lower reaction time (10–15 min) and high to excellent yield (75%–95%). The results also revealed that aromatic aldehydes containing electron donating groups or electron withdrawing groups react well to give the corresponding products 4a–q in high yields under the present reaction conditions. All the new products were characterized by spectroscopic and elemental analyses and for the known compounds by comparison of their spectroscopic data and melting points with those of reported ones.

Table 3.

Synthesis of pyrido[2,3-d]pyrimidines using Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ nanoparticles ^a .

Entry	Substrate	Time (min)	Yield b (%)	M.p. (°C)
4a	C6H5	10	95	>300 (13)
4b	3-HOC6H4	10	78	>300 (13)
4c	4-HOC6H4	15	75	>300 (18)
4d	4-CF3C6H4	10	85	>300
4e	Furan-2-yl	10	81	>300 (8)
4f	3-O2NC6H4	10	88	>300 (7)
4g	4-O2NC6H4	10	90	>300 (13)
4h	4-MeC6H4	10	81	>300 (7)
4i	4-MeOC6H4	10	92	>300 (7)
4j	3,4-(MeO)2C6H3	15	89	>300 (21)
4k	2-ClC6H4	15	89	>300 (13)
4l	4-ClC6H4	10	85	>300 (7)
4m	3,4-Cl2C6H3	10	89	>300 (6)
4n	2,4-Cl2C6H3	10	94	>300 (7)
4o	2-BrC6H4	10	86	>300 (21)
4p	4-BrC6H4	10	89	>300 (21)
4q	4-FC6H4	10	93	>300 (7)

a

Reaction conditions: aryl aldehyde (1 mmol), 6-aminouracil (1 mmol), malononitrile (1 mmol), and nanocatalyst (20 mg) at 80 °C.

b

Isolated yields.

A plausible mechanism for the formation of pyrido[2,3-d]pyrimidine catalyzed by Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ is shown in Scheme 1. It is believed that the reaction may proceed initially through the Knoevenagel condensation between arylaldehyde and malononitrile to form intermediate I. Then, Michael addition of 6-aminouracils to intermediate I affords II. Intermediate II converts to III after tautomerization. Then, intermediate III gives IV via cyclization.

Scheme 1.

A plausible mechanism for the formation of pyrido[2,3-d]pyrimidine catalyzed by Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀.

In the next step, intermediate IV converts to V after tautomerization. Finally, the desired product 4 is obtained by aromatization of V. The recyclability of Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ nanocatalyst was studied in the model reaction of benzaldehyde, 6-aminouracil, and malononitrile under optimized reaction conditions. The recovered catalyst washed with CH₂Cl₂, dried at room temperature, and reused for a similar reaction. The result showed that after 10 successive runs, catalytic activity of the catalyst was retained without ostensible loss of activity (led to 92.7% average yield).

Experimental

Material and methods

Chemical materials were purchased from Merck and Fluka and utilized without further purification. Melting points were measured on a Buchi B-545 apparatus in open capillary tubes. FT-IR spectra (KBr) were determined on α-Bruker spectrometer. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DRX (400 MHz for ¹H, 100 MHz for ¹³C) in DMSO-d₆ as solvent and TMS as an internal standard; δ was quoted in parts per million (ppm) and J in hertz (Hz). Elemental analyses used a Carlo-Erba EA1110CNNO-S analyzer and the results agreed with the calculated values. XRD was performed on a Philips Xpert XRD diffractometer (CuK, radiation, λ = 0.154056 nm). Scanning electron microphotographs (SEM) and EDX were done on a Zeiss DSM-960A SEM operated at an accelerating voltage of 20 kV. Magnetic properties of catalyst were obtained by vibrating sample magnetometer/Alternating Gradient Force Magnetometer LakeShore Cryotronics 7404. TEM images were recorded using Zeiss EM900.

Preparation of the nanocatalyst

Synthesis of the magnetic Fe₃O₄ nanoparticles

Fe₃O₄ nanoparticles were prepared by co-precipitation of FeCl₃·6H₂O and FeCl₂·4H₂O.^19,20 FeCl₃·6H₂O (540 mg) and FeCl₂·4H₂O (198 mg) were dissolved in 80 mL of distilled water and reacted with ultrasound at 70 °C. Then polyvinylpyrrolidone (PVP) (198 mg) was added slowly into the solution. With adding sodium hydroxide under continuous Ar atmosphere bubbling, pH was changed to 10. The black precipitate formed was isolated by external magnet, washed with distilled water and acetone, and dried at 50 °C for 24 h (Scheme 1).

Synthesis of the magnetic Fe₃O₄–ZnO–NH₂ nanoparticles

For synthesis of Fe₃O₄–ZnO at first, freshly prepared Fe₃O₄ nanoparticles (300 mg) were suspended in ethanol (95%) and sonicated. Then zinc acetate dihydrate (1.2 g) was added slowly into the solution and sonicated for 30 min at 65 °C. A solution of NaOH (25% M) (25 mL) and ethanol was added into the reaction mixture and sonicated for 4 h at 65 °C. The formed precipitate was isolated and washed with distilled water and ethanol.

In next step, for synthesis of Fe₃O₄–ZnO–NH₂ nanoparticle, Fe₃O₄–ZnO (200 mg) was suspended in dry ethanol and irradiated by ultrasound under continuous Ar atmosphere bubbling. 3-Aminopropyltrimethoxysilane (APTMS) (1 mL) was added and after 30 min, the mixture refluxed for 12 h. The precipitate was isolated, washed with distilled water, ethanol, and acetone, and dried at 50 °C for 12 h.

Synthesis of the magnetic Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ (Fe₃O₄·PMO1) nanoparticles

Fe₃O₄–ZnO–NH₂ (150 mg) was suspended in distilled water (20 mL) with ultrasound irradiation. H₃PW₁₂O₄₀ (350 mg) was added to the solution and the resulting suspension was mechanically stirred at room temperature for 12 h. Precipitate was isolated by external magnet, washed with distilled water and acetone, and dried at 50 °C for 12 h (Supporting Information).

General procedure for the synthesis of pyrido[2,3-d]pyrimidines

A mixture of aromatic aldehyde (1 mmol), 6-aminouracil (1 mmol), and malononitrile (1 mmol) in the presence of Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ nanoparticle (20 mg) was stirred in water (5 mL) at 80 °C for the appropriate time, as shown in Table 3. After completion of the reaction, which was monitored by TLC (EtOAc/n-Hexane/MeOH, 8:4:1), the catalyst was easily separated from the reaction mixture by an external magnet and washed with EtOH. The reaction mixture was diluted with water and the solid product obtained was filtered and purified by washing with EtOH and hot distilled water.

Spectral data of new product

7-Amino-2,4-dioxo-5-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (4d): M.p. >300 °C. FT-IR (KBr): 3110 (NH₂), 3015 (aromatic C–H), 2219 (C≡N), 1731 (C=O), 1662, 1595, 1444 (aromatic C=C), 1387, 1207 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ; 11.57 (s, 1H, NH), 11.02 (s, 1H, NH), 7.81 (d, 2H, J = 8.2 Hz), 7.77 (br s, 2H, NH₂), 7.52 (d, 2H, J = 8.2 Hz) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ; 161.2 (C=O), 160.6 (C=O), 157.8, 156.0, 150.7, 141.6, 129.1 (²J_C-F = 25.0 Hz), 129.0, 125.1 (³J_C-F = 4.0 Hz), 124.8 (¹J_C-F = 270.0 Hz), 115.7, 98.7, 88.7 ppm; Anal. calcd for C₁₅H₈F₃N₅O₂ (347.25): C, 51.88; H, 2.32; N, 20.17; found: C, 51.73; H, 2.21; N, 20.02%.

Conclusion

In conclusion, we have prepared Fe₃O₄–ZnO–NH₂–PW₁₂O₄₀ nanocatalyst as a highly active and stable catalyst and used it in three-component reaction of aromatic aldehydes, malononitrile, and 6-aminouracil in water to produce pyrido[2,3-d]pyrimidines in short reaction times and high to excellent yields. Reusability of the nanocatalyst, operational simplicity, using water as green media, mild reaction conditions, and cleaner reaction profiles, are the main advantages of this protocol.

Supplemental Material

supplementary_material – Supplemental material for An expeditious one-pot synthesis of pyrido[2,3-d]pyrimidines using Fe3O4–ZnO–NH2–PW12O40 nanocatalyst

Supplemental material, supplementary_material for An expeditious one-pot synthesis of pyrido[2,3-d]pyrimidines using Fe3O4–ZnO–NH2–PW12O40 nanocatalyst by Pegah Farokhian, Manouchehr Mamaghani, Nosrat Ollah Mahmoodi, Khalil Tabatabaeian and Abdollah Fallah Shojaie in Journal of Chemical Research