Synthesis, characterization, and application of Cu₂O and NiO nanoparticles supported on natural nanozeolite clinoptilolite as a heterogeneous catalyst for the synthesis of pyrano[3,2-b]pyrans and pyrano[3,2-c]pyridones

Abstract

In this research, Cu₂O and NiO nanoparticles supported on natural nanozeolite clinoptilolite (CP) was found to be a recoverable catalyst system for synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran derivatives in aqueous media. The nanocatalysts were characterized by various techniques such as XRD, BET, SEM, TEM, TEM-EDS, and XPS analyses. TEM study reveals that the Cu₂O and NiO nanoparticles have particle size less than 10 nm. XRD and XPS characterizations show the existence of forms of Cu₂O or NiO on the surface of natural nanozeolite CP. The easy recovery of the catalyst and high yield of the products make the protocol attractive and economic. Furthermore, the nanocatalysts could be recycled and reused several times without significant loss in their catalytic activities.

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1. Introduction

Zeolite clinoptilolite (CP) is a microporous aluminosilicate of tetrahedral [SiO₄]⁴⁻ and [AlO₄]⁴⁻ that link together to form a three-dimensional structure of well-defined pores and channels. There is a negative charge associated with each Al atom. The general formula for the composition of CP is M_x/n[(AlO₂)_x(SiO₂)_y]·mH₂O, where M represents cations of n valence that balance the negative charges on the framework. The aluminium in the zeolite framework has a substantial negative charge that is balanced by exchangeable cations such as Na⁺ or K⁺. These cations can be easily exchanged by simply stirring the zeolite in an aqueous solution containing the desired cation.

Because of its unique properties, CP can be employed as a catalyst for the synthesis of organic compounds.¹ Further investigation of the use of CP as a reliable catalyst is merited. We considered the applicability of this valuable multipurpose compound as a support of metal catalyst because of its high and adjustable acidity, well-defined pore structures with channels and cavities of molecular dimensions, and high ion exchange capabilities.²

Pyranopyridone derivatives have been found to possess a wide spectrum of biological actions such as antibacterial,³ antifungal and antialgal,⁴ anti-inflammatory,⁵ antileishmanial,⁶ platelet aggregation,⁷ and nitric oxide production.⁸ Furthermore, several alkaloids including pyranopyridones exhibit cancer cell growth inhibitory activity and are under investigation as anticancer agents.⁹ Pyranopyran derivatives also are an important class of structural pattern of many natural and synthetic compounds which have a high activity profile because of their wide range of biological activities such as anticancer,¹⁰ anti-tuberculosis,¹¹ anti-HIV,¹² calcium channel antagonist activity,¹³ antifungal,¹⁴ antimicrobial,¹⁵ antiproliferative,¹⁶ antidiabetic,¹⁷ anti-inflammatory, and antiviral.¹⁸ Pyranopyranones are also known for their biological properties including antioxidant and cytotoxic activities.¹⁹ Therefore, synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran skeletons are of enormous importance in organic synthesis.

In recent years, efficient methods have been developed for synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran derivatives with the aim of preparing a new series of fused heterocyclic systems exhibiting high levels of biologically activity using a range of different catalysts.^3–18,20 Although these methods are effective, most still have some drawbacks resulting in significant limits in their synthetic applications, for example synthesis is laborious, time-consuming, requires high reaction temperatures, use of toxic solvents and has only moderate yields. Thus, development of a simple, eco-benign, low cost protocol, using a neutral and reusable catalyst for one-pot synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran derivatives, remains an attractive goal for researchers. In this work, in continuation of our investigations into the development of new catalysts,²¹ we describe synthesis, characterization, and application of Cu₂O and NiO nanoparticles supported on nanozeolite CP as a heterogeneous catalyst in the synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran derivatives in aqueous media.

2. Results and discussion

The nanozeolite CP was prepared according to a simple method developed recently by our group.^21a Initially the nanozeolite clinoptilolite was converted to the homoionic Na⁺-exchanged form by stirring in 2 M NaCl solution, then activated with 4 M sulfuric acid. The activated nanozeolite CP was designated as AT-nano CP. This was put in a round bottom flask and an aqueous solution of MCl₂ (M = Cu and Ni) was added under vigorous stirring condition to afford Cu and Ni exchanged AT-nano CP. The M-containing products were separated out by heating under air to give Cu₂O and NiO nanoparticles in pores of AT-nano CP. The nano catalysts were characterized by XRD, BET, SEM, TEM, TEM-EDS, and XPS.

The XRD pattern of AT-nano CP (Fig. 1a) shows peaks at 2θ = 22.0°, 27.96° and 35.92°, which agree with the natural zeolite of clinoptilolite (JCPDS 00-025-1349). This, surface modification of AT-nano CP does not cause phase change. X-ray diffraction of nano Cu₂O–CP (Fig. 1b) shows the above peaks together with obvious diffusion peaks at 42.4°, 62.5°, and 73.6°, which could correspond to the (200), (220), and (311) planes of Cu₂O crystal with a cubic phase (JCDS 78-2076). The pattern of nano NiO–CP (Fig. 1c) also includes two characteristic diffraction peaks at 45.4° and 63.5°, which correspond to the (200) and (220) planes of NiO crystal with a cubic phase (JCPDS, no. 71-1179). These new peaks, observed in the XRD patterns of nano Cu₂O–CP and nano NiO–CP may be caused by encapsulation of nano Cu₂O or NiO in the cavity of nanozeolite CP. Further, little change occurred in the relative peak intensities of nanozeolite upon introducing nano Cu₂O–CP or nano NiO–CP. These observations indicate that the crystallinity of the nanozeolite has not undergone any significant change during the process of encapsulation. The average crystallite size for nano Cu₂O and nano NiO was calculated based on the strongest intensity of (220) peak using Debye–Scherrer's formula D = 0.89λ/(β cos θ); where D is the grain size, β is the angular line width of half-maximum intensity in radians, θ is Bragg diffraction angle, and λ is the X-ray wavelength used. The average size was found to be below 10 nm.

Fig. 1 XRD patterns of (a) AT-nano CP, (b) nano Cu₂O–CP and (c) nano NiO–CP.

The N₂ adsorption–desorption isotherms for nano CP, AT-nano CP, nano Cu₂O–CP, and nano NiO–CP were measured and the specific surface area (S), the total pore and micropore volumes (V_tot and V_mic), the specific surface area (S_BET), and the average pore diameter (D) were calculated using the Brunauer–Emmett–Teller (BET) method (ESI†). Using the Barrett–Joyner–Halenda (BJH) method, the mesopore surface area S_BJH and the mesopore volume V_BJH were calculated for nano CP, AT-nano CP, nano Cu₂O–CP and nano NiO–CP, and these are summarized in Table 1. According to the Brunauer, Deming, Derning, and Teller (BDDT) classification, these are characteristic of mesoporous solids.²² All the materials displayed typical type IV with an H₃ hysteresis loop at P/P_o ∼ 0.984. The nano CP with average pore diameters ∼12.20 nm contained a specific surface area of 49.7 m² g⁻¹ and a specific pore volume of 0.15 cm³ g⁻¹. Increase in the specific surface area from 49.7 m² g⁻¹ to 55.6 m² g⁻¹ and a slight decrease in the specific pore volume from 0.15 cm³ g⁻¹ to 0.11 cm³ g⁻¹ observed after the activation of nano CP might be caused by leaching of Al from sites of the zeolite matrix and decationation during acid activation. The BJH curves of nitrogen desorption display descent distribution of pore volume in the mesoporous section (1–100 nm). The pore diameter decreased from 1.64 nm to 1.21 nm and the pore volume from 0.15 cm³ g⁻¹ to 0.1 cm³ g⁻¹ after activation of nano CP. According to the analysis of the data listed in Table 1, the specific surface area and pore volume decreased after encapsulation of nano Cu₂O or NiO in the cavity of AT-nano CP, which could be caused by clogging of some pores by nano Cu₂O or NiO. As no sudden change occurred in the specific pore volume and surface area of AT-nano CP on introducing nano Cu₂O–CP or nano NiO–CP, this further indicates that pores of AT-nano CP are not clogged by nano Cu₂O–CP or nano NiO–CP larger than the pore size of AT-nano CP. Accordingly, from the obtained results one could conclude that nano Cu₂O–CP or nano NiO–CP were grafted on the pores of AT-nano CP.

Table 1 Surface properties of different nanozeolite based support/catalysts

Sample	Specific surface area [m^2 g^−1]		Pore volume [cm^3 g^−1]		Pore diameter [nm]
	SBET	SBJH	Vtot (BET)	V (BJH)	Dav	D (BJH)
Nano CP	49.70	45.68	0.15	0.15	12.19	1.64
AT-nano CP	55.63	39.52	0.11	0.1	8.05	1.21
Nano Cu2O–CP	47.4	38.41	0.09	0.11	10.07	1.63
Nano NiO–CP	49.1	35.47	0.08	0.12	8.88	1.26

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Structural and morphological characterization of nano CP, AT-nano CP, nano Cu₂O–CP, and nano NiO–CP were performed using SEM (Fig. 2). Comparison of the SEM images of nano CP (Fig. 2a), AT-nano CP (Fig. 2b), nano Cu₂O–CP (Fig. 2c), and nano NiO–CP (Fig. 2d) shows that the morphological features are not changed significantly, for example the spherical or ellipsoidal shape and non-aggregation characteristics. SEM images of nano Cu₂O–CP and nano NiO–CP showed that the average particle size was in the range of 35–85 nm.

Fig. 2 SEM images of (a) nano CP, (b) AT-nano CP, (c) nano Cu₂O–CP, and (d) nano NiO–CP.

The morphology and size of nano Cu₂O–CP (Fig. 3a) and nano NiO–CP (Fig. 3b) were investigated by transmission electron microscopy (TEM). The pictures show that the average particle size of Cu₂O and NiO is below 10 nm. As shown in Fig. 3a and b, the anchored crystal Cu₂O and NiO nanoparticles distributed evenly on the nanozeolite CP without obvious aggregations and particles can deposit on the pores of these nanozeolite. The results from the TEM studies are, in general, in agreement with the results obtained from X-ray diffraction measurements. The Cu₂O and NiO nanoparticle deposition on the AT-nano CP was further confirmed by energy-dispersive X-ray spectroscopy on a TEM (TEM-EDS). The results reveal the presence of C, O, Al, Si, and Cu in nano Cu₂O–CP (Fig. 3c), and C, O, Al, Si, and Ni in nano NiO–CP (Fig. 3d).

Fig. 3 TEM images of (a) nano Cu₂O–CP and (b) nano NiO–CP. TEM-EDS data of (c) nano Cu₂O–CP and (d) nano NiO–CP.

The surface properties of nano Cu₂O–CP and nano NiO–CP were analyzed using XPS. Peaks were clearly observed at 931.9 and 952.3 eV, corresponding to Cu 2p_3/2 and Cu 2p_1/2 as shown in Fig. 4a. The Cu 2p_3/2 peak can be assigned to Cu₂O in accordance with existing data in the literature.²³ Fig. 4b shows the core level spectra for the Ni 2p peak over the binding energy ranges from 850 to 885 eV. The Ni 2p XPS spectrum shows two edges of Ni 2p_3/2 (from about 855 eV to 865 eV) and Ni 2p_1/2 (from about 868 eV to 885 eV), which confirm the presence of the corresponding elements for the NiO nano metal shell. The Ni 2p_1/2 (872.1 eV) and Ni 2p_3/2 (854.3 eV) peaks were assigned to the Ni(II) ions in NiO.²⁴ The splitting separation between these two main peaks, 17.8 eV, indicated the well-defined symmetry of the Ni(II) ion in oxide form.

Fig. 4 XPS spectrum of (a) Cu 2p spectral peaks of nano Cu₂O–CP and (b) Ni 2p spectral peaks of nano NiO–CP.

The nanocatalysts were then investigated as potential heterogeneous catalysts for synthesis of pyrano-[3,2-c]pyridones and of pyrano[3,2-b]pyrans derivatives via a three-component reaction.

To find the best reaction conditions for the synthesis of pyrano-[3,2-c]pyridones, reaction of 4-hydroxy-1,6-dimethylpyridin-2(1H)-one 1 (1 mmol) with benzaldehyde 2 (1 mmol) and malononitrile 3 (1 mmol) was chosen as a model reaction in water at room temperature (Scheme 1).

Scheme 1 The model reaction for the synthesis of pyrano-[3,2-c]pyridone 4a.

The reaction was carried out in the presence of nano Cu₂O–CP, nano NiO–CP, AT-nano CP, CuO and NiO nanoparticles, and the results are presented in Table 2. In the absence of catalyst, only a trace amount of the desired product was obtained, even after an increase in reaction time (Table 2, entry 1). The results show that all of the nanocatalysts could promote the reaction, but nano Cu₂O–CP catalyst is significantly more effective than the others in the synthesis of pyrano-[3,2-c]pyridone 4a, and provides better results with high yields.

Table 2 Optimization of reaction conditions for the synthesis^a of pyrano-[3,2-c]pyridone 4a

Entry	Solvent	Catalyst	Amount of the catalyst [g]	Yield^b [%]
a Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), 4-hydroxy-1,6-dimethylpyridin-2(1H)-one (1 mmol) and solvent (5 mL) after 1 h at room temperature.b Isolated yields.c After 2 h at room temperature.
1	H2O	—	—	Trace^c
2	H2O	Nano NiO	0.01	40
3	H2O	Nano Cu2O	0.01	55
4	H2O	AT-nano CP	0.01	70
5	H2O	Nano NiO–CP	0.004	50
6	H2O	Nano NiO–CP	0.008	65
7	H2O	Nano NiO–CP	0.01	80
8	H2O	Nano Cu2O–CP	0.004	65
9	H2O	Nano Cu2O–CP	0.008	88
10	H2O	Nano Cu2O–CP	0.01	92
11	H2O	Nano Cu2O–CP	0.02	92
12	EtOH	Nano Cu2O–CP	0.01	85
13	DMF	Nano Cu2O–CP	0.01	65
14	Toluene	Nano Cu2O–CP	0.01	45
15	CH2Cl2	Nano Cu2O–CP	0.01	50

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To optimize the reaction conditions, the catalytic efficiency was studied with various amounts of nano Cu₂O–CP in the model reaction (Table 2, entries 8–10). The results reveal that 0.01 g of nanocatalyst provided the highest purity of products (Table 2, entry 10). Beyond that, increasing amounts of the catalyst (0.02 gr) did not improve the yield or the reaction time (Table 2, entry 11). The model reaction was also performed in other solvents such as EtOH, DMF, toluene, and CH₂Cl₂ instead of H₂O (Table 2, entries 12–15). Changing the solvent showed no further increase in the yield under optimized conditions. Therefore, the best results were obtained from the reaction of the components in water (5 mL) in the presence of 0.01 g of nano Cu₂O–CP at room temperature, affording the pyrano-[3,2-c]pyridone 4a at a 92% yield (Table 2, entry 10).

The acid strength and acid distribution of AT-nano CP, nano Cu₂O–CP, and nano NiO–CP measured by an amine titration method (n-butylamine titration) using Hammett indicators are listed in Table 3. The limits of the H₀ of samples were recognized by observing the colour of the adsorbed form of the Hammett indicators. The total acid amounts for AT-nano CP, nano Cu₂O–CP, and nano NiO–CP obtained were 2.4, 2.9, and 2.7 mmol g⁻¹, respectively. Measurements of surface acidity using the amine titration method showed an increased number of Lewis acid sites in the presence of Cu₂O and NiO. These results could explain the better performance of nano Cu₂O–CP than other mesoporous materials in the synthesis of pyrano-[3,2-c]pyridone 4a (Table 2, entries 4–10). Higher activity of nano Cu₂O–CP compared with AT-nano CP and nano NiO–CP was explained by the presence of stronger acid sites connected to zeolite.

Table 3 Acid distribution of AT-nano CP, nano Cu₂O–CP, and nano NiO–CP catalysts

Catalyst	Acid amount (mmol g^−1)				Total
	H0 ≤ +2.8	H0 ≤ +3.3	H0 ≤ +4.8	H0 ≤ +6.8
AT-nano CP	0.9	0	0.7	0.8	2.4
Nano Cu2O–CP	0.9	0.2	0.9	0.9	2.9
Nano NiO–CP	0.9	0.1	0.8	0.9	2.7

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Encouraged by the remarkable results, and to show the generality and scope of this new protocol, a variety of pyrano-[3,2-c]pyridone derivatives were synthesized from the three-component reaction of pyridin-2-ones 1a or 1b (1 mmol), aromatic aldehydes 2 (1 mmol), and malononitrile 3 (1 mmol) in the presence of nano Cu₂O–CP (0.01 gr) in aqueous medium at room temperature. The results are summarized in Table 4. The substrates with electron-withdrawing groups gave better yields than those with electron-donating groups. To develop this reaction into a more general method, other pyridin-2-one substrates, 4-hydroxy-6-methylpyridin-2(1H)-one 1b were also used (Table 4). They all gave the corresponding products in good to excellent yields.

Table 4 Synthesis of pyrano[3,2-c]pyridones 4 and 5 catalyzed by nano Cu₂O–CP^a

a Reaction conditions: pyridin-2-ones 1a or b (1 mmol), aldehyde 2 (1 mmol), malononitrile 3 (1 mmol), nano Cu₂O–CP (0.01 gr) in 5 mL of water for 1 h at room temperature.

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To further explore the potential of this protocol, we also examined three-component reactions using another reactant, kojic acid 5, instead of pyridin-2-ones 1a and 1b, under similar reaction conditions (Table 5). A variety of substituted aromatic aldehydes were applied for synthesis of pyrano[3,2-b]pyran derivatives using nano Cu₂O–CP under the optimal reaction conditions, and the results are summarized in Table 5. All substituted benzaldehydes containing electron-donating or electron-withdrawing substituents in the aromatic ring were reacted with malononitrile to provide the corresponding products 6 in good to excellent yields under optimized reaction conditions.

Table 5 Synthesis of pyrano[3,2-b]pyrans 6 catalyzed by nano Cu₂O–CP^a

a Reaction conditions: kojic acid 5 (1 mmol), aromatic aldehydes 2 (1 mmol), malononitrile 3 (1 mmol), nano Cu₂O–CP (0.01 gr) in 5 mL of water for 1 h at room temperature.

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The recyclability of the catalyst was investigated also. The catalyst was recovered by filtration technique after each experiment and washed with hot distilled water (2 mL) and ethanol (2 mL) twice. The recovered catalyst was dried in an oven and reused successively several times (up to eight uses) without any significant loss of activity (Fig. 5). The strong interaction of Cu₂O nanoparticles with the zeolite surface could be the reason for the repetitive use of the catalyst in a greater number of catalytic runs with high efficiency.

Fig. 5 The reusability of nano Cu₂O–CP catalyst.

In the present study, a reproducible synthetic procedure has been developed to prepare Cu₂O and NiO nanoparticles in nanopores of modified nanozeolite clinoptilolite. The presence of nano NiO and Cu₂O in the nanozeolite has a significant influence on the acidity of the clinoptilolite skeleton, leading to an increase in the number of Lewis acid sites. Our results show that nano Cu₂O–CP has potential for use as a catalyst in synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran derivatives, with good to excellent yields. This nanocatalyst is thermally stable, inexpensive, and easy to prepare. In addition, it can be separated from the reaction mixture easily and reused several times without any significant loss in activity.

3. Experimental section

3.1. Materials

All reagents were prepared from analytical reagent grade chemicals unless specified otherwise and purchased from Merck Company. The raw zeolite material was an Iranian commercial clinoptilolite (Afrandtooska Company) obtained from deposits in the region of Semnan (ca. 1 $ per kg).

3.2. Instrumentation

X-ray powder diffraction (XRD) of the catalyst was carried out on a Philips PW 1830 X-ray diffractometer with Cu Kα source (λ = 1.5418 Å) in a range of Bragg's angle (10–90°) at room temperature. N₂ sorption measurement was performed using Belsorp mini II at 273 K. Prior to the measurements, all the samples were degassed at 393 K in a vacuum line overnight. The specific surface area and pore volume were calculated with the Brunauer–Emmett–Teller (BET) method, and the pore size distribution was calculated with desorption branch based on the Barrett–Joyneer–Halenda (BJH) model. Scanning electron microscope (SEM) pictures were taken using a KYKY-EM3200 microscope (acceleration voltage 26 kV). Transmission electron microscopy (TEM) experiments were conducted on a JEOL-2100 microscope operated at 150 KV. The TEM model samples were sonicated by mixing with 95% ethanol for 30 min, and subsequently dropped onto copper grids coated with carbon film, and dried thoroughly in an electronic drying cabinet at a temperature of 25 °C and relative humidity of 45%. The chemical composition and crystallinity analysis of the samples were characterized using an energy-dispersive X-ray spectrometer (EDS, INCA) operated at 150 KV. X-ray photoelectron spectra (XPS) were recorded on a BESTEC GmbH-8025 spectrometer using an Mg Kα (hν = 1253.6 eV) and Al Kα (hν = 1486.6 eV) X-ray source. ¹H, ¹³C NMR spectra were recorded on a Bruker DRX-400 Avance spectrometer.

3.3. Catalyst preparation

3.3.1. Preparation of AT-nano CP. The nanozeolite clinoptilolite was converted to the homoionic Na⁺-exchanged form by stirring in 2 mol L⁻¹ of NaCl solution for about 24 h at 25 °C, and then the Na⁺-nanozeolite clinoptilolite was filtrated and washed with distilled water (50 mL) two times. The Na⁺-nanozeolite was dried in an oven at 100 °C. The Na⁺-nanozeolite clinoptilolite (5 g) was put into a 250 mL round bottom flask and 100 mL 4 M sulfuric acid was added to it. The flask mixture was refluxed for 1 h. After cooling, the supernatant was discarded and the activated nanozeolite clinoptilolite was repeatedly washed with deionized water (250 mL) until the solution became neutral, then dried in an oven at 80 °C overnight to obtain the white solid product. The activated nanozeolite clinoptilolite was designated as AT-nano CP.

3.3.2. Preparation of Cu and Ni oxide nanoparticles on the surface of AT-nano CP. One gram of AT-nano CP was put into a 100 mL round bottom flask and 100 cm³ of 25 mmol L⁻¹ MCl₂ (M = Cu and Ni) was added slowly under vigorous stirring. The resulting mixture was stirred for 24 h at room temperature, and the M-containing product was then recovered by filtration. The suspension was filtered off, washed with water, and dried at 80 °C. Dehydration of the M-containing products was carried out by heating under air. The obtained Cu and Ni exchanged AT-nano CP were heated at a rate of 10 °C min⁻¹ to 550 °C, and then were isothermally heated for 60 min. The influence of Cu₂O and NiO loading on AT-nano CP was studied using the same experimental conditions. According to atomic absorption results of copper and nickel determination, their Cu₂O and NiO contents were 200 and 95 mg Cu₂O and NiO per gram of the catalyst, respectively.

3.3.3. General procedure for the synthesis of pyrano-[3,2-c]pyridone and pyrano[3,2-b]pyran derivatives. A mixture of 4-hydroxy-1,6-dimethylpyridin-2(1H)-one or 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one or 4-hydroxy-6-methylpyridin-2(1H)-one (1 mmol), aldehyde (1 mmol), malononitrile (1 mmol), and catalyst (0.01 g) in 5 mL of water was stirred at room temperature for 1 h (Table 3 and 4). After this time, the catalyst was removed by filtration, washed with ethanol (2 mL), dried in vacuum, and reused. The filtrate was evaporated under reduced pressure to give the desired product and recrystallized from hot ethanol to afford pure products. The products were characterized by ¹H and ¹³C NMR.

3.4. Spectral data of the synthesized compounds

3.4.1. 2-Amino-5,6-dihydro-6,7-dimethyl-5-oxo-4-phenyl-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4a). Mp 250–252 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.38 (s, 3H, CH₃), 3.35 (s, 3H, CH₃), 4.42 (s, 1H, CH), 6.12 (s, 1H, CH), 7.09 (s, 2H, NH₂), 7.15–7.21 (m, 3H, ArH), 7.27–7.30 (m, 2H, ArH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 21.6, 31.3, 37.5, 58.2, 98.2, 105.0, 120.1, 125.1, 128.2, 128.9, 146.3, 149.5, 155.2, 160.4, 162.7.

3.4.2. 2-Amino-4-(4-chlorophenyl)-5,6-dihydro-6,7-dimethyl-5-oxo-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4b). Mp 253–256 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.35 (s, 3H, CH₃), 3.31 (s, 3H, CH₃), 4.32 (s, 1H, CH), 6.02 (s, 1H, CH), 7.03 (s, 2H, NH₂), 7.14 (d, 2H, J = 8.3 Hz, ArH), 7.35 (d, 2H, J = 8.3 Hz, ArH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 21.1, 31.3, 37.4, 57.8, 98.2, 105.5, 120.4, 128.8, 129.5, 131.4, 144.3, 148.4, 155.1, 160.4, 161.4.

3.4.3. 2-Amino-4-(4-bromophenyl)-5,6-dihydro-6,7-dimethyl-5-oxo-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4c). Mp 256–257 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.33 (s, 3H, CH₃), 3.32 (s, 3H, CH₃), 4.35 (s, 1H, CH), 6.09 (s, 1H, CH), 7.09 (s, 2H, NH₂), 7.15 (d, 2H, J = 8.3 Hz, ArH), 7.49 (d, 2H, J = 8.3 Hz, ArH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 21.5, 30.9, 37.2, 57.4, 97.2, 105.3, 119.9, 120.1, 130.6, 132.4, 144.5, 148.4, 155.2, 159.6, 161.8.

3.4.4. 2-Amino-4-(4-methylphenyl)-5,6-dihydro-6,7-dimethyl-5-oxo-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4d). Mp 250–253 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.20 (s, 3H, CH₃), 2.35 (s, 3H, CH₃), 3.33 (s, 3H, CH₃), 4.34 (s, 1H, CH), 6.07 (s, 1H, CH), 6.98 (s, 2H, NH₂), 7.05 (d, 2H, J = 8.3 Hz, ArH), 7.12 (d, 2H, J = 8.3 Hz, ArH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 21.6, 22.2, 30.7, 37.1, 58.4, 97.3, 106.1, 120.5, 128.1, 129.3, 136.2, 142.3, 147.8, 156.0, 159.4, 161.2.

3.4.5. 2-Amino-5,6-dihydro-6,7-dimethyl-4-(4-nitrophenyl)-5-oxo-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4e). Mp 242–244 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.37 (s, 3H, CH₃), 3.35 (s, 3H, CH₃), 4.58 (s, 1H, CH), 6.12 (s, 1H, CH), 7.13 (br s, 2H, NH₂), 7.52 (d, 2H, J = 8.6 Hz, ArH), 8.20 (d, 2H, J = 8.6 Hz, ArH); ¹³C NMR (100 MHz, DMSO-d₆) δ: 21.2, 31.2, 37.5, 57.3, 97.6, 105.2, 120.6, 124.5, 130.2, 147.6, 149.2, 152.2, 156.3, 159.5, 161.7.

3.4.6. 2-Amino-6,7-dimethyl-5-oxo-4-(3,4,5-trimethoxyphenyl)-5,6-dihydro-4H-pyrano[3,2-c]pyridine-3-carbonitrile (4f). Mp 259–262 °C. ¹HNMR (400 MHz, DMSO-d₆) δ: 2.32 (s, 3H, CH₃), 3.36 (s, 3H), 3.62 (s, 3H, CH₃), 3.73 (s, 6H, 2CH₃), 4.45 (s, 1H, CH), 6.09 (s, 1H, CH), 6.75 (s, 2H, NH₂), 7.05 (s, 2H, ArH); 13C NMR (100 MHz, DMSO-d₆) δ: 21.2, 31.4, 37.5, 56.7, 58.6, 61.3, 97.1, 104.8, 106.5, 121.2, 138.3, 141.2, 148.6, 153.5, 155.8, 159.7, 161.6.

3.4.7. 2-Amino-5,6-dihydro-7-methyl-5-oxo-4-phenyl-4H-pyrano[3,2-c]pyridine-3-carbonitrile (5a). Mp 279–282 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.13 (s, 3H, CH₃), 4.29 (s, 1H, CH), 5.84 (s, 1H, CH), 7.03 (s, 2H, NH₂), 7.16–7.22 (m, 3H, ArH), 7.28–7.32 (m, 2H, ArH), 11.47 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 19.4, 37.5, 58.2, 96.3, 106.2, 121.4, 127.1, 127.7, 128.5, 145.4, 147.2, 157.4, 159.1, 161.9.

3.4.8. 2-Amino-4-(4-chlorophenyl)-5,6-dihydro-7-methyl-5-oxo-4H-pyrano[3,2-c]pyridine-3-carbonitrile (5b). Mp 245–247 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.16 (s, 3H, CH₃), 4.35 (s, 1H, CH), 5.87 (s, 1H, CH), 7.07 (s, 2H, NH₂), 7.18 (d, 2H, J = 8.3 Hz, ArH), 7.36 (d, 2H, J = 8.3 Hz, ArH), 11.47 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 18.7, 36.4, 56.4, 96.3, 106.7, 120.4, 129.2, 129.8, 131.7, 144.8, 147.5, 157.3, 159.5, 161.7.

3.4.9. 2-Amino-5,6-dihydro-4-(4-methoxyphenyl)-7-methyl-5-oxo-4H-pyrano[3,2-c]pyridine-3-carbonitrile (5c). Mp 224–225 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 2.10 (s, 3H, CH₃), 3.75 (s, 3H, CH₃), 4.35 (s, 1H, CH), 5.92 (s, 1H, CH), 6.98 (d, 2H, J = 8.1 Hz, ArH), 7.05 (s, 2H, NH₂), 7.12 (d, 2H, J = 8.1 Hz, ArH), 11.56 (s, 1H, NH). ¹³C NMR (100 MHz, DMSO-d₆) δ: 18.6, 35.8, 55.5, 58.7, 96.7, 106.9, 114.2, 120.7, 128.7, 137.2, 146.1, 156.8, 158.2, 159.4, 161.9.

3.4.10. 2-Amino-6-(hydroxymethyl)-8-oxo-4-phenyl-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6a). Mp 222–225 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 4.15 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.26 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 5.35 (t, 1H, J = 6.3 Hz, OH), 5.65 (s, 1H, CH_vinyl), 6.33 (s, 1H, CH_aiiph), 7.10 (s, 2H, NH₂), 7.27–7.52 (m, 5H, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 40.4, 55.8, 57.5, 111.5, 117.2, 119.2, 128.7, 131.0, 132.3, 135.2, 136.5, 148.1, 159.2, 169.4, 169.9, 195.4.

3.4.11. 2-Amino-4-(4-chlorophenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6b). Mp 195–197 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 4.12 (dd, 1H, J = 16.5 Hz, J = 6.3 Hz, CH_aliph), 4.22 (dd, 1H, J = 16.5 Hz, J = 6.3 Hz, CH_aliph), 4.65 (s, 1H, CH_vinyl), 5.55 (t, 1H, J = 6.3 Hz, OH), 6.32 (s, 1H, CH_aliph), 6.77 (s, 2H, NH₂), 7.20 (d, 2H, J = 8.3 Hz, CH_arom), 7.33 (d, 2H, J = 8.3 Hz, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆): δ = 40.5, 55.9, 59.7, 111.5, 119.2, 129.1, 129.5, 134.1, 136.8, 139.2, 148.5, 159.9, 169.3, 170.4.

3.4.12. 2-Amino-4-(2-chlorophenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6c). Mp 212–215 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 4.18 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.54 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 5.21 (t, 1H, J = 6.3 Hz, OH), 5.77 (s, 1H, CH_vinyl), 6.39 (s, 1H, CH_aliph), 7.09 (s, 2H, NH₂), 7.25–7.59 (m, 4H, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 40.1, 54.7, 59.5, 111.5, 118.9, 128.3, 129.8, 130.5, 131.2, 131.9, 136.7, 137.5, 148.3, 159.6, 167.8, 169.2, 196.1.

3.4.13. 2-Amino-4-(2,4-dichlorophenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6d). Mp 240–241 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 4.13 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.32 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 5.52 (t, 1H, J = 6.3 Hz, OH), 5.89 (s, 1H, CH_vinyl), 6.45 (s, 1H, CH_aliph), 7.49 (s, 2H, NH₂), 7.50 (d, 1H, J = 8.3 Hz, CH_arom), 7.92 (d, 1H, J = 2.5 Hz, CH_arom), 7.95 (dd, 1H, J = 8.3, J = 2.5 Hz, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 39.7, 55.3, 59.4, 117.5, 119.1, 128.4, 129.4, 129.7, 130.6, 131.9, 136.5, 138.2, 149.1, 159.9, 169.1, 170.2, 192.3.

3.4.14. 2-Amino-4-(3-bromophenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6e). Mp 244–245 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 4.18 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.35 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 5.78 (t, 1H, J = 6.3 Hz, OH), 5.84 (s, 1H, CH_vinyl), 6.73 (s, 1H, CH_aliph), 7.24 (s, 2H, NH₂), 7.48–7.83 (m, 4H, CH_arom); ¹³CNMR(100 MHz, DMSO-d₆) δ = 38.9, 55.1, 59.5, 112.9, 119.5, 123.1, 127.1, 131.5, 130.7, 135.6, 137.1, 143.3, 145.4, 159.5, 168.3, 169.6, 195.2.

3.4.15. 2-Amino-4-(4-fluorophenyl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6f). Mp 249–252 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 4.19 (dd, 1H, J = 16.3, J = 6.0 Hz, CH_aliph), 4.33 (dd, 1H, J = 16.3, J = 6.0 Hz, CH_aliph), 4.78 (t, 1H, J = 6.0 Hz, OH), 5.69 (s, 1H, CH_vinyl), 6.44 (s, 1H, CH_aliph), 7.20–7.27 (m, 2H, CH_arom), 7.30 (s, 2H, NH₂), 7.35–7.46 (m, 2H, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 39.5, 56.5, 59.4, 112.4, 116.5 (d, J = 25.0 Hz, C–F), 119.7, 129.5 (d, J = 9.8 Hz, C–F), 136.5, 137.5 (d, J = 3.8 Hz, C–F), 149.1, 160.2, 162.4 (d, J = 295.2 Hz, C–F), 168.5, 169.7, 198.6.

3.4.16. 2-Amino-6-(hydroxymethyl)-8-oxo-4-m-tolyl-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6g). Mp 221–222 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 2.38 (s, 3H, CH₃), 4.28 (dd, 1H, J = 16.2, J = 6.2 Hz, CH_aliph), 4.26 (dd, 1H, J = 16.2, J = 6.2 Hz, CH_aliph), 4.81 (t, 1H, J = 6.2 Hz, OH), 5.72 (s, 1H, CH_vinyl), 6.38 (s, 1H, CH_aliph), 6.79 (d, 1H, J = 8.0 Hz, CH_arom), 7.18 (d, 1H, J = 8.0 Hz, CH_arom), 7.12 (s, 2H, NH₂), 7.32 (t, 1H, J = 8.0 Hz, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 32.9, 55.5, 59.2, 111.4, 119.6, 125.1, 128.1, 128.8, 137.3, 138.3, 141.1, 149.4, 159.2, 167.4, 169.5, 195.6.

3.4.17. 2-Amino-4-(furan-2-yl)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6h). Mp 223–225 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 4.18 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.27 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.72 (t, 1H, J = 6.3 Hz, OH), 5.24 (s, 1H, CH_vinyl), 6.47 (s, 1H, CH_aliph), 7.21 (s, 2H, NH₂), 7.47 (d, 2H, J = 4.8 Hz, CH_arom), 7.56–7.67 (m, 2H, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 34.5, 55.6, 59.3, 107.6, 110.7, 112.1, 112.9, 118.5, 142.1, 142.8, 153.4, 159.5, 169.1, 197.2.

3.4.18. 2-Amino-6-(hydroxymethyl)-8-oxo-4-(thiophen-2-yl)-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile (6i). Mp 233–236 °C. ¹H NMR (400 MHz, DMSO-d₆) δ = 4.22 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 4.32 (dd, 1H, J = 16.5, J = 6.3 Hz, CH_aliph), 5.14 (t, 1H, J = 6.2 Hz, OH), 5.31 (s, 1H, CH_vinyl), 6.37 (s, 1H, CH_aliph), 7.02 (s, 2H, NH₂), 7.44 (d, 2H, J = 5.4, CH_arom), 7.52–7.69 (m, 2H, CH_arom); ¹³C NMR (100 MHz, DMSO-d₆) δ = 37.1, 57.3, 59.3, 111.7, 112.7, 119.7, 124.6, 125.4, 128.3, 140.2, 143.2, 164.1, 169.3, 196.4.

Acknowledgements

This research is supported by the Iran National Science Foundation (INSF) (INSF 92013217) and the Islamic Azad University, Ayatollah Amoli Branch, Iran.

References and notes

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra10537k

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