(CTA)₃[SiW₁₂]–Li⁺–MMT: a novel, efficient and simple nanocatalyst for facile and one-pot access to diverse and densely functionalized 2-amino-4H-chromene derivatives via an eco-friendly multicomponent reaction in water

Abstract

A simple, facile and highly efficient one-pot synthesis of a pharmaceutically interesting diverse kind of functionalized 2-amino-4H-chromene by a straightforward three-component reaction of an aromatic aldehyde, malononitrile (or ethyl cyanoacetate) and diverse enolizable C–H activated acidic compounds in the presence of a catalytic amount of (CTA)₃[SiW₁₂]–Li⁺–MMT is reported as a novel, environmentally friendly, reusable and promising nanocatalyst reaction in refluxing water. Based on the procedure, it was feasible to synthesize 2-amino-3-cyano-pyrano[3,2-c]chromen-5(4H)-one (4a–4y), 2-amino-3-cyano-pyrano[3,2-c]quinolin-5(4H)-one (6a–6s), 2-amino-3-cyano-7,8-dihydro-4H-chromen-5(6H)-one (8a–8u), 2-amino-3-cyano-pyrano[4,3-b]pyran-5(4H)-one (12a–12f), 2-amino-3-cyano-pyrano[3,2-c]pyridine-6(5H)-one (13a–13f), and 1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-dione (14a–14f). The structure of the nanocatalyst was confirmed by various techniques such as IR, SEM, TGA-DTG, EDX, ICP and XRD analyses. In comparison to the conventional methods, the salient features of the present protocol are green reaction conditions, high quantitative yields, short reaction time, high atom economy, low cost, easy isolation of products, and no column chromatographic separation.

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Introduction

The usage of heterogeneous catalysts in organic synthesis is an interesting method to access green catalysis, which is compatible with the environment and is of high interest in different processes of chemical transformations which occur by catalysis in heterogeneous conditions.¹ In recent years, the synthesis of catalysts based on heteropolyacids and related compounds, due to reasons such as the lack of need for separation through distillation or extraction, has attracted high attention in the synthetic chemistry, technology and pharmaceutical industry fields² and only partial changes in their selectivity and activity provide the possibility of their reuse.³ Heteropolyacids have attracted high attention due to their unique Keggin structures, strong acidity and solubility in non-polar solutions.⁴ This class of compounds as excellent and versatile catalysts, due to some interesting features including non-corrosiveness, flexible acidic strength, high reductivity, high hydrolytic and thermal stability, and also low toxicity, can be utilized to catalyze a wide range of homogeneous and heterogeneous catalytic processes.⁵ Nevertheless, drawbacks such as the problem of separation from the reaction mixture and a low surface area (1–10 m² g⁻¹) have been encountered with the above-mentioned advantages as difficulties.⁶ It seems that the heterogenization of heteropolyacids in an insoluble organic and separable matrix with a wide surface extent such as zeolite and clay or by formation of micro- and mesoporous salts of cesium or potassium (Cs_2.5H_0.5PW or K_2.5H_0.5PW) makes the increase of access to acid sites and control of the acidic strength of the solid possible.⁷ Montmorillonite (MMT) is one of the most applicable compounds of layered silicate, and its usage has attracted high attention due to its large specific surface area, high modulus, layered structure, high cation exchange capacity, and chemical and mechanical stability, as well as it having natural resources.⁸ The building blocks of montmorillonite layers consist of an aluminum octahedral layer [Al(OH₆)⁻³] sandwiched between two tetrahedral silicon–oxygen (Si₂O₅⁻²) layers.⁹ According to the ion exchange property of montmorillonite, the ions of Mg²⁺ and Fe²⁺ can be replaced with Al³⁺. Due to these substitutions, a negative electric charge appears in the lattice, and the unit of positive electrical charge as an alkali cation or earth alkaline such as Na⁺, K⁺, Ca⁺ and Mg²⁺ can replace itself in the space between layers and the bond in the three-unit layers of montmorillonite are established by these cations.¹⁰ Montmorillonite layers with a thickness of approximately 1 nm and lateral dimensions of 30 nm up to several micrometers are known as nanoporous with a regular structure.¹¹ The common phenomenon of the broken bonds of layered silicate causes the formation of hydroxyl groups that can be used for chemical modifications.¹² It should be noted that the distribution property of MMT in water increases its basic distance and this swell can be attributed to the cation collection in its interlayers. Although clay soil benefits from a high adsorption capacity, the modification of its structure increases the efficacy of these compounds so that they can react with reactants better.¹³

4H-Pyrans and 4H-pyran-annulated heterocyclic scaffolds, namely, 4H-chromene moieties, are the key building block of numerous oxygen-containing heterocyclic natural compounds possessing distinct properties of general interest. This structural motif is broadly represented by several types of alkaloids manifesting diverse biological and pharmacological activities including anti-tumor,¹⁴ anti-HIV,¹⁵ anti-inflammatory,¹⁶ antimicrobial and antifungal,¹⁷ and anti-allergenic¹⁸ ones, along with anti-neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s Diseases (HD) and a few others.¹⁹ Furthermore, many of these functionalized 4H-pyran derivatives demonstrate cancer cell growth inhibitory activity and are surveyed as potential anti-cancer agents.²⁰ Moreover, it was found that natural products containing the chromene moiety can play an important role in synthetic approaches to promising compounds in the fields of biodegradable agrochemicals,²¹ medicine,²² and the pigments and cosmetics industries.²³ These valued features have inspired chemists to simulate such natural designs in developing derived analogues of alkaloids, for instance, arisugacin,²⁴ amarogentin,²⁵ (+)-calanolide A,²⁶ huajiaosimuline and veprisine,²⁷ which all contain the key pyran-annulated pharmacophoric motif (Scheme 1).

Scheme 1 Examples of bioactive compounds bearing pyran-annulated scaffolds.

Experimental

General

All chemical materials were purchased from Fluka and Merck companies and used without further purification. The purity determination of the product and reaction monitoring were accomplished by TLC on silica gel PolyGram SILG/UV 254 plates. The melting points were determined using an Electrothermal 9100 apparatus and are uncorrected. The IR spectra were recorded as KBr pellets on a PerkinElmer PXI instrument. The NMR spectra were obtained using a BRUKER DRX-300 AVANCE spectrometer at room temperature in DMSO using TMS as an internal standard. Inductively coupled plasma atomic emission spectrometry (ICP-AES) measurements were performed on a VARIAN VISTA-MPX. Thermogravimetric analysis (TGA) was conducted using a Linseis SAT-PT 1000 thermoanalyzer instrument. Samples were heated from 25 to 650 °C at a ramp rate of 10 °C min⁻¹ under N₂ atmosphere. Scanning election microscopy (SEM) was carried out on a SEM-LEO 1430VP. The low and broad angle X-ray diffraction (XRD) measurements were accomplished in the 2θ range of 3–80° at room temperature on a Siemens D-500 X-ray diffractometer (Germany), using Ni-filtered Co Kα radiation. Elemental analyses were conducted on a Carlo-Erba EA1110CNNO-S analyzer and agreed (within 0.30) with the calculated values.

Catalyst synthesis

Preparation of Li⁺–MMT. The ion-exchanged Li⁺–MMT clays were prepared via cation exchange between natural montmorillonite (Cloisite®Na⁺, Southern Clay Products) and lithium chloride. Cloisite®Na⁺ slowly dispersed into LiCl solution with vigorous stirring. The suspension was stirred with a magnetic stirrer for 48 hours at 40 °C to replace the sodium completely by lithium cations and then centrifuged at 5000 rpm to separate the Li⁺–MMT clay from the supernatant containing the excess ions. The mixture was washed with deionized water until the chloride ions were completely removed as indicated by the AgNO₃ test. The modified samples were dried in a vacuum oven at 60 °C for 24 hours and were ground. The analysis of atomic absorption for this solid metal has shown that it has 0.05 mol% concentration of dissolved Li⁺ ions.

Preparation of CTA–Li⁺–MMT. In a 250 mL round bottom flask, 4.50 g Li⁺–montmorillonite was taken in 50 mL of distilled water and magnetically stirred until a uniform dispersion was formed. 2.90 g hexadecyltrimethylazanium bromide (CTAB) was then dissolved in 20 mL distilled water and the two solutions were mixed together. After completion of the addition, the reaction mixture was stirred for 1 day. The resultant solid sample was collected by centrifugation and washed several times with deionized water to remove the free CTAB until no bromide ions were detected with a 0.1 mol L⁻¹ aqueous AgNO₃ solution. Finally, the material was kept at 100 °C for 2 days to obtain CTA–Li⁺–MMT as a white powder.

Preparation of (CTA)₃[SiW₁₂]–Li⁺–MMT. 1.40 g of H₄SiW₁₂O₄₀ (HPA) was dissolved in 20 mL methanol and added drop-wise to a 50 mL aqueous suspension of 4.70 g of CTA–Li⁺–MMT. Then, the reaction mixture was stirred at ambient temperature for 1 day. The heterogeneous catalyst was filtered off and washed with deionized water several times and thereafter it was dried in an oven at 120 °C for 7 hours to obtain (CTA)₃[SiW₁₂]–Li⁺–MMT.

General procedure for the preparation of 2-amino-4H-chromene derivatives (4, 6, 8, 12–14). In an oven-dried screw cap test tube equipped with a magnetic stir bar, enolizable compound (1, 5, 7, 9–11, 1 mmol), aldehyde (2, 1 mmol), malononitrile (or ethyl cyanoacetate) (3, 1.1 mmol) and (CTA)₃[SiW₁₂]–Li⁺–MMT (10 mg) were combined with each other in water (5 mL) and the mixture was refluxed at 100 °C. The progress of the reaction was monitored using silica gel coated on aluminum sheets and ethyl acetate–petroleum ether as eluent. After completion of the reaction, the reaction mixture was filtered off and the catalyst was washed twice with CH₂Cl₂ (8 mL). With the evaporation of the solvent under reduced pressure pure product was almost obtained.

Spectral data of the new products

2-Amino-5-oxo-4-(naphthalen-1-yl)-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (Table 2, 4t). Yellow powder (92%); m.p. > 300 °C; IR (KBr) ν_max (cm⁻¹): 1384, 1365 (N–H bend), 1669 (C=O), 2195 (CN), 3163 (N–H amidic), 3390, 3454 (N–H amine); ¹H NMR (400.22 MHz, DMSO-d₆, ppm): δ 5.50 (s, 1H, CH), 7.17 (d, 1H, CH), 7.22 (s, 2H, NH₂), 7.34 (dt, 1H, CH), 7.37 (d, 1H, CH), 7.41 (t, 1H, CH), 7.55 (dt, 1H, CH), 7.37–7.57 (m, 2H), 7.80 (d, 1H, CH), 7.95 (dd, 1H, CH), 7.99 (d, 1H, CH), 8.49 (d, 1H, CH); ¹³C NMR (100.6 MHz, DMSO-d₆, ppm): 56.4, 59.9, 109.7, 112.5, 116.0, 1120.4, 122.3, 122.6, 124.5, 125.5, 126.1, 126.3, 126.4, 127.6, 129.0, 131.5, 131.8, 133.9, 138.9, 141.9, 152.1, 159.5, 161.0.

2-Amino-5-oxo-4-(thiophen-2-yl)-4,5-dihydropyrano[3,2-c]quinoline-3-carbonitrile (Table 3, 6r). White powder (93%); m.p.: 285–287 °C; IR (KBr) ν_max (cm⁻¹): 1389, 1367 (N–H bend), 1665 (C=O), 2198 (CN), 3174 (N–H amidic), 3325, 3462 (N–H amine); ¹H NMR (400.22 MHz, DMSO, ppm): δ 4.90 (s, 1H, CH), 6.94 (dd, 1H, CH), 7.30 (dt, 1H, CH), 7.34 (dd, 1H, CH), 7.36 (d, 1H, CH), 7.41 (s, 2H, NH₂), 7.57 (dt, 1H, CH), 7.59 (dt, 1H, CH), 7.89 (dd, 1H, CH), 7.90 (dd, 1H, CH), 11.90 (s, 1H, NH); ¹³C NMR (100.6 MHz, DMSO, ppm): δ 33.2, 58.1, 110.5, 112.8, 116.0, 120.1, 122.4, 122.6, 125.0, 125.3, 127.5, 132.0, 138.4, 149.4, 151.9, 160.3, 161.0.

Results and discussion

Catalyst characterization

ICP analysis of (CTA)₃[SiW₁₂]–Li⁺–MMT. Inductively coupled plasma atomic emission spectrometry (ICP-AES) was used to show insertion of H₄SiW₁₂O₄₀ (SiW₁₂) to CTA–Li⁺–MMT. The ICP analysis showed that about 0.09 mmol per gram of H₄SiW₁₂O₄₀ heteropolyacid is successfully encapsulated into the montmorillonite layers.

IR analysis of (CTA)₃[SiW₁₂]–Li⁺–MMT. The infrared spectra of the pure Na⁺–MMT, Li⁺–MMT and (CTA)₃[SiW₁₂]–Li⁺–MMT samples in the region of 400–4000 cm⁻¹ are presented in Fig. 1. In the spectrum of pure Na⁺–MMT, the observed peak at 3629 cm⁻¹ is related to the OH groups attached to the aluminum and/or magnesium while the peaks appearing in the 3439 and 1645 cm⁻¹ region can be respectively attributed to the stretching and bending vibrations of the water molecule OH bonds. The 1040 and 916 cm⁻¹ bands in this sample have been collectively assigned to the Si–O stretching vibrations. The presented spectrum of Li⁺–MMT is nearly identical with that of Na⁺–MMT, indicating that FTIR is not sensitive to the changes occurring in the system. In the case of (CTA)₃[SiW₁₂]–Li⁺–MMT, the absorption peaks at 2855 and 2927 cm⁻¹ have been assigned to the stretching vibration of the C–H bond. The presence of this bending vibrations band at 1400–1500 cm⁻¹ is associated to the CTA⁺ cation arrival to this material. The presence of Keggin-type HPW groups was confirmed by stretching vibrations appearing at approximately 925 cm⁻¹ (Si–O in central tetrahedra), 975 cm⁻¹ (terminal W=O), 896 cm⁻¹ (W–O–W in corner-shared octahedra) and 807 cm⁻¹ (W–O–W in edge-shared octahedra) in the FTIR spectrum. Therefore, despite these peaks, it can be concluded that [SiW₁₂] is surrounded within Li⁺–MMT.

Fig. 1 FTIR spectra of (CTA)₃[SiW₁₂]–Li⁺–MMT, Li⁺–MMT and Na⁺–MMT.

Thermal studies of (CTA)₃[SiW₁₂]–Li⁺–MMT. TGA and DTG analysis have been carried out to characterize the (CTA)₃[SiW₁₂]–Li⁺–MMT and Li⁺–MMT samples towards each other. The results of these analyses are provided in Fig. 2. The TGA curve of Li⁺–MMT demonstrates a weight loss of approximately 6% up to a temperature of 150 °C, which is concerned with the loss of trapped and interlayer moisture. In addition, there is a slight weight loss between 150 and 600 °C, probably corresponding to the breaking of structural OH groups of lithium montmorillonite. TGA of (CTA)₃[SiW₁₂]–Li⁺–MMT illustrates approximately 5% weight loss in the range from 350 to 400 °C due to the decomposition of the organic part of CTAB and degradation of the tungstophosphoric acid. Furthermore, a small weight loss of approximately 5% appears up to 650 °C, which is associated with the decomposition of the remaining organic compound and conversion of the silicotungstate anion to the tungsten and silicon oxides.²⁸

Fig. 2 TGA/DTG curves of (a) Li⁺–MMT and (b) (CTA)₃[SiW₁₂]–Li⁺–MMT.

SEM analysis of (CTA)₃[SiW₁₂]–Li⁺–MMT. The surface morphology, size distribution and particle shape of Li⁺–MMT and the (CTA)₃[SiW₁₂]–Li⁺–MMT nanocatalyst were investigated by SEM (scanning electron microscopy) as represented in Fig. 3. The SEM images for Li⁺–MMT and modified Li⁺–MMT clearly show variations in the surface of these nanoparticles. In the case of (CTA)₃[SiW₁₂]–Li⁺–MMT with disappearance of the lumpy shape of Li⁺–MMT, some layers were formed as a uniform and flaky structure, which could be attributed to the reduction of the hydrophilicity property and adherence among montmorillonite particles.

Fig. 3 SEM images of Li⁺–MMT (a) and (CTA)₃[SiW₁₂]–Li⁺–MMT (b).

EDX analysis of (CTA)₃[SiW₁₂]–Li⁺–MMT. EDX (energy dispersive X-ray) mapping was carried out to verify the composition of the Li⁺–MMT and (CTA)₃[SiW₁₂]–Li⁺–MMT nanocatalysts (Fig. 4a and b, respectively). The EDX analysis confirmed the existence of a number of tungsten peaks. Moreover, strong oxygen and silicon peaks in the nanocatalyst denoting tungstophosphoric acid are shown successfully in the mesoporous Li⁺–MMT.

Fig. 4 EDX spectra of (a) Li⁺–MMT and (b) (CTA)₃[SiW₁₂]–Li⁺–MMT.

XRD analysis of (CTA)₃[SiW₁₂]–Li⁺–MMT. Fig. 5a represents the XRD (X-ray diffraction) patterns of the used Li⁺–MMT and (CTA)₃[SiW₁₂]–Li⁺–MMT catalyst to illustrate the changes of distance between the montmorillonite layers (d₀₀₁). The calculated basal spacing for Li⁺–MMT appeared at 2θ = 8.9°, while in the pattern of (CTA)₃[SiW₁₂]–Li⁺–MMT, this peak has shifted to a lower value at 2θ = 6.1°. These observations suggest that CTAB as a long chain alkyl group and HPA as a bulky mineral group have been intercalated into the montmorillonite interlayer spaces. The presence of these groups in the montmorillonite layers increases the lipophilic character of this compound, which can lead to its performance improving in organic reactions. Also, Fig. 5b illustrates the XRD (X-ray diffraction) patterns of the used Li⁺–MMT and (CTA)₃[SiW₁₂]–Li⁺–MMT catalyst. As observed in the XRD patterns, a similar nature in the spectrum of the Li⁺–MMT and (CTA)₃[SiW₁₂]–Li⁺–MMT samples indicates the retention of the original crystalline structure and morphology of the montmorillonite nanoparticles.

Fig. 5 Low angle (a) and broad angle (b) XRD patterns of (CTA)₃[SiW₁₂]–Li⁺–MMT and Li⁺–MMT.

In continuation of our efforts to the synthesis of pyran-annulated compounds and in performing organic transformations with the aid of green synthetic methodologies,²⁹ we decided to investigate the synthesis of 2-amino-3-cyano-4H-pyrans with diverse substituents from the reaction of C–H-activated acid varieties, aldehyde and malononitrile (or ethyl cyanoacetate) in water reflux conditions using (CTA)₃[SiW₁₂]–Li⁺–MMT as a novel, eco-friendly, reusable and promising nanocatalyst (Scheme 2).

Scheme 2 One-pot three-component reaction of different C–H-activated acidic compounds, aldehydes and active methylene nitriles catalyzed by (CTA)₃[SiW₁₂]–Li⁺–MMT in water.

In order to screen the reaction conditions for the synthesis of 2-amino-4-(4-chlorophenyl)-3-cyano-pyrano[3,2-c]chromene-5(4H)-one (4c), a systematic study considering different variables affecting the reaction yield has been investigated in the reaction of 4-hydroxycoumarin (1), 4-chlorobenzaldehyde (2c) and malononitrile (3a) (molar ratio 1 : 1 : 1.1) as the model reaction (Scheme 2). The results are indicated in Table 1. The primary optimization experiments revealed that any formation of the desired product 4c was achieved under solvent-free conditions even at 100 °C (entries 1 and 2). However, the trial reaction in the presence of water as a solvent afforded the desired product 4c in a slightly higher yield compared to the solvent-free conditions (entries 3 and 4). As can be seen in entry 4, the use of reflux conditions improved the yield of the desired product. Unfortunately, the utilization of different solvents such as DMF, DMSO, CH₂Cl₂, CHCl₃ and toluene resulted in low product yields under reflux conditions (entries 5–9). It was found that H₂O is the best solvent for the chemical reaction under study. In the next phase of survey, the effect of catalyst loading on the completion of the reaction was evaluated (entries 12–14). After several screening experiments with different amounts of catalyst, it was found that the highest yield (97%) was obtained when a catalytic amount (10 mg) of (CTA)₃[SiW₁₂]–Li⁺–MMT was applied in H₂O under reflux conditions (entry 13). Decreasing the amount of catalyst (10 mg to 5 mg) resulted in a lower yield of the product, while increasing the amount of catalyst required for the reaction from 10 mg to 15 mg did not affect the duration of the reaction and the product yield (entries 12 and 14). In addition, to delineate the role of catalyst and temperature effect under solvent-free conditions, the reaction was investigated with and without heating with the same amount of catalyst (10 mg) (entries 10 and 11). It was observed that the use of heating leads to a faster reaction and a higher yield.

Table 1 Optimization of the three-component reaction of 4-hydroxycoumarin (1), 4-chlorobenzaldehyde (2c) and malononitrile (3a) conditions under various conditions^a

Entry	Catalyst	Catalyst loading (mg)	Solvent	Temperature (°C)	Time (min)	Yield^b
a Reaction conditions: 4-hydroxycoumarin (1 mmol), 4-chlorobenzaldehyde (1 mmol), malononitrile (1.1 mmol), water (5 mL) and the required amount of catalyst.b The yields refer to the isolated product.
1	—	—	—	r.t.	6	—
2	—	—	—	100	6	—
3	—	—	H2O	r.t.	6	15%
4	—	—	H2O	Reflux	6	33%
5	—	—	DMF	Reflux	6	18%
6	—	—	DMSO	Reflux	6	20%
7	—	—	CH2Cl2	Reflux	6	17%
8	—	—	CHCl3	Reflux	6	17%
9	—	—	Toluene	Reflux	6	21%
10	(CTA)3[SiW12]–Li^+–MMT	10	—	r.t.	6	49%
11	(CTA)3[SiW12]–Li^+–MMT	10	—	100	6	73%
12	(CTA)3[SiW12]–Li^+–MMT	5	H2O	Reflux	6	66%
13	(CTA)3[SiW12]–Li^+–MMT	10	H2O	Reflux	6	97%
14	(CTA)3[SiW12]–Li^+–MMT	15	H2O	Reflux	6	91%

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In order to generalize the optimum conditions, we extended the reaction of 4-hydroxycoumarin (1) with a range of appropriate aldehydes (2a–t), malononitrile (3a) or ethyl cyanoacetate (3b) under similar conditions (using H₂O/(CTA)₃[SiW₁₂]–Li⁺–MMT), furnishing the respective 2-amino-3-cyano-pyrano[3,2-c]chromen-5(4H)-one derivatives (4a–y) in high yields (Scheme 3). The optimized results are listed in Table 2. It was found that aromatic aldehydes with electron-donating groups (entries 7–15 and 25, Table 2) showed relatively low reactivity compared to the electron-withdrawing groups (entries 2–6 and 22–24). In addition to the aromatic aldehydes, the generality and substituent scope of this method were evaluated by employing several heterocyclic aldehydes, obtaining high to excellent yields (entries 16–19, Table 2). It is also remarkable that with malononitrile (3a) a slightly lower reaction time was required compared to ethyl cyanoacetate (3b) (entries 21–25, Table 2).

Scheme 3 One-pot three-component condensation of 4-hydroxycoumarin (1), various aldehydes (2) and malononitrile or ethyl cyanoacetate (3a–b).

Table 2 Synthesis of derivatives of 2-amino-3-cyano-pyrano[3,2-c]chromen-5(4H)-one (4) via condensation of 4-hydroxycoumarin (1), various aldehydes (2) and malononitrile or ethyl cyanoacetate (3a–b) in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT^a

Entry	RCHO (2)	Carbon acid (3) (X)	Product	Time (min)	Yield (%)^c	m.p. (obsd) (°C)^b	m.p. (lit) (°C)
a Reaction conditions: 4-hydroxycoumarin (1 mmol), aldehyde (1 mmol), malononitrile or ethyl cyanoacetate (1.1 mmol), water (5 mL, reflux), (CTA)3[SiW12]–Li^+–MMT (10 mg).b All compounds are known and their structures were determined from their spectral data and melting points as compared with literature values.c The yields refer to the isolated products.
4a		3a (CN)		9	95	257–259	256–258 (ref. 30a)
4b		3a (CN)		6	96	245–246	244–246 (ref. 30b)
4c		3a (CN)		6	97	265–267	263–265 (ref. 30l)
4d		3a (CN)		4	95	258–259	260–262 (ref. 30a)
4e		3a (CN)		8	92	259–261	260–262 (ref. 30c)
4f		3a (CN)		8	95	251–253	250–252 (ref. 30c)
4g		3a (CN)		10	89	258–260	260–262 (ref. 30a)
4h		3a (CN)		10	90	253–255	252–254 (ref. 30a)
4i		3a (CN)		15	96	235–237	236–238 (ref. 30h)
4j		3a (CN)		12	90	241–243	242–244 (ref. 30h)
4k		3a (CN)		12	91	220–222	221–223 (ref. 30b)
4l		3a (CN)		10	89	227–229	228–230 (ref. 30a)
4m		3a (CN)		12	96	254–256	253–254 (ref. 30j)
4n		3a (CN)		10	97	259–260	259–261 (ref. 30e)
4o		3a (CN)		15	87	264–266	265–267 (ref. 30a)
4p		3a (CN)		6	91	250–251	251–253 (ref. 30d)
4q		3a (CN)		6	90	255–256	256–258 (ref. 30m)
4r		3a (CN)		15	87	253–255	255–257 (ref. 30c)
4s		3a (CN)		15	89	239–241	238–240 (ref. 30k)
4t		3a (CN)		8	92	285–287	—
4u		3b (COOEt)		20	91	208–210	210–212 (ref. 30f)
4v		3b (COOEt)		15	89	210–212	209–212 (ref. 30g)
4w		3b (COOEt)		18	88	190–192	192–194 (ref. 30h)
4x		3b (COOEt)		10	90	233–235	232–234 (ref. 30i)
4y		3b (COOEt)		20	87	197–199	199–201 (ref. 30i)

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In the following conducted study, and in order to expand the use of this nanocatalyst to other reactions of these categories, a series of poly-functionalized 2-amino-3-cyano-pyrano[3,2-c]quinolin-5(4H)-one derivatives (6a–s) were prepared from an aqueous reaction mixture of 4-hydroxyquinolone (5), different aldehydes (2a–s) and malononitrile (3a) in the presence of a catalytic amount of (CTA)₃[SiW₁₂]–Li⁺–MMT (10 mg) under reflux conditions (Scheme 4). A similar trend of reactivity was obtained for different aldehydes when the reaction was repeated with 4-hydroxyquinolone (5) under the optimized conditions, which is shown in Table 3.

Scheme 4 One-pot three-component reaction of 4-hydroxyquinolone (5), different aldehydes (2) and malononitrile (3a).

Table 3 Synthesis of derivatives of 2-amino-3-cyano-pyrano[3,2-c]quinolin-5(4H)-one (6) via condensation of 4-hydroxycoumarin (5), various aldehydes (2) and malononitrile (3a) in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT^a

Entry	RCHO (2)	Carbon acid (3) (X)	Product	Time (min)	Yield (%)^c	m.p. (obsd) (°C)^b	m.p. (lit) (°C)
a Reaction conditions: 4-hydroxyquinolin-2(1H)-one (1 mmol), aldehyde (1 mmol), malononitrile or ethyl cyanoacetate (1.1 mmol), water (5 mL, reflux), (CTA)3[SiW12]–Li^+–MMT (10 mg).b All compounds are known and their structures were determined from their spectral data and melting points as compared with literature values.c The yields refer to the isolated products.
6a		3a (CN)		10	93	295–297	>300 (ref. 31a)
6b		3a (CN)		8	94	>300	>300 (ref. 31b)
6c		3a (CN)		6	95	>300	>300 (ref. 31c)
6d		3a (CN)		8	98	298–300	>300 (ref. 31b)
6e		3a (CN)		5	95	>300	>300 (ref. 31b)
6f		3a (CN)		7	96	>300	>300 (ref. 31a)
6g		3a (CN)		8	97	>300	>300 (ref. 31c)
6h		3a (CN)		6	93	>300	>300 (ref. 31a)
6i		3a (CN)		9	94	>300	>300 (ref. 31b)
6j		3a (CN)		12	92	>300	>300 (ref. 31a)
6k		3a (CN)		12	91	>300	>300 (ref. 31a)
6l		3a (CN)		13	93	>300	>300 (ref. 31a)
6m		3a (CN)		12	88	>300	>300 (ref. 31c)
6n		3a (CN)		12	89	297–299	>300 (ref. 31b)
6o		3a (CN)		13	89	296–298	>300 (ref. 31a)
6p		3a (CN)		12	94	>300	>300 (ref. 31a^)
6q		3a (CN)		7	93	>300	>300 (ref. 31a)
6r		3a (CN)		7	93	>300	—
6s		3a (CN)		13	92	>300	>300 (ref. 31a)

---

After successfully synthesizing a series of 2-amino-3-cyano-pyrano[3,2-c]-quinolin-5(4H)-ones in good to high yields, we turned our attention to the synthesis of 2-amino-3-cyano-7,8-dihydro-4H-chromen-5(6H)-one under similar conditions. We replaced the dimedone compound with 4-hydroxyquinolone under the same conditions (Scheme 5). In this case, the use of dimedone, as an enolic component, improved the reaction time of the desired product 8 slightly (Table 4).

Scheme 5 One-pot three-component reaction of dimedone (7), different aldehydes (2) and malononitrile or ethyl cyanoacetate (3a–b).

Table 4 Synthesis of derivatives of 2-amino-3-cyano-7,8-dihydro-4H-chromen-5(6H)-one (8) via condensation of dimedone (7), various aldehydes (2) and malononitrile or ethyl cyanoacetete (3a–b) ​ in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT^a

Entry	RCHO (2)	Carbon acid (3) (X)	Product	Time (min)	Yield (%)^c	m.p. (obsd) (°C)^b	m.p. (lit) (°C)
a Reaction conditions: dimedone (1 mmol), aldehyde (1 mmol), malononitrile or ethyl cyanoacetate (1.1 mmol), water (5 mL, reflux), (CTA)3[SiW12]–Li^+–MMT (10 mg).b All compounds are known and their structures were determined from their spectral data and melting points as compared with literature values.c The yields refer to the isolated products.
8a		3a (CN)		15	95	233–235	234–235 (ref. 32d)
8b		3a (CN)		15	97	213–215	198–200 (ref. 32b)
8c		3a (CN)		12	95	214–216	215–217 (ref. 32a)
8d		3a (CN)		14	97	208–210	210–211 (ref. 32d)
8e		3a (CN)		17	96	227–228	228–230 (ref. 32j)
8f		3a (CN)		12	95	205–207	207–209 (ref. 32i)
8g		3a (CN)		11	93	215–217	214–216 (ref. 32a)
8h		3a (CN)		11	89	181–183	179–180 (ref. 32c)
8i		3a (CN)		13	91	226–228	227–230 (ref. 32i)
8j		3a (CN)		20	91	219–221	220–222 (ref. 32e)
8k		3a (CN)		22	89	200–202	201–202 (ref. 32d)
8l		3a (CN)		19	91	225–227	224–226 (ref. 32d)
8m		3a (CN)		27	96	239–241	238–240 (ref. 32f)
8n		3a (CN)		19	95	211–213	210–212 (ref. 30g)
8o		3a (CN)		12	96	221–223	220–223 (ref. 32g)
8p		3a (CN)		15	95	223–225	224–226 (ref. 32h)
8q		3a (CN)		15	87	213–215	214–216 (ref. 32k)
8r		3b (COOEt)		45	88	150–152	151–153 (ref. 32e)
8s		3b (COOEt)		29	92	152–155	153–154 (ref. 32e)
8t		3b (COOEt)		32	93	153–155	154–156 (ref. 30g)
8u		3b (COOEt)		45	89	149–151	151–152 (ref. 30g)

---

The scope of the present protocol was further surveyed with other C–H-activated acidic compounds such as 4-hydroxy-6-methylpyrone (9), 4-hydroxy-6-methylpyridone (10) and pyrimidine-2,4,6-trione (11). All of the C–H-activated acids 9, 10 and 11 undergo smooth condensation under the reaction conditions providing the desired products, 2-amino-3-cyano-pyrano[4,3-b]pyran-5(4H)-ones (12a–12f), 2-amino-3-cyano-pyrano[3,2-c]pyridine-6(5H)-ones (13a–13f) and 1H-pyrano[2,3-d]pyrimidine-2,4(3H,5H)-diones (14a–14f), respectively in good to high yields (83–97%) within a sensible time frame (Scheme 6). However, the three-component reaction of pyrimidine-2,4,6-trione (11), as a cyclic 1,3-dicarbonyl, required longer reaction times compared to 4-hydroxy-6-methylpyrone (9) and 4-hydroxy-6-methylpyridone (10) under similar reaction conditions (Table 5).

Scheme 6 One-pot three-component reaction of C–H-activated acids (9–11), different aldehydes (2) and malononitrile (3a).

Table 5 Synthesis of derivatives of 2-amino-3-cyano-4H-pyran (12–14) via condensation of C–H-activated acids (9–11), various aldehydes (2) and malononitrile (3a) in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT^a

Entry	RCHO (2)	Carbon acid (3) (X)	Product	Time (min)	Yield (%)^c	m.p. (obsd) (°C)^b	m.p. (lit) (°C)
a Reaction conditions: 4-hydroxycoumarin (1 mmol), aldehyde (1 mmol), malononitrile (1.1 mmol), water (5 mL, reflux), (CTA)3[SiW12]–Li^+–MMT (10 mg).b All compounds are known and their structures were determined from their spectral data and melting points as compared with literature values.c The yields refer to the isolated products.
12a		3a (CN)		18	93	235–237	236–238 (ref. 33a)
12b		3a (CN)		15	97	230–232	231–232 (ref. 33b)
12c		3a (CN)		15	95	222–224	223–225 (ref. 33c)
12d		3a (CN)		15	95	217–219	218–220 (ref. 33c)
12e		3a (CN)		15	96	221–223	220–222 (ref. 33d)
12f		3a (CN)		20	85	209–211	210–212 (ref. 33e)
13a		3a (CN)		20	90	277–278	279–282 (ref. 34)
13b		3a (CN)		18	93	241–242	245–247 (ref. 34)
13c		3a (CN)		18	92	257–258	258–259 (ref. 33c)
13d		3a (CN)		18	93	253–254	254–255 (ref. 33c)
13e		3a (CN)		15	95	277–278	278–279 (ref. 33c)
13f		3a (CN)		18	85	223–225	224–225 (ref. 34)
14a		3a (CN)		35	90	205–207	206–209 (ref. 35a)
14b		3a (CN)		30	94	234–236	234–237 (ref. 35b)
14c		3a (CN)		30	93	191–193	194–196 (ref. 32k)
14d		3a (CN)		30	91	233–235	235–236 (ref. 35c)
14e		3a (CN)		25	95	226–228	227–229 (ref. 35b)
14f		3a (CN)		35	83	281–283	280 (ref. 35d)

---

We herein suggest a mechanism in Scheme 7 for the one-pot three-component condensation of various enols, aldehydes and active methylene nitriles catalyzed by (CTA)₃[SiW₁₂]–Li⁺–MMT in water. Firstly, cyanocinnamonitriles or ethyl cyanocinnamates (15) were formed from the Knoevenagel condensation reaction of aldehyde and malononitrile (or ethyl cyanoacetate) in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT. Then the product of the first step by Michael addition was reacted with the enolate of the C–H-activated acid (1, 5, 7, 9, 10 or 11) in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT to create a Michael adduct (16). The Michael adduct (16) tautomerizes and cyclizes using the (CTA)₃[SiW₁₂]–Li⁺–MMT catalyst to form an intermediate (17) which then tautomerizes to give the desired product (4, 6, 8, 12, 13 or 14).

Scheme 7 A plausible mechanism for the one-pot three-component reaction of various enols (1, 5, 7, 9, 10, 11), aldehydes (2) and active methylene nitriles (3) catalyzed by (CTA)₃[SiW₁₂]–Li⁺–MMT in water.

In the next phase of the study, the recovery and reuse cycle of (CTA)₃[SiW₁₂]–Li⁺–MMT was also evaluated. Hence, we investigated the recyclability of (CTA)₃[SiW₁₂]–Li⁺–MMT for five consecutive cycles to afford the synthesis of 2-amino-4-(4-chlorophenyl)-3-cyano-pyrano[3,2-c]chromene-5(4H)-one (4c). As shown in Fig. 6, this nanocatalyst can be recycled at least five times without a significant decrease in the catalytic activity, and the yields ranged from 97% to 93%.

Fig. 6 Reusability of the catalyst.

Furthermore, the catalytic efficiency and the capability of (CTA)₃[SiW₁₂]–Li⁺–MMT for some of the obtained results in this study were compared with those of other methodologies which have been reported using other earlier homogeneous and heterogeneous catalysts for the synthesis of different 4H-pyran derivatives (Table 6). It is obvious that a suitable methodology in terms of product yield, reaction time and using a green solvent compared to several of the others has been developed.

Table 6 Comparison of the present method with other reported strategies for the synthesis of compound 4c

Entry	Catalyst	Catalyst loading	Solvent	Temp (°C)	Time (min)	Yield (%)	Ref.
1	SDS	20 mol%	H2O	60	150	88	30a
2	CuO nanoparticles	15 mol%	H2O	100	6	93	36a
3	DBU	10 mol%	H2O	100	5	94	30h
4	TBAB	10 mol%	H2O	100	45	93	30d
5	POPINO	5 mol%	H2O	Reflux	10	96	36b
6	(CTA)3[SiW12]–Li^+–MMT	10 mg	H2O	Reflux	6	97	This work
7	S-Proline	10 mol%	H2O/EtOH	100	180	78	36c
8	DAHP	10 mol%	H2O/EtOH	25	240	85	30g
9	Urea	10 mol%	H2O/EtOH	25	420	93	32k
10	PBBS	100 mg	H2O/EtOH	Reflux	150	90	36d
11	TBBDA	0.18 mmol	H2O/EtOH	Reflux	170	91	36d
12	Hexamethylenetetramine (HMT)	10 mol%	EtOH	78	40	95	30j
13	Nano Al2O3	25 mol%	EtOH	25	300	89	36e
14	MNP@AVOPc	20 mg	—	25	15	94	36f
15	[Sipim]HSO4	0.08 mmol	—	100	30	90	36g

---

Conclusions

In conclusion, we have introduced a simple, facile, green and conveniently practical one-pot methodology for the synthesis of a wide range of biologically and pharmacologically interesting functionalized 2-amino-4H-chromenes in the presence of (CTA)₃[SiW₁₂]–Li⁺–MMT as an eco-friendly and reusable nanocatalyst via a one-pot Knoevenagel condensation of C–H-activated acids, aldehydes and malononitrile (or ethyl cyanoacetate) in water under reflux conditions. The use of a cost-effective and eco-friendly catalyst, aqueous conditions, the absence of hazardous organic solvents, operational simplicity, excellent yields, high atom- economy and avoidance of tedious separation procedures as well as the reusability of the reaction media are the most important advantages of the present method. Considering that the synthetic significance of such densely functionalized and biologically important 2-amino-4H-chromenes scaffolds directly relates to pharmaceutical chemistry, the present strategy with green reaction conditions and easy work-up offers the possibility of its use with affordable and eco-friendly features as appropriate ways for the scale-up of these one-pot three-component reactions.

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