Facile synthesis of pyranopyrazoles and 3,4-dihydropyrimidin-2(1H)-ones by a Ti-grafted polyamidoamine dendritic silica hybrid catalyst via a dual activation route

Abstract

A simple, highly efficient and ecofriendly approach for the preparation of biologically potent pyranopyrazoles and 3,4-dihydropyrimidin-2(1H)-ones are described here. A Ti-grafted polyamidoamine dendritic silica hybrid catalyst was successfully synthesized, and its catalytic performance was studied in two important multicomponent reactions such as Biginelli reaction and pyranopyrazole synthesis. Studies demonstrate that the crystalline pore wall structure of the dendritic silica hybrid catalyst makes adsorption of reactants easy. Combining the Lewis acidic and Lewis basic properties of the silica surface facilitates and accelerates the synthesis of the desired products in high yields. The key advantages of the present method are the excellent yield of the products, low catalyst loading, shorter reaction times, facile work-up, and purification of the products by non-chromatographic methods and the reusability of the catalyst.

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1. Introduction

Designing organic reactions in aqueous media and under solvent-free conditions has gained popularity in recent years.^1,2 Organic synthesis in water is a rapidly growing area of research since it holds great promise for the future in terms of cheap and environment friendly production of materials.³ The use of water has numerous benefits in terms of selectivity and reactivity that are not achieved in organic solvents.⁴ Another approach is to carry out reactions without solvents. Solvent-free reactions usually need shorter reaction times, and simpler reactors, resulting in simpler and more efficient work up procedures, improved selectivity, easier separation and purification steps. So an environmentally benign approach can be developed by using a solvent-free method.^5,6

Periodic mesoporous organosilica (PMO) represents an exciting new class of organic–inorganic nanocomposite targeted for a broad range of applications such as catalysis and sensing, separations, and microelectronics. Recent progress regarding the design and synthesis of heterogeneous mesoporous silica catalysts, particularly, PMO catalysts, is quite impressive.⁷ Several PMO materials have been successfully prepared for catalytic applications. Dendrimers are a new class of polymeric materials. They are highly branched, monodisperse macromolecules. Several groups have promoted the synthesis and characterization of metal encapsulated dendrimers on inorganic and organic supports.^8,9 The high surface area of the PMO materials together with strong covalent attachment of catalytically active metal centers at the mesopore surface can make them promising candidates for heterogeneous catalysis together with good reusability and a minimum possibility for leaching of the grafted metals. Hence utility of these catalysts is gaining significant attention and becomes a more potential thrust area for the synthesis of highly functionalized pharmaceutically significant heterocyclic compounds.¹⁰

Pyranopyrazoles and 3,4-dihydropyrimidin-2(1H)-ones are important classes of heterocyclic compounds, and they find application in pharmaceutical and agricultural field. Their derivatives possess significant biological activities such as anti-inflammatory, molluscicidal, insecticidal, antitumor, and anticancer properties.¹¹ Classical Biginelli reaction required long reaction times, harsh reaction conditions and unsatisfactory yields.¹² This problem has led to the development of many strategies that overcome the problems of classical reaction.^13–18 Pyranopyrazoles and their derivatives have attracted much attention in recent years because of the possibility of diversity generation which can lead to new libraries of bioactive compounds. Thus several improved catalytic systems have been reported recently using ionic liquids, ammonium acetate, piperidine, L-proline, MgO, β-cyclodextrin, alumina, meglumine and also solvent free condition.¹⁹ These methods are effective in terms of high yield, but suffer several short comings, such as use of toxic base, organic solvents, longer reaction time, and non recoverable catalyst. With these considerations, development of facile, commercially, and environmentally benign synthetic strategies for these heterocycles is highly desirable. Several synthetic methods using the cooperative combination of Lewis base with Lewis acid have been reported and have proved to yield the desired products in more efficient C–C bond forming reactions.^20–22

In this paper, we report a simple, ecofriendly, rapid and high yielding one pot three component reaction protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives and four component method for the synthesis of pyranopyrazoles using Ti-grafted polyamidoamine dendritic silica hybrid materials. Combining the property of Lewis acid and Lewis base property of the silica surface facilitates and accelerates the desired products in high yields. The cooperative catalytic activity of hybrid catalyst enhanced the rate of reaction by activating the formation of intermediates within short period of time.

2. Experimental

2.1. Materials and methods

All the solvents were purified according to the standard procedures. All reagents and solvents used in the preparation and modification of mesoporous silica were used as received. 1,4-Bis(triethoxysilyl)benzene, cetyltrimethylammoniumbromide (CTAB), 3-aminopropyl trimethoxysilane and titanium(IV) isopropoxide (98%) were received from Aldrich. Amorphous silica was purchased from Loba Chemie Pvt. Ltd., India. TLC was done on silica coated alumina plates (Merck, 60 F254). Powder X-ray diffraction (PXRD) patterns of the corresponding mesoporous silica were collected using Bruker AXS D8 Advance diffractometer. ²⁹Si cross-polarized magic angle-spinning (CP-MAS) NMR spectra were recorded on a Bruker 300 MHz instrument and obtained from NCL, Pune. Infrared spectra were recorded using JASCO FTIR Spectrometer as KBr pellets. Solution NMR spectra were taken on Bruker 400 MHz instrument with TMS as internal standard in CDCl₃ (SAIF-STIC, CUSAT). Nitrogen adsorption–desorption experiments were performed on a Micromeritics Gemini 2360 V5.01 Surface Area Analyzer. X-ray photoelectron spectroscopy (XPS) analysis was carried out on a Kratos Axis Ultra X-ray photoelectron spectroscope (UK) with Al Kα radiation of 1486.6 eV (AIMS, KOCHI). TG analysis was performed on Perkin Elmer Pyris Diamond 6 thermogravimetric/differential thermal analyzer by heating the sample at rate of 10 °C min⁻¹ from 40 °C to 730 °C in N₂ (SAIF-STIC, CUSAT). The diffuse reflectance UV-Vis spectra of the solid samples were recorded using UV-Vis-NIR Ocean Optics Spectrophotometer SD 2000 model equipped with a diffuse reflectance accessory. GC analysis was carried out on a 1200 L single quadruple, Varian Gas Chromatograph model. Metal content on the samples were measured by Atomic Absorption Spectroscopy (AAS) using the model Thermo Electron Corporation with M Series AA Spectrometer.

2.2. Synthesis of benzene mesoporous silica and polyamidoamine dendrimer (2G) on silica

The periodic mesoporous benzene–silica with crystal-like pore walls (BS) was prepared using the 1,4-bis(triethoxysilane)benzene monomer precursor and CTAB using the similar procedure described earlier.²³ Polyamidoamine up to second generation was developed on benzene silica according to a similar procedure described in literature.²⁴

2.2.1. Synthesis of amine-functionalized mesoporous silica (BS–NH₂). Mesoporous benzene silica (BS ∼ 4 g) was suspended in 40 mL of toluene and 3-aminopropyl trimethoxysilane (4 g) in methanol (4 mL) was slowly added to avoid gel formation under nitrogen atmosphere. The mixture was refluxed with continuous stirring for 20 h followed by extraction with methanol at 60 °C for 8 h. After filtration and washing with methanol, the recovered powder was oven dried at 100 °C for 12 h.

White powder; IR (cm⁻¹): 2930 (C–H stretching), 1700–1400 (C–H bending), 1650–1580 (N–H bending).

2.2.2. Synthesis of first-generation dendritic mesoporous silica (BS-1G). The propylamine group grafted onto the mesoporous silica (BS–NH₂) can easily undergo Michael addition with methyl methacrylate to yield an amino propionate ester which in turn on amidation with ethylenediamine resulted in the formation of the first generation of mesoporous silica. In a closed vessel under nitrogen, aminopropyl-functionalised mesoporous silica hybrid (3 g) was suspended in methyl methacrylate solution (6 g, 60 mmol) in methanol and the mixture was heated at 55 °C and stirred for 60 h. After filtration, the powder was repeatedly washed with methanol and completely dried under vacuum. The methyl propyl aminopropionate derivative of mesoporous silica was designated as BS-0.5G. And BS-0.5G (∼3 g) was further suspended in ethylenediamine solution (30 mL) in methanol (30 mL) in a closed vessel under nitrogen atmosphere and stirred at ambient conditions for 4 days. After filtration and subsequent washing with ethanol and dichloromethane the resulting material was vacuum dried and kept in desiccator. The obtained mesoporous silica hybrid material was designated as BS-1G.

BS-0.5G (white powder); IR (cm⁻¹): 1742 (CO stretching of ester).

BS-1G (light yellow powder); IR (cm⁻¹): 1650–1515 (N–H bending of secondary amide), 1640 (CO stretching of secondary amide), 3500–3400 (N–H stretching of secondary amide).

2.2.3. Synthesis of second generation dendritic mesoporous silica (BS-2G). Under nitrogen atmosphere BS-1G (∼3 g) was stirred with methyl methacrylate solution (6 g, 60 mmol) in methanol (60 mL) at 55 °C for 4 consecutive days followed by filtration and washing with methanol. The recovered vacuum dried material was designated as BS-1.5G. It was (∼3 g) further suspended in ethylenediamine solution (100 mL) in methanol (50 mL) and stirred at ambient conditions for 6 days to yield the corresponding second generation mesoporous silica designated as BS-2G.

BS-1.5G (yellow powder); IR (cm⁻¹): 1742 (CO stretching of ester).

BS-2G (yellow powder); IR (cm⁻¹): 1650–1515 (N–H bending of secondary amide), 1640 (CO stretching of secondary amide), 3500–3400 (N–H stretching of secondary amide).

2.2.4. Preparation of Ti-grafted polyamidoamine dendritic silica hybrid catalyst. The periodic mesoporous dendritic silica hybrid (∼2 g) was suspended in CH₂Cl₂ (40 mL). To this Ti(OiPr)₄ (1.2 mL, 4 mmol) was added. The mixture was stirred for 24 h under N₂ atmosphere. After the reaction, the product was filtered and washed with isopropanol (30 mL × 3 times) and dry ether (30 mL × 3 times) and dried at 50 °C.

2.2.5. Preparation of Ti incorporated SiO₂. Ti activated on amorphous silica (Ti–SiO₂) was prepared by stirring an isopropanol solution of Ti(OiPr)₄ (2 mmol, 0.6 mL) with 1 g SiO₂ for 12 h. It was filtered, and washed with ethanol in a Soxhlet extractor and dried under vacuum. The metal intake capacity was found to be 0.49 mmol of Ti per gram silica.

2.2.6. Estimation of –NH₂ group capacity. The amine content of functionalized BS silica materials was estimated via dil. HCl consumption using the acid–base titration method. Typically, 100 mg of functionalized BS silica material was suspended in 30 mL of 0.1 M HCl solution and stirred at ambient temperature for 24 h. The filtrate was titrated with NaOH solution (0.1 M).

2.3. Procedure for Biginelli reaction and pyranopyrazole synthesis

2.3.1. Biginelli reaction. Aldehyde (25.0 mmol), β-dicarbonyl compound (25.0 mmol), urea (37.5 mmol) and BS-2G–Ti (0.15 mol%) were successively charged into a 50 mL round bottomed flask with a magnetic stirring bar. The reaction proceeded at 70 °C for 30 min during which time a solid product was gradually formed. After the reaction, the resulting solid product with pale yellow color was crushed and washed with ethyl acetate, filtered and extracted with water; organic layer was collected and dried under vacuum to afford the primary product. The pure product was obtained by further recrystallization of the primary product with ethyl acetate.

2.3.2. Synthesis of pyranopyrazoles. To a magnetically stirred aqueous solution of ethyl acetoacetate (1 mmol) and hydrazine hydrate (1.5 mmol), aldehyde (1 mmol), malononitrile (1 mmol), and a catalytic amount of BS-2G–Ti (2 mol%) were successively added. The resulting suspension was stirred and heated at 70 °C for appropriate reaction time as specified in (Table 6). The progress of the reaction was monitored by TLC (3 : 7, ethyl acetate : hexane). After completion, the reaction mixture was cooled to room temperature, and acetonitrile was added and shaken well for 5 min, filtered and poured over crushed ice, stirred for 10 min, precipitated product was filtered, washed with water, dried and recrystallized from methanol.

3. Results and discussion

Mesoporous benzene silica was synthesized using cetyltrimethylammonium bromide (CTAB) as surfactant under basic condition. The precursor used for the synthesis of mesoporous benzene silica was 1,4-bis(triethoxysilyl)benzene (BTEB). Mesoporous silica was prepared by the hydrolysis and condensation of the precursors in the presence of surfactant under basic condition, the sample was designated as BS.²⁹ Si CP MAS NMR spectrum of BS silica (Fig. 1) showed characteristic signals attributed to (HO)Si(OSi)₃ (Q³ δ ∼ 103 ppm), which clearly indicated that a proportion of the Si–C bonds have been cleaved, as well as a strong signal at −80 ppm showed the presence of the organic moieties attributed to CSi(OSi)₃ T³ state.

Fig. 1 ²⁹Si CP MAS NMR of periodic mesoporous benzene silica.

BS silica was functionalized with 3-aminopropyl trimethoxysilane. The product was designated as BS–NH₂. The propylamine group grafted onto the mesoporous silica can easily undergo a Michael addition with methyl methacrylate to yield an aminopropionate ester which in turn on amidation with ethylenediamine under nitrogen atmosphere resulted in the formation of the first generation mesoporous silica dendrimer (BS-1G). Repetition of the two reactions produced the desired generation of the mesoporous silica dendrimers (BS-2G). It was complexed with titanium(IV) isopropoxide in dichloromethane under nitrogen atmosphere, represented as (BS-2G–Ti). Schematic representation of the preparation of hybrid catalyst is shown in Scheme 1.

Scheme 1 (A) Synthesis of periodic mesoporous benzene silica, (B) generation of PAMAM dendrimer on benzene silica, (C) preparation of Ti-grafted silica.

3.1. Characterization of periodic mesoporous dendritic silica hybrids

The structural order of the samples was studied by PXRD. Low angle refection in low angle region confirms the presence of mesophase in the synthesized sample. Diffraction patterns in small angle region are typical of ordered mesoporous materials. Well-defined first order (100), second order (110) and (200) signals are observed, which can be assigned to a 2D-hexagonal mesostructure. After functionalization, this meso-scale periodicity was diminished (Fig. 2).

Fig. 2 Low angle XRD of BS and BS-2G–Ti.

Wide angle X-ray diffraction analysis was performed in order to investigate the texture properties of mesoporous silica. Strong peaks were observed between 10 < 2θ < 50 angles, indicating crystalline nature and molecular-scale periodicity of synthesized materials. After functionalization, there was no considerable decrease in intensity which showed that crystalline nature and molecular-scale periodicity was maintained (Fig. 3).

Fig. 3 Wide angle XRD pattern of BS and BS-2G–Ti.

Nitrogen sorption measurements were performed to examine the porosity of the different materials (Fig. 4). A summary of the textural properties of these materials is shown in Table 1.

Fig. 4 Nitrogen adsorption–desorption plot of BS and BS-2G–Ti.

Table 1 Structural properties of the BS and functionalized BS silica materials^a

Sample	SBET (m^2 g^−1)	Vp (cm^3 g^−1)	PD (nm)
a PD = pore diameter, Vp = pore volume.
BS	580	0.77	4.0
BS–NH2	478	0.68	3.8
BS-1G	321	0.29	3.6
BS-2G–Ti	185	0.19	2.0

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The materials exhibit high specific surface area (S_BET) ranging from 580 to 185 m² g⁻¹. Bare BS silica has a large total pore volume around 0.77 cm³ g⁻¹. The S_BET, pore volume and pore diameter decreases when the material is functionalized from lower generation to higher generation. This is due to pore filling at relatively low pressure range, thus indicating the formation of dendritic species inside the mesopores resulting in a significant reduction in the pore size.

Further, the dendritic functionalization was monitored using infrared spectroscopy (IR) at each step of preparation. And the results are given in Fig. 5. The C–H stretching vibrations observed in the 2950–2900 cm⁻¹ region confirmed the grafting of aminopropyl groups on to the mesoporous silica. The N–H stretching vibrations occur as two weak absorption bands in the 3500–3400 cm⁻¹ region. Here the bands are masked by the bands of silanol groups. The N–H bending vibrations of primary amines are observed in the 1650–1580 cm⁻¹ region. After Michael addition with methylmethacrylate group the material yielded an aminopropoinate ester, which showed a strong vibration at 1742 cm⁻¹ attributed to the CO stretching of the ester group (BS-0.5G and BS-1.5G). In BS-1G and BS-2G a band in the region of 1650–1515 cm⁻¹ is caused by N–H bending of secondary amide which is a strong evidence for amidation with ethylenediamine. The C=O stretching vibration 1640 cm⁻¹ and the N–H stretching vibrations 3500–3400 cm⁻¹ are observed in the secondary amide. Further, the IR results confirmed the presence of the designed functional groups with higher intensity in the second-generation dendritic mesoporous silica hybrids prepared by the repetition of a set of the aforementioned reactions.

Fig. 5 FT-IR spectra of functionalized BS silica.

The FT-IR bands due to the primary amino groups get shifted from 3441 to 3389 cm⁻¹ after complexation with titanium isopropoxide as shown in Fig. 6.

Fig. 6 FT-IR spectra of BS-2G & BS-2G–Ti.

This shows that the complexation was taking place with primary amino groups of the dendrimers. The carbonyl-stretching band of the amide groups remained unaltered at 1654 cm⁻¹ which proved that the amide group was not involved in the complex formation.

Another evidence of complexation of dendrimer was obtained from DRS-UV-Vis spectra (Fig. 7).

Fig. 7 UV-Vis-DRS spectra of BS-2G & BS-2G–Ti.

The DRS-UV-Vis spectroscopic analysis is a tool to evaluate the coordination state of Ti(IV) (species in tetrahedral coordination at 220–260 nm and species in octahedral coordination at 260–290 nm) as well as the degree of isolation of Ti(IV) species in the silica matrix.²⁵ BS-2G does not show any characteristics absorption band other than original band at 273 nm caused by benzene bridging group in PMO pore walls. BS-2G–Ti showed an intense broad absorption band centered at 278 nm and a new band at 450 nm. This indicated that successful incorporation of Ti(iOPr)₄ and broadness of the band may be due to the overlapping of the existing band of BS silica. Oxana et al. reported that peak at 270–290 nm indicated the presence of hexa-coordinated Ti species in the supported matrix.²⁶ They noted that UV-Vis-DRS spectrum of the sample with high Ti surface concentration (0.60–1.0 Ti per nm²) revealed the characteristic broad band in the range of 270–290 nm. Based on the above reports, we have assumed that titanium is hexa-coordinated onto the silica frame work. And the peak at 450 nm may be due to the charge transfer transition from ligand to metal.

The thermal stability of dendritic silica system was studied by thermogravimetric analysis. TG plots of the hybrid material (Fig. 8) showed a weight loss below 100 °C due to loss of physically adsorbed water.

Fig. 8 TG and DTG plots of functionalized silica hybrids.

Weight loss of 3.1% in BS-1G, 6.2% in BS-2G and 2.1% in BS-2G–Ti was observed between 100 and 150 °C which may be due to the elimination of amine moiety. In addition, a weight loss at 560 °C can be observed in all hybrid materials suggested the decomposition of benzene fragment from the pore walls. In BS-2G–Ti, a weight loss at 450 °C corresponding to the decomposition of titanium fragment and the residue may correspond to the formation of TiO₂. A continuous weight loss may be due to the oxidation of dendritic functionality from the silica frame work. These results revealed the incorporation and integrity of designed functional groups in the mesoporous silica hybrids. The amine capacity of hybrid material was measured by titration method and UV-Visible analysis.²⁷ The capacity of –NH₂ group was further verified using thermogravimetric analysis (TGA/DTA). The amine group capacity of functionalized materials is listed in Table 2.

Table 2 Amine capacity of functionalized BS^a

Sample	NH2 content^a (mmol g^−1)	NH2 content^b (mmol g^−1)	NH2 content^c (mmol g^−1)
a Titration method.b UV-Vis method.c TG/DTA.
BS–NH2	0.774	0.763	0.789
BS-1G	1.820	1.890	1.800
BS-2G	3.050	3.680	3.450
BS-2G–Ti	1.260	1.310	1.210

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Elemental composition on the silica surface was studied using X-ray photoelectron spectroscopy (Fig. 9). In high resolution spectra Ti shows a Ti (2p_3/2) and Ti (2p_1/2) doublet with a separation of 5.72 eV (Fig. 10). The lower binding energy values of 2p_3/2 and 2p_1/2 from the acceptable value reveals that titanium exist as Ti⁴⁺ and also has coordinated to amine moiety on the silica frame work which confirms the incorporation of titanium species. Based on the results from XPS, and UV-DRS it was clear that titanium is hexa-coordinated onto the silica frame work. The Ti content from XPS measurement (0.54 mmol g⁻¹) agreed with the result obtained from AAS measurement (0.58 mmol g⁻¹).

Fig. 9 XPS spectra of BS & BS-2G–Ti.

Fig. 10 High resolution spectra of Ti⁴⁺.

3.2. Catalytic studies

3.2.1. Biginelli reaction. Here, we have attempted to synthesize 3,4-dihydropyrimidin-2(1H)-one under solvent free condition, since the use of organic solvents decreased the catalytic activity and selectivity. Firstly, no desirable product could be detected in the absence of catalyst, indicating a catalyst must be needed for the Biginelli reaction. Conversion of reactant was increased with increasing amount of catalyst upto 10 mg (0.1 mol%), results are shown in Table 3. Effect of solvent was studied by selecting different solvents at 70 °C, good result was obtained in water. Under solvent free conditions the corresponding product was obtained in high-to-quantitative yield with high purity (Table 4). Reaction was also carried out at 30 °C giving the desired product with low yield and required more time. The optimized condition was applied to various aldehydes, it was noticed that all the employed aldehydes reacted very well under the solvent free condition (Table 5 and Scheme 2).

Table 3 Effect of amount catalyst^a

a Reaction conditions: C6H5CHO (25.0 mmol), CH3COCH2COOC2H5 (25.0 mmol), urea (37.5 mmol), 70 °C, 0.5 h, solventless.
Catalyst amount (mg)	7	10	13
Yield (%)	85	96	95

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Table 4 Effect of solvent^a

Entry	Solvent	Yield (%)
a Reaction conditions: C6H5CHO (25.0 mmol), CH3COCH2COOC2H5 (25.0 mmol), urea (37.5 mmol), 70 °C, 0.5 h.
1	Ethanol	82
2	Acetonitrile	86
3	DMF	86
4	Water	90
5	No solvent	96

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Table 5 BS-2G–Ti catalyzed synthesis of DHPMS^a

Entry	R	X	Product	Yield %	M.p (°C)
					Found	Reported
a Reaction conditions: C6H5CHO (25.0 mmol), CH3COCH2COOC2H5 (25.0 mmol), urea/thiourea (37.5 mmol), 70 °C, solvent less, 0.5 h.
1	Ph	O	1a	96	202–204	201–203 (ref. 13b)
2	2-OH–C6H4–	O	1b	92	200–202	201–202 (ref. 13c)
3	4-OCH3–C6H4–	O	1c	95	198–200	199–201 (ref. 13b)
4	4-OCH3–C6H4–	S	1d	90	145–146	142–145 (ref. 13b)
5	–C10H11–	O	1e	85	247–249	246–248 (ref. 13b)
6	4-Cl–C6H4–	O	1f	85	209–211	210–212 (ref. 13b)
7	4-Cl–C6H4–	S	1g	80	192–194	192–194 (ref. 13b)
8	Ph	S	1h	86	207–209	206–208 (ref. 13e)
9	4-Br–C6H4–	O	1i	85	218–220	219–221 (ref. 13d)
10	4-NO2–C6H4–	O	1j	85	206–208	205–207 (ref. 13b)
11	Ph–CH=CH	O	1k	96	230–231	230–232 (ref. 13b)

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Scheme 2 BS-2G–Ti catalysed Biginelli reaction.

A dual activation mechanism is shown in Scheme 3. The primary amino group on the side chain of the catalyst activates ethyl acetoacetate through the formation of an enamine. The imine formed between benzaldehyde and urea is attacked by Ti activated enamine complex to form intermediate I, which, after hydrolysis, intramolecular cyclization, and dehydration reaction, yielded the desired product.

Scheme 3 Dual activation mechanism of Biginelli reaction.

3.2.2. Pyranopyrazole synthesis. The reaction between hydrazine hydrate, ethyl acetoacetate (EAA), malononitrile, and benzaldehyde, in water was chosen as a model condensation reaction for optimization. Initially the reaction was conducted without catalyst, no product was obtained. By adding 1 mol% of BS-2G–Ti catalyst the reaction proceeded slowly at room temperature and took more than 15 h for completion. To enhance the rate of reaction the temperature was raised to 70 °C, so the reaction was completed within 1 h. Further increases of temperature did not affect the yield (Scheme 4).

Scheme 4 BS-2G–Ti catalysed pyranopyrazole synthesis.

In order to quantify the amount of catalyst, reaction was carried out by adding different amounts of catalyst. When catalyst amount was increased from 5 mg to 15 mg, yield of the desired product was increased. It was found that 13 mg (2 mol%) of the catalyst was sufficient for the reaction.

To examine the influence of solvent, the reaction was conducted in protic and aprotic solvents such as ethanol, water and acetonitrile. The reaction in protic solvent showed satisfying performance but in the aprotic solvent (acetonitrile) efficiency was poor (Table 6). This suggests that the solvent polarity also contributed a significant role to the synthesis of pyranopyrazoles and better result was obtained in water.

Table 6 Effect of solvent^a

Entry	Solvent	Yield (%)	Temperature (°C)
a Yield obtained in the case of benzaldehyde.
1	Ethanol	65	70
2	Acetonitrile	45	70
3	DMF	60	70
4	Water	95	Reflux
5	Water	96	70

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To evaluate the scope of the reaction, it was performed with various substrates under the optimized condition and the corresponding results are given in Table 7. Almost all the employed aldehydes resulted in good to-excellent yield of the corresponding products without any side products. Aldehydes having electron-withdrawing substituents reacted faster and gave high yield as compared to the aldehydes having electron-donating substituents. The reaction proceeded satisfactorily with aliphatic aldehyde and cyclic ketone.

Table 7 Synthesis of substituted pyranopyrazole using BS-2G–Ti in aqueous medium^a

Entry	Carbonyl compounds	Product	Yield %	Time (min)	M.p °C
					Found	Reported
a Reaction was tried on benzaldehyde (1 mmol), EAA (1 mmol), malononitrile (1 mmol), hydrazine·hydrate (1.5 mmol) in aqueous medium at 70 °C.
1	Ph	2a	94	60	246–248	244–246 (ref. 19f)
2	4-OCH3–C6H4–	2b	91	70	209–211	210–212 (ref. 19f)
3	3-NO2–C6H4	2c	85	90	243–245	244–246 (ref. 19a)
4	–CH=CH–Ph	2d	94	60	235–238
5	4-Cl–C6H4–	2e	95	60	234–236	233–234 (ref. 19g)
6	2-OH–C6H4–	2f	90	90	210–212	280–210 (ref. 20b)
7	4-Br–C6H4–	2g	95	70	183–185	184–186 (ref. 20b)
8	4-NO2–C6H4–	2h	96	90	250–252	251–253 (ref. 19f)
9	4-OH–C6H4–	2i	94	70	222–224	224–226 (ref. 19f)
10	2-NO2–C6H4–	2j	96	90	221–223	220–222 (ref. 19f)
11	2-Thiophenyl	2k	75	60	242–246	246–248 (ref. 20a)
12	CH3–CHO	2l	45	100	156–158	155–158 (ref. 22b)
13	4-Methyl acetophenone	2m	50	90	182–184	184–185 (ref. 19g)
14	Cyclohexanone	2n	56	90	150–152	148–150 (ref. 22b)

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The possible mechanism for BS-2G–Ti catalyzed synthesis of pyranopyrazoles is shown in Scheme 5. Initially, ethyl acetoacetate was activated by Lewis acid part on the catalyst and hydrazine attacks the carbonyl group of the activated ethyl acetoacetate. Loss of H₂O, and intramolecular nucleophilic attack by NH₂ group of hydrazine to the next carbonyl group of ethyl acetoacetate affords 5-methyl-2,4-dihydropyrazol-3-one (intermediate I) and removes EtOH. Simultaneously, there is formation of arylidene malononitrile (III) by the Knoevenagel condensation between aldehyde and malononitrile. This step is activated by free amine group on the catalyst. Michael addition of pyrazolone (I) to arylidene malononitrile (III), followed by cyclization and then tautomerization, afforded the pyranopyrazole.

Scheme 5 Dual activation mechanism of pyranopyrazole synthesis.

To examine the catalytic efficiency of BS-2G–Ti, both reactions were also performed in the presence of BS-2G under identical reaction condition. It was found that this dendritic functionalized catalyst also exhibited high catalytic activity, but took more time for the completion of reaction and the product yield was lower compared to BS-2G–Ti. The results are given in Table 8.

Table 8 BS-2G catalysed reactions

Catalyst	Reaction	Time (h)	Yield (%)
a Reaction conditions: C6H5CHO (25.0 mmol), CH3COCH2COOC2H5 (25.0 mmol), urea (37.5 mmol), no solvent, 70 °C.b Reaction conditions: C6H5CHO (1 mmol), malononitrile (1 mmol), CH3COCH2COOC2H5 (1 mmol), hydrazine·hydrate (1.5 mmol), H2O 70 °C.
BS-2G (10 mg)	Biginelli reaction^a	2	85
BS-2G (13 mg)	Pyranopyrazole synthesis^b	4	88

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In order to examine the dual activity of BS-2G–Ti, we have compared the result with other catalysts reported earlier for the synthesis of heterocyclic compounds and Knoevenagel adducts. Knoevenagel condensation is a very useful reaction and played a vital role in the mechanism of pyranopyrazole synthesis. We have also investigated Biginelli reaction and pyranopyrazole synthesis with Ti activated on amorphous silica. The metal intake capacity was found to be 0.49 mmol of Ti in one gram silica from AAS measurement. Catalytic activity of Ti–SiO₂ was performed in Biginelli reaction and pyranopyrazole synthesis under identical reaction conditions. The targeted products were obtained with 80 and 85% yield respectively with prolonged reaction time. Ti–SiO₂ catalyst showed significant metal leaching after reaction where BS-2G–Ti showed high stability, and negligible metal leaching and can be reused with same activity.

As demonstrated in Table 9 all the catalysts other than BS-2G–Ti required high amount of catalyst loading and longer reaction time. In BS-2G–Ti hybrid catalyst, the amine and acid functionality exhibited synchronous effect and created a driving force for the completion of reaction. Recently, Shingare and co-workers explored the catalytic reactivity of molecular sieves (MS 4 Å) as catalyst in pyranopyrazole synthesis. The authors described the presence of Lewis acidic sites and basic sites over MS 4 Å which made stronger interaction between molecular sieves and organic molecules, the resultant effect could drive the reaction easily.^22b

Table 9 Comparison of the present results with previously reported methods

Entry	Catalyst	Reactions	Reaction conditions	Time	Yield (%)
1	Ti–PCS (5 mol%)	Biginelli reaction	EtOH, reflux	8 h	82 (ref. 28)
2	Ti–clay (100 mg)	Tetra substituted imidazole synthesis	Solvent free	3 h	80 (ref. 29)
3	Ti–PCS (5 mol%)	Knoevenagel condensation	EtOH, rt	12 h	100 (ref. 30)
4	PANPF-3 (0.5 g)	Knoevenagel condensation	EtOH, reflux	1.5 h	95 (ref. 31)
5	Ti–SiO2 (15 mg)	Biginelli reaction	Solvent less	5 h	80
6	Ti–SiO2 (15 mg)	Pyranopyrazole synthesis	H2O, 70 °C	5 h	85
7	BS-2G–Ti	Biginelli reaction	Solvent less	30 min	96
8	BS-2G–Ti	Pyranopyrazole synthesis	H2O, 70 °C	90 min	98

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3.2.3. Recycling of catalyst. It was found that the catalyst could be efficiently recycled and reused for 3 repeating cycles without much loss of efficiency (Fig. 11). This indicated that Ti-grafted amine functionalized mesoporous silica was an efficient catalyst for both the reactions. For the recycling study, catalyst was washed with methanol (3 times), dried at 50 °C and subjected to recycling.

Fig. 11 Recycling study of BS-2G–Ti in Biginelli reaction (a) and pyranopyrazole synthesis (b). Reaction conditions: (a) C₆H₅CHO (25.0 mmol), CH₃COCH₂COOC₂H₅ (25.0 mmol), urea (37.5 mmol), 70 °C, 0.5 h, (b) reactions were tried on carbonyl compound (1 mmol), ethyl acetoacetate (1 mmol), malononitrile (1 mmol), hydrazine hydrate (1.5 mmol) in aqueous medium.

The spectroscopic data of all the products are given as ESI,† and the obtained products were identical with those of authentic samples.^13,19,20,22

4. Conclusions

In summary, Ti-grafted polyamidoamine dendritic silica hybrid catalyst was synthesized and characterized by various techniques. It was found that this dendirtic silica hybrid catalyst exhibited high catalytic activity in the synthesis of 3,4-dihydropyrimidin-2-one under solvent free condition and pyranopyrazole synthesis in aqueous medium. Dual nature of the hybrid catalyst played a vital role in the mechanism of both the reactions by activating the formation of intermediates resulting in the desired products in excellent yield within short period of time. Facile synthesis, easy purification, and the reusability of the catalyst are the key advantages of this method. Also this protocol meets the requirements of vigorously increasing applications of mesoporous silica hybrid materials in organic synthesis.

Acknowledgements

One of the authors (SPS) acknowledges CUSAT and UGC-BSR for providing fellowship and authors are grateful to SAIF-STIC (CUSAT), NCL (Pune), Department of Physics (CUSAT), AIMS (Kochi) for various analytical facilities.

References

1. (a) J. O. Metzger, Angew. Chem., Int. Ed., 1998, 37, 2975; (b) C. J. Li and T. H. Chan, Tetrahedron, 1999, 55, 11149.
2. G. W. V. Cave, C. L. Raston and J. L. Scott, Chem. Commun., 2001, 21, 2159.
3. (a) Organic Synthesis in Water, ed. P. A. Grieco, Blackie Academic and Professional, London, 1998; (b) C. J. Li, Chem. Rev., 1993, 93, 2023; (c) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751.
4. M. O. Simon and C. J. Li, Chem. Soc. Rev., 2012, 41, 1415.
5. C. Imrie, P. Kleyi, V. O. Nyamori, T. I. A. Gerber, D. C. Levendis and J. Look, J. Organomet. Chem., 2007, 692, 3443.
6. Y. Gu, Green Chem., 2012, 14, 2091.
7. (a) C. Y. Ishii, T. Asefa, N. Coombs, M. J. MacLachlan and G. A. Ozin, Chem. Commun., 1999, 2539; (b) F. Hoffmann, M. Cornelius, J. Morell and M. Froba, Angew. Chem., Int. Ed., 2006, 45, 3216; (c) W. J. Hunks and G. A. Ozin, J. Mater. Chem., 2005, 15, 3716.
8. (a) J. P. K. Reynhardt, Y. Yang, A. Sayari and H. Alper, Adv. Funct. Mater., 2005, 15, 1641; (b) J. P. K. Reynhardt, Y. Yang, A. Sayari and H. Alper, Chem. Mater., 2004, 16, 4095; (c) J. Bu, Z. M. A. Judeh and C. B. Ching, Catal. Lett., 2003, 85, 183.
9. (a) E. J. Acosta, C. S. Carr, E. E. Simanek and D. F. Shantz, Adv. Mater., 2004, 16, 985; (b) J. P. K. Reynhardt, Y. Yang, A. Sayari and H. Alper, Adv. Synth. Catal., 2005, 347, 137.
10. (a) S. B Sapkal, K. F. Shelke, B. B. Shingate and M. S. Shingare, Tetrahedron Lett., 2009, 50, 1754; (b) K. Yamamoto, Y. G. Chen and F. G. Buono, Org. Lett., 2005, 7, 4673; (c) S. S. Kim, B. S. Choi, J. H. Lee, K. K. Lee, T. H. Lee, Y. H. Kim and S. Hyunik, Synlett, 2009, 599.
11. (a) H. Wamhoff, E. Kroth and K. Strauch, Synthesis, 1993, 11, 1129; (b) G. Tacconi, G. Gatti and D. T. Prakt, Chem. Commun., 1980, 322, 831; (c) C. O. Kappe, Acc. Chem. Res., 2000, 33, 879; (d) S. S. Panda, P. Khanna and L. Khanna, Curr. Org. Chem., 2012, 16, 507.
12. (a) P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360; (b) K. S. Atwal, G. C. Rovnyak, B. C. O'Reilly and J. Schwartz, J. Org. Chem., 1989, 54, 5898; (c) J. Barluenga, M. Tomas, A. Ballesteros and L. A. Lopez, Tetrahedron Lett., 1989, 30, 4573.
13. (a) Y. Ma, C. Qian, L. Wang and M. Yang, J. Org. Chem., 2000, 65, 3864; (b) J. S. Yadav, B. V. Subba Reddy, P. Sridhar, J. S. S. Reddy, K. Nagaiah, N. Lingaiah and P. S. Saiprasad, Eur. J. Org. Chem., 2004, 552; (c) Li Q. Kang, D. Y. Jin and Y. Q. Cai, Synth. Commun., 2013, 43, 1896; (d) G. Aridoss and Y. T. Jeong, Bull. Korean Chem. Soc., 2010, 31, 863; (e) C. V. Reddy, M. Mahesh, P. V. K. Raju, T. R. Babu and V. V. N. Reddy, Tetrahedron Lett., 2002, 43, 2657.
14. (a) A. S. Paraskar, G. K. Dewkar and A. Sudalai, Tetrahedron Lett., 2003, 44, 3305; (b) A. Shaabani and F. Bazgir, Tetrahedron Lett., 2003, 44, 857.
15. (a) J. Peng and Y. Deng, Tetrahedron Lett., 2001, 42, 5917; (b) J. Lu, H. Ma and W. C. Li, J. Org. Chem., 2000, 20, 815.
16. (a) S. L. Jain, S. Singhal and B. Sain, Green Chem., 2007, 9, 740; (b) D. Rodriguez, O. Bemardi and G. Kirsch, Tetrahedron Lett., 2007, 48, 5777.
17. (a) S. R. Narahari, B. R. Reguri, O. Gudaparthi and K. Mukkanti, Tetrahedron Lett., 2012, 53, 1543; (b) P. K. Sahu and D. D. Agarwal, RSC Adv., 2013, 3, 9854; (c) X. Shi, H. Yang, M. Tao and W. Zhang, RSC Adv., 2013, 3, 3939.
18. (a) Y. Wang, J. Yu, H. Yang, Z. M. Miao and R. Chen, Lett. Org. Chem., 2011, 8, 264; (b) S. Gore, S. Baskaran and B. Koenig, Green Chem., 2011, 13, 1009; (c) Y. Ren, C. Cai and R. Yang, RSC Adv., 2013, 3, 7182; (d) H. G. O. Alvim, T. B. Lima, A. L. de Oliveira, H. C. B. de Oliveira, F. M. Silva, F. C. Gozzo and A. D. N. Brenno, J. Org. Chem., 2014, 79, 3383.
19. (a) H. V. Chavan, S. B. Babar, R. U. Hoval and B. P. Bandgar, Bull. Korean Chem. Soc., 2011, 32, 3963; (b) G. Vasuki and K. Kumaravel, Tetrahedron Lett., 2008, 49, 5636; (c) N. M. H. Elnagdi and N. S. Al-Hokbany, Molecules, 2012, 17, 4300; (d) M. Babaie and H. Sheibani, Arabian J. Chem., 2011, 4, 159; (e) H. Mecadon, R. M. Rohman, I. Kharbangar, B. M. Laloo, I. Kharkongor, M. Rajbangshi and B. Myrboh, Tetrahedron Lett., 2011, 5, 3228; (f) H. Mecadon, M. R. Rohman, M. Rajbangshi and B. Myrboh, Tetrahedron Lett., 2011, 52, 2523; (g) G. R. Yun, Z. M. An, L. P. Mo, S. T. Yang, H. X. Liu, S. X. Wang and Z. H. Zhang, Tetrahedron, 2013, 69, 9931.
20. (a) M. A. Zolfigol, M. Tavasoli, A. R. Moosavi, P. M. Zare, H. G. Kruger, M. Shirid and V. Khakyzadeha, RSC Adv., 2013, 3, 25681; (b) M. A. E. Aleem and A. A. El-Remaily, Tetrahedron, 2014, 70, 2971.
21. (a) Y. F. Cai, H. M. Yang, L. Li, K. Z. Jiang, G. Q. Lai, J. X. Jiang and L. W. Xu, Eur. J. Org. Chem., 2010, 26, 4986; (b) B. Boumoud, I. Mennanaa and T. Boumoud, Lett. Org. Chem., 2013, 10, 8.
22. (a) N. A. Brunelli, K. Venkatasubbaiah and C. W. Jones, Chem. Mater., 2012, 24, 2433; (b) J. B. Gujar, M. A. Chaudhari, D. S. Kawade and M. S. Shingare, Tetrahedron Lett., 2014, 55, 6030.
23. S. Inagaki, S. Guan, T. Ohsuna and O. Terasaki, Nature, 2002, 416, 304.
24. M. P. Kapoor, Y. Kasama, T. Yokoyama, M. Yanagi and S. Inagaki, J. Mater. Chem., 2006, 16, 4714.
25. M. Guidotti, E. Gavrilova, A. Galarneau, B. Coq, R. Psaroa and N. Ravasio, Green Chem., 2011, 13, 1806.
26. A. K. Oxana, I. D. Ivanchikova, M. Guidotti, C. Pirovano, N. Ravasio, M. V. Barmatova and Y. A. Chesalova, Adv. Synth. Catal., 2009, 351, 1877.
27. C. O. Kim, J. Colloid Interface Sci., 2003, 24, 374.
28. K. Mangala, Ph. D. thesis, Cochin University of Science and Technology, 2011.
29. V. Kannan and K. Sreekumar, J. Mol. Catal. A: Chem., 2013, 376, 34.
30. K. Mangala and K. Sreekumar, Appl. Organomet. Chem., 2013, 27, 73.
31. G. Li, J. Xiao and W. Zhang, Green Chem., 2011, 13, 1828.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra16723j

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