Ag@TiO2 Nanocomposite as an Efficient Catalyst for Knoevenagel Condensation

In the present study, a new series of different heterocycles was synthesized through base-free Knoevenagel condensation of various aldehydes and active methylene-containing compounds using the hydrothermal developed Ag@TiO2 as a heterogeneous catalyst. The catalyst was synthesized by mixing TiO2 (P25) with AgNO3 and hydrothermally treated in ethanol at 180 °C for 12 h. The developed Ag@TiO2 catalyst was directly applied for Knoevenagel condensation, and the optimized procedure involved stirring the aldehydes and active methylene-containing compounds with Ag@TiO2 in ethanol at 65 °C. The reaction scope was investigated for various aromatic and heterocyclic aldehydes with active methylene-containing compounds, and the isolated yields were significantly high. The reusability of the catalyst was investigated for up to five cycles, where an insignificant decrease in the catalyst’s reactivity was observed. Also, the reaction could proceed in water as a solvent, and the isolated yield was 40%. Hence, this protocol features mild reaction conditions, a facile procedure, and clean reaction profiles.


INTRODUCTION
Knoevenagel condensation is a reaction involving nucleophilic addition of a hydrogen active species to a carbonyl compound generally aldehyde or ketone followed by dehydration, resulting in olefin compounds, and this reaction commonly occurs in the presence of a weakly basic amine catalyst. 1−3 This reaction has originally been described by the German chemist Emil Knoevenagel, and it can be described as a modification of the aldol condensation. 4 The importance of this reaction originated from its feasibility route for the synthesis of various biologically active compounds containing C�C bonds. 3 The α,β-unsaturated products produced from the Knoevenagel reaction had mostly been used as potential intermediates in the synthesis of many naturally occurring compounds, 5 therapeutic agents, 6,7 adequate chemicals, 8 and polymers containing different functional groups. 9 As mentioned above, the Knoevenagel reaction is common in academics and industry, with broad applications in pharmaceutical synthesis. 7,10 Usually, the reaction is homogeneously catalyzed by organic bases such as piperidine, and this convention method suffers from many difficulties like timeconsuming work-up procedures, undesired side products, applying high temperatures, difficult catalyst isolation, and hazardous reaction residues. 11 Because of these limitations, many efforts have been devoted in this area to find alternative routes to perform this reaction under base-free conditions. Previous studies have reported the use of different heterogeneous catalysts containing zeolites, mesoporous silica, ionic liquids, and graphitic carbon nitride. 12,13 Also, composites containing metal oxides showed high reactivity as heterogeneous catalysts for Knoevenagel condensation, and the metal oxides in these composites were prior chemically modified or doped with metals. 14−17 Titanium dioxide (TiO 2 )-based catalysts are considered promising and recyclable catalysts for organic synthesis, and metal or nonmetal dopants would enhance the catalytic stability and activity. 18 Noble metal-doped TiO 2 catalysts are widely used for the synthesis of Schiff bases, 19 reduction of nitrobenzenes to hydrazobenzens, 20 and dehydrogenation of nheterocycles. 21 One of these promising catalysts is Ag@TiO 2 , which is used as an effective catalyst in the synthesis of bis(pyrazol-5-ol) and dihydropyrano [2,3-c]pyrazole, pyrido-[2,3-d]pyrimidine, benzimidazole, and benzoxazole derivatives. 22−25 For the Knoevenagel condensation, composites of TiO 2 -La 2 O 2 CO 3 , Fe 3 O 4 @SiO 2 @TiO 2 , and mesoporous TiO 2 −CeO 2 were reported to be effective catalysts. 15,26,27 Inspired by these studies, Ag@TiO 2 was utilized in this study as the catalyst for the reactions between 3-chloro-1H-indole-2-carbaldehydes and other aromatic aldehydes with different compounds containing active methylene. Indolecontaining compounds represent an important class of heterocyclic compounds because of their use as alkaloid precursors, 28 and their biological activities, such as antitumor, 29 antiviral, 30 and anti-inflammatory activity. 31 Besides, the 3-chloro-1H-indole-2-carbaldehyde is an easily accessible source for indole carbaldehyde, which can be functionalized at the 2-position to produce various heterocyclic compounds with the chlorine atom at the 3-position, which may boost their biological activities. 32−36 Reaction optimization and detailed scope are comprehensively studied. Also, the recyclability of the catalyst is investigated, and the reaction mechanism is suggested. Such a comprehensive study of Knoevenagel condensation on Ag@TiO 2 has not been previously reported to the best of our knowledge. Successful completion of Knoevenagel condensation using such recyclable Ag@TiO 2 catalyst without applying other hazardous homogenous catalysts would pave the way for a facile, green, and environmental-friendly synthetic method of heterocyclic compounds.

Synthesis of Ag@TiO 2 .
One gram of TiO 2 (P25, Degussa, 20 nm, the Brunauer−Emmett−Teller (BET) surface area is 50 ± 15 m 2 /g), 20 mL of water, and 20 mL of ethanol were transferred into a Teflon vessel. After that, a Teflon container was sonicated in an ultrasonic cleaning bath (40 kHz) and magnetically stirred for 20 min each. The calculated amounts of AgNO 3 (Sigma, ≥99%) were added into the Teflon container, sonicated, and stirred for 20 min for homogenous mixing with TiO 2 to prepare Ag(5%)@TiO 2 . After that, the Teflon container was sealed and transferred into a hydrothermal synthesis autoclave reactor and heated at 180°C for 12 h. After completing the hydrothermal process, the reactor was left to be cooled down in an ambient environment, and the Ag@TiO 2 was separated using a centrifuge at 4000 rpm. The product was washed three times using deionized water and dried at 60°C for 24 h.

General Method for Knoevenagel Condensation.
3-Chloro-1H-indole-2-carbaldehyde (1a, 0.5 g, 3 mmol) was introduced into a 50 mL reaction vessel with ethyl cyanoacetate (0.41 g, 3.9 mmol), 20 mL of solvent, and the developed catalyst (50 mg). The resulting mixture was warmed and stirred at 60°C in an oil bath for 1 h. Ethyl acetate (20 mL) was added to the reaction mixture after TLC confirmed that the reaction had been completed. The catalyst was then filtered out of the mixture. Under reduced pressure, the solvent was evaporated, disclosing the desired final product.

Characterization Instruments.
The XRD measurements of the developed catalysts were investigated by A Philips 1700 version diffractometer with Cu Kα radiation. The morphology and crystallinity of the developed catalyst were examined by TEM (JEOL, JEM-2100F, Japan), where an accelerating voltage of 200 kV was applied. Also, the element mapping was investigated by applying energy-dispersive X-ray spectroscopy (EDX). The XPS analysis was performed using a Kratos Axis Supra spectrometer with a monochromatic Al Kα radiation (1486.7 eV) at low pressure (<10 −6 Pa). The collected spectra were analyzed by CasaXPS software. The BET method was applied to estimate the surface area and average pore size of Ag@TiO 2 samples using NOVA 2200e (Quantachrome Instruments). The degasification was per-formed prior to the measurements under vacuum at 100°C for 12 h. Fourier transform infrared (FTIR) spectra of the developed catalysts were collected using a Bruker Tensor 37 spectrometer, where an ATR accessory was used with 4 cm −1 resolution. NMR spectra were collected using an INOVA-500 MHz instrument (Varian, Palo Alto, CA, USA), and trimethylsilyl propanoic acid (TSP) was used as an internal standard. Figure 1a Figure 1b shows the XRD spectra of normalized Ag(5%)@TiO 2 after subtracting the normalized XRD spectrum of TiO 2 to resolve the overlapping between the characteristic peaks of Ag and TiO 2 . A characteristic peak at 2θ of 38°was observed, which is indexed to the (111) crystallographic planes of Ag nanoparticles. 41,42 Peaks attributed to the (200), (220), and (311) crystallographic planes of Ag were also found at the same position. These XRD data illustrated that the Ag(0) was successfully formed on TiO 2 without changing the phases of TiO 2 . 40−42 Figure 2a shows the XPS Ag3d spectrum, where two peaks were observed at 368.4 and 374.4 eV, which are attributed to 3d 5/2 and 3d 3/2 , respectively. The energy separation between the two peaks is 6 eV, which illustrates the reduction of Ag + to metallic Ag nanoparticles. 40−42 The XRD spectrum of Ti2p is shown in Figure 2b, where two peaks corresponding to 2p 3/2 and 2p 1/2 were observed at 458.8 and 464.5 eV. 40,42 The separation between the two peaks is 5.7 eV which is the characteristic of Ti +4 of TiO 2 . Figure S1 shows the TEM image after the hydrothermal deposition of Ag nanoparticles on TiO 2 , where the sizes of Ag and TiO 2 nanoparticles were almost <10 nm and >20 nm, respectively. Besides, Ag nanoparticles with a size of <5 nm were observed and well distributed. Figure 2c shows the high resolution (HR)TEM image, where the d spacing  (111) and anatase TiO 2 (101), respectively. 19,42 The polycrystallinity of Ag@TiO 2 due to the presence of Ag, anatase TiO 2 , and rutile TiO 2 nanoparticles was also indicated from the SAED image illustrated in Figure S2. The EDX mapping of TiO 2 and Ag(5%)@TiO 2 components is illustrated in Figure S3, where the distribution of titanium, oxygen, and silver elements is shown. The BET surface area of TiO 2 (P25) increased to 78 m 2 /g after 5% Ag doping, which indicates the increase in the catalyst reactivity after doping.

Knoevenagel Condensation. 3.2.1. Optimal Reaction Conditions.
As previously stated, 3-chloro-1H-indole-2carbaldehyde (1a) represents an easily accessible source for the synthesis of 3-chloro-2-substituted indoles, so compound 1a was selected as a model substrate for this transformation, which then was allowed to react with ethyl cyanoacetate as the active hydrogen-containing compound, as illustrated in Table  1. Carrying out the reaction in the absence of the catalyst gave no product at all. However, the addition of TiO 2 (P25) nanoparticles to the reaction slightly enhanced the reaction activity, and product 3a was separated in a 10% yield (entry 2). Following the optimal conditions that we have previously obtained for the synthesis of Schiff bases using Au (5%)@ TiO 2 , 19 we successfully isolated the Knoevenagel product in a 70% yield (entry 3). The use of the Pt@TiO 2 catalyst gave a 50% yield product (entry 4). It has been reported that higher loadings of Au or Pt on TiO 2 would reduce the catalytic activity because of the increase in the sizes of the nanoparticles leading to a decrease in the active sites. 43,44 Interestingly, the Ag (5%)@TiO 2 catalyst smoothly delivered the product in a 90% yield as the best reaction yield (entry 5). Moreover, trying different Ag doping amounts on TiO 2 represented in 1% and 3% successfully delivered the product, but the yields were 60% and 65%, respectively (entries 6 and 7). Previous studies showed that the Ag loadings on TiO 2 with up to 10% would increase the adsorption capacity and photocatalytic activities of TiO 2 . 45,46 In Figure S1, the Ag nanoparticles with <5 nm were also observed and well distributed on TiO 2 , which could illustrate the reactivity increase with increasing Ag loadings.
Furthermore, optimization using different solvents (entries 8− 10) suggested that ethanol is the optimal solvent. Besides, increasing the catalyst load to 15 or 20 mg did not result in high yields, but when the load was attenuated to 0.5 or 5 mg, it led to the diminishing of the isolated yield (entries 11 −14). Reaction time and temperature were finally screened showing that the product smoothly obtained in a good yield when the reaction was conducted at 65°C for 1 h (entries 15−19).

Reaction Scope.
After identifying the optimal reaction conditions, the scope of this transformation using different aldehydes and active methylene-containing compounds was investigated. The target of this study is to find an eco-friendly approach for synthesizing different heterocyclic moieties through Knoevenagel condensation because of their biological importance. Hence, we turned our attention to the screening of different heterocyclic carbaldehydes, as shown in Table 2. The reaction proceeded smoothly with a wide range of heterocyclic aldehydes providing an interesting class of α,βunsaturated heterocycles. Both monocyclic and fused heterocyclic aldehydes were tolerated in this transformation under the optimal conditions. Aldehydes containing thiophene and pyrazole moieties gave the products 3e, 3j with an excellent yield up to 99%, while furan-2-carbaldehyde gave the product 3d in only 50% yield after 1 h; however, for a prolonged time of 3 h, 3d was isolated in 90% yield. Thiophene is well known to be adsorbed on noble metals like Au or Ag, which might facilitate the condensation and enhance the isolated yield. 47,48 Fused heterocyclic aldehydes underwent the reaction smoothly to afford Knoevenagel derivatives in good yields (up to 95%), where coumarin, quinoline, and naphthalene-containing carbaldehydes have fascinatedly tolerated in this conversion  with acceptable yields. Notably, tricyclic benzoquinoline aldehyde 1g underwent Knoevenagel condensation to give the product 3g in a 90% yield after 3 h. Interestingly, the reaction of 2-hydroxy-1-naphthaldehyde (1h) with ethyl cyanoacetate under the optimal conditions led to the formation of 3-oxo-3H-benzo[f ]chromene-2-carbonitrile (3h) instead of α,β-unsaturated product, which resulted from the cyclic condensation of the Knoevenagel intermediate by loss of the ethanol molecule, which has been further assigned by mass spectroscopy.
The scope of active methylene-containing compounds with 3-chloro-1H-indole-2-carbaldehyde was also examined under the standard reaction conditions, as shown in Table 3; various active methylene derivatives were found to be suitable substrates in this transformation with a good yield (between 80 and 99%). The use of cyanoacetamide and cyanothioacetamide produced derivatives 3m and 3o in 85 and 80%, respectively, while malononitrile and acetylacetone gave the 3k and 3n products in 82 and 99% yields, respectively. Moreover, the condensation of aldehyde 1a with malonic acid under the standard conditions gave the acrylic acid derivative 3l in 98%, which resulted from the decarboxylation of the Knoevenagel intermediate. 32 Furthermore, the substrates of indole-bearing active hydrogen were compatible enough in this methodology, producing 3p in 85%.
The generality of the current catalytic system has also extended to include different aromatic aldehydes that make the catalytic system more effective, as shown in Table 4. To achieve this goal, benzaldehyde was allowed to react with ethyl cyanoacetate under the standard conditions, and the product 3na was delivered in a 95% yield. Moreover, different aromatic aldehydes with electron-donating or electron-withdrawing substituents in o-, p-, and m-positions have been examined. p-Tolualdehyde reacted smoothly to give the product 3oa in 95% yield, whereas benzaldehyde with an electron deficiency NO 2 group in the p-position exhibited more activity, and the product 3pa separated in 98% yield. Also, p-chlorobenzaldehyde has successfully reacted to produce the product 3qa in a 95%yield. Furthermore, different aromatic aldehydes with osubstituents, namely, o-nitrobenzaldehyde and o-anisaldehyde have been examined, and the 3ra and 3sa products were isolated in 94 and 95%, respectively. Moreover, m-substituted  benzaldehyde including m-chlorobenzaldehyde and m-anisaldehyde have also successfully checked in this reaction, which gave products 3ta and 3ua in 95 and 97% yields, respectively. Finally, more substituted 2,4,5-trimethoxy benzaldehyde and cinnamaldehyde have also been tolerated, which afforded the products 3va and 3wa in excellent yields.
To show the synthetic utility of the Ag(5%)@TiO 2 , the yield of the 3na product and the applied procedures of some catalysts that have been reported are listed in Table 5. The present protocol offers advantages in the isolated yields, reaction time, and reaction conditions compared to the other catalysts.
To explore the synthetic practicality of our designed reaction, a scale-up protocol was carried out by the reaction of benzaldehyde (1n) with ethylcyano acetate (2a) under the optimal reaction conditions ( Figure 3). It proceeded smoothly to deliver the product 3na in a 95% yield. Given the versatile reactivity of the Knoevenagel products, in addition, indolestethered pyrazole or pyrimidine are considered one of the essential scaffolds in the medicinal chemistry field and found to exhibit a variety of biological activities, 63,64 a variety of further transformations can be carried out to generate new structures. For example, the hydrazinolysis of 3c in ethanol gave an interesting aminopyrazolidenone derivative 4. 65 Moreover, the reaction of compound 3c with thiourea in ethanol delivered the indolyl thioxopyrimidine derivative 5. Furthermore, the reaction of compound 3c with urea in ethanol and potassium carbonate gave the Biginelli product dihydropyrimidine 6.
3.2.3. Reaction Mechanism. According to the abovementioned findings and based on the previously reported studies concerning Knoevenagel condensation, the suggested mechanism for Ag@TiO 2 catalyzed Knoevenagel condensation is illustrated in Figure 4. 66,67 Among various condensation reactions, Knoevenagel condensation is a well-known reaction, and it can be catalyzed by different kinds of organic bases, acids, or catalysts containing both acid and basic sites. 15,68 The mechanism can be explained as, in the first step, the acidic centers of Ag@TiO 2 would activate the carbonyl group of aldehydes to coordinate between these centers and the oxygen of carbonyl groups. 15,19,24 The active hydrogen species would attach to the carbon of the carbonyl group, which then protonated and underwent water elimination, resulting in the product. The coordination environment surrounding the Ag centers is anticipated to prevent the sterically congested Z-type product.
3.2.4. Recyclability. Catalyst recycling was performed by separating the catalysts from the reaction mixture. Then, the separated catalyst was washed in ethanol three times and dried at 80°C for 12 h. The recycled catalyst was characterized by FTIR and XRD. The XRD pattern ( Figure S4) of the recycled catalyst, where the characteristic peaks of Ag nanoparticles, rutile TiO 2, and anatase TiO 2 were still observed without significant changes compared to the as-prepared Ag@TiO 2   Figure S5, where the absorption bands at 1400 and <700 cm −1 were ascribed to Ti−O−Ti (TiO 2 ). 19,69 Bands at 1615 and 3413 cm −1 were attributed to the absorbed water. 19,69 No significant changes were observed after recycling. As previously described, the development of the Ag@TiO 2 catalyst is facile without requiring complicated steps or careful handling. Besides, the use of this catalyst for performing Knoevenagel condensation did not require harsh conditions or applying hazardous materials. Also, the catalyst was effective alongside 5 cycles without a significant decrease in the isolated yield, as shown in Figure 5. These results illustrate the reactivity of Ag@TiO 2 in catalyzing the Knoevenagel condensation for several cycles. Also, green, and eco-friendly conditions can be applied during Knoevenagel condensation in the presence of Ag@TiO 2 , and the yield approaches up to 40%. Besides, the reuse of the catalyst does not require specific treatments.

CONCLUSIONS
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