Efficient synthesis of benzoacridines and indenoquinolines catalyzed by acidic magnetic dendrimer

A novel solid acid catalyst with recoverability, named as Fe3O4@SiO2@TAD-G2-SO3H, was successfully synthesized by immobilizing sulfonic acid groups on triazine dendrimer-modified magnetic nanoparticles. This nanomaterial structure and composition were thoroughly characterized using various analytical techniques, including thermogravimetric analysis (TGA), elemental analysis, Fourier transform infrared spectroscopy (FT-IR), energy-dispersive X-ray spectroscopy (EDX), elemental mapping, acid–base titration, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and vibrating sample magnetometry (VSM). The acid-decorated magnetic dendrimer was served as a highly effective catalyst for the synthesis of tetrahydrobenzo[c]acridin-8(9H)-one and benzo[h]indeno[1,2-b]quinoline-8-one derivatives. The reaction proceeded smoothly under mild conditions through the one-pot condensation of aromatic aldehydes, 1-naphthylamine, and either dimedone or 1,3-indanedione, affording the desired products in high yields ranging from 90 to 96%. The catalyst was easily separated from the reaction mixture by employing a magnetic field, allowing for its recycling up to five times with slight loss in its activity (only 10%). Nearly, quantitative recovery of catalyst (up to 95%) could be obtained from each run. So, this catalyst facilitates the reaction progress and simplifies the purification process. Other remarkable features of this method are operational simplicity, excellent yields, mild condition, and a wide range of substrate applicability.

The development of efficient and environmentally friendly synthesis methods for complex organic molecules is crucial in modern organic chemistry.Traditionally, organic synthesis involved multiple steps, each requiring individual reactions and purification processes.This approach consumed significant amounts of energy and generated substantial waste.multicomponent reactions (MCRs), on the other hand, enable the simultaneous assembly of multiple reactants into complex molecules in a single step.The development and utilization of MCRs has revolutionized the field of organic and medicinal chemistry 1 .The ability to combine multiple starting materials in a one-pot reaction greatly streamlines the synthesis process, minimizes energy consumption and waste generation, saves time and resources, and enhance overall synthetic efficiency.In addition, MCRs often exhibit high atom economy, meaning that a large proportion of the starting materials are incorporated into the final product without generating unnecessary byproducts 2 .
Acridine derivatives have attracted considerable attention for their potential pharmacological activity.These compounds have shown promising results in various areas of medicine, including anticancer, antimalarial, antimicrobial, anti-inflammatory, and calcium antagonist activities [3][4][5][6][7][8] .Their ability to inhibit DNA (deoxyribonucleic acid) replication and induce apoptosis has made them attractive candidates for the development of novel chemotherapeutic agents 9 .
The wide range of biological activities exhibited by quinoline derivatives has garnered significant interest among organic chemists.Consequently, numerous synthetic pathways have been devised to facilitate the synthesis of quinoline-fused heterocycles.Indenoquinoline derivatives exhibit various pharmacological effects, including antitumor, antimalarial, anti-inflammatory, steroid reductase and acetylcholinesterase inhibitory, and anticancer activities [10][11][12] .These properties render them highly promising candidates for the development of diverse

Experimental
Cyanuric chloride, tetrabutylammonium bromide, ethanolamine, chlorosulfonic acid, dioxane were commercially supplied by Merck and Acros companies.FeCl 3 .(H 2 O) 6 , FeCl 2 .(H 2 O) 4 , KOH, NaOH, HCl, and ethanol were commercially supplied by neutron chemical company (Iran).All the materials and reagents were used without any further purification.Fourier-transform infrared spectroscopy (FT-IR) measurements were conducted using a KBr pellet and an Alpha Bruker Fourier transform (FT-IR) spectrophotometer, covering the range of 400-4000 cm −1 .The crystallinity of the nanomaterials was assessed using.A Philips Xpert X-ray powder diffraction (XRD) instrument, employing Cu-Kα radiation with a wavelength of λ = 0.1545 was applicated to evaluate the crystallinity of nanomaterials.To examine the surface morphology and elemental distribution, a MIRA 3-XMU field emission scanning electron microscope (FE-SEM) equipped with energy dispersive X-ray analysis (EDX) was employed.Thermogravimetric analysis (TGA) was performed on a Mettler TA4000 system under a nitrogen atmosphere, within the temperature range of 25-800 °C, with a heating rate of 15 °C/min.The magnetic properties of the nanoparticles were investigated using a 730 vibrating sample magnetometer (VSM) at room temperature.
The Fe 3 O 4 @SiO 2 -TzCl 2 (1 g) was dispersed in 20 mL of dioxane for a duration of 20 min.Subsequently, K 2 CO 3 (5 mmol, 0.7 g) and ethanolamine (10 mmol, 0.7 g) were introduced to the mixture and subjected to reflux for a period of 24 h.The resulting solid was collected using an external magnet, rinsed with ethanol, and then dried under vacuum at a temperature of 50 °C.
Fe 3 O 4 @SiO 2 @TAD-G1 (1 g) was poured into a round-bottom flask and dispersed in dichloromethane (50 mL) for 10 min.Then, Cyanuric chloride (10 mmol, 1.8 g), tetrabutylammonium bromide (TBAB) (0.001 g), and 1 mL of NaOH (10 M) were added to the suspension and stirred for 2 h at 5 °C in an ice water bath.Afterward, the mixture was stirred at room temperature for 24 h.The resulting black precipitate was isolated using an external magnet, washed with dichloromethane, and dried.Next, the obtained particles (1 g) were mixed with K 2 CO 3 (10 mmol, 1.4 g) and ethanolamine (20 mmol, 1.2 g) in dioxane (50 mL).The suspension was refluxed for 24 h.The resulting precipitate was isolated, washed with ethanol, and dried under vacuum at 50 °C.
Preparation of acid-decorated dendritic nanoparticles (Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H) Fe 3 O 4 @SiO 2 @TAD-G2 (1 g) was dispersed in 40 mL of dichloromethane and stirred for 20 min.Subsequently, a solution of chlorosulfonic acid (2 mL) in 5 mL of dichloromethane was meticulously prepared and slowly added to the mixture over the course of 1 h.The resulting solid was collected using an external magnet, thoroughly washed with dichloromethane, and subsequently dried under vacuum at 50 °C.

Acidity of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H
The concentration of sulfonic acid groups was determined by quantitatively estimating it using back titration with HCl (0.01 N).Initially, 2 mL of KOH (0.01 N) was added to 0.02 g of the Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H nanoparticles, and the mixture was stirred for a duration of 30 min.Subsequently, the catalyst was separated and thoroughly washed with deionized water.To determine the excess amount of KOH, it was titrated with HCl (0.01 N) in the presence of phenolphthalein as an indicator.To ensure precision, three separate titrations were conducted, and the average value was calculated to ascertain the acid content of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H.The findings revealed that this nanostructure possessed an acid content of 2.5 mmol g −1 .

General procedure for the synthesis of benzo[c]acridin-8(9H)-ones (5a-i):
In a 25 mL round bottom flask, an aromatic aldehyde (1 mmol), dimedone (1 mmol, 0.14 g), and 1-naphthylamine (1 mmol, 0.143 g) were combined in 5 ml of ethanol/water (1:1).This mixture was stirred in the presence of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H (0.03 g) at a temperature of 70 °C.To monitor the progress of the reaction, thin-layer chromatography (TLC) with a solvent mixture of n-hexane and ethyl acetate (2:1) was used.Once the reaction was completed, the catalyst separated from the reaction medium using a magnet.Next, the solvent was evaporated and the product recrystallized using ethanol.Finally, the product was dried in an oven at 50 °C.

General procedure for the synthesis of benzo[h]indeno[1,2-b]quinolin-8-ones (6a-h):
In a 25 mL round bottom flask, an aromatic aldehyde (1 mmol), 1,3-indanedione (1 mmol, 0.146 g), 1-naphthylamine (1 mmol, 0.143 g), and Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H (0.03 g) was combined in 5 mL of a 1:1 mixture of ethanol/water.The mixture was stirred in the presence of 5 mL of a 1:1 mixture of ethanol and water at a temperature of 70 °C.Thin-layer chromatography (TLC) with a solvent mixture of n-hexane and ethyl acetate in a ratio of 3:1 was used to monitor the progress of the reaction.Once the reaction was completed, the catalyst was separated from the reaction medium using a magnet, and the solvent was evaporated.Finally, the product was recrystallized using ethanol and dried in an oven at 50 °C.

Results and discussion
In this study, sequential reactions were employed to introduce dendrimers onto solid supports (divergent strategy).This was achieved by attaching a linker onto the surface of magnetic nanoparticles and the triazine-based poly-aminoethanol (TAD) dendrimers was successfully grown on the surface of silica-coated magnetite nanoparticles via sequential reactions (Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H, Fig. 2).Initially, magnetite (Fe 3 O 4 ) nanoparticles were easily prepared via the chemical co-precipitation of Fe 2+ and Fe 3+ ions in basic solution.Next, a layer of silica was placed on the magnetic iron nanoparticles, via Stober method, to prevent their aggregation and oxidation.Then, the (3-aminopropyl)triethoxysilane (APTMS) as a linker was grafted to the surface of Fe 3 O 4 @SiO 2 particles under nitrogen atmosphere to produce the Fe 3 O 4 @SiO 2 @PrNH 2 nanostructure 49 .In the subsequent stages, TAD dendrons (functional arms) up to generation two (G2) were constructed through a sequential and progressive nucleophilic aromatic substitution of ethanolamine on the aromatic triazine ring 34,50 .Ultimately, the nanoparticles were decorated with acidic groups through a reaction of active -NH and -OH groups with chlorosulfonic acid.Figure 3, shows the FT-IR spectra of Fe 3 O 4 , Fe 3 O 4 @SiO 2 , Fe 3 O 4 @SiO 2 -PrNH 2 , Fe 3 O 4 @SiO 2 -TzCl 2 , Fe 3 O 4 @ SiO 2 @TAD-G1, Fe 3 O 4 @SiO 2 -Tz-BEA-TzCl 4 , Fe 3 O 4 @SiO 2 @TAD-G2, Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H in the wavenumber range of 400-4000 cm −1 .The FT-IR spectrum of the bare magnetic Fe 3 O 4 nanoparticles exhibited the characteristic Fe-O absorption band in the range of 580 cm −1 (Fig. 3a).The bands observed at 1101, 900-800, and 450 cm −1 , correspond to asymmetric stretching, symmetric stretching, in-plane bending of the Si-O-Si and Si-O bonds, respectively (Fe 3 O 4 @SiO 2 spectrum, Fig. 3b).The band in the region of 1300 cm −1 is related to the stretching bond S = O (Fig. 3h).The broad band in the range 3200-3500 cm −1 appertained to the stretching www.nature.com/scientificreports/vibration mode of Si-OH bonds and the weak band at 1630 cm −1 related to the twisting vibration mode of H-O-H adsorbed in the silica layer.The presence of alkyl groups has been corroborated by the weak symmetric and asymmetric stretching vibrations at 2980 and 2895 cm −1 (Fig. 3c-h).Also, the bands corresponding to C = N, C = C, and C-N appeared at 1350-1600 cm −1 (Fig. 3d-h) 34,51 .The N-H bending vibration is overlapped with O-H vibration.Therefore, these results confirm the successful bonding of different functional groups at each fabrication step.The crystallinity of Fe 3 O 4 (a), and Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H (b) was analyzed using X-ray powder diffraction patterns (Fig. 4).By comparing the XRD patterns of Fe 3 O 4 and Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H, it can be confirmed that the ferrite core remains stable without undergoing any phase changes during the functionalization process 52 .The XRD patterns of the prepared Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H show distinct diffraction peaks at 2θ = 30.2°,35.4°, 43.7°, 56.6°, and 63.0°, corresponding to the (220), (311), (400), (422), (511), and (440) Miller planes of Fe 3 O 4 nanoparticles.These XRD patterns confirm that the material structure has a cubic spinel phase (Fig. 4a,b) and match with the standard Fe 3 O 4 sample (JCPDS file No. 19-0629) 53,54 .The presence of the SiO 2 layer is confirmed by the appearance of a broad peak at 2θ = 18° to 25° (Fig. 4b).To determine the average crystallite size of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H, the Scherrer equation (D = Kλ/βcosθ) was employed.In this equation, λ is the x-ray Cu wavelength, β is the width of the X-ray peak on the 2θ axis which measured as the line broadening at half the maximum intensity, θ is Bragg angle, and K is the so-called Scherrer constant.The crystallite size calculated from the width of the peak at 2θ = 35.4°(311), is approximately 102 nm 41 .
The size and morphology of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H are investigated by field emission scanning electron microscopy (FE-SEM).As shown in Fig. 5, the Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H nanostructure possesses nearly spherical morphology with an average size of 100-130 nm.
The results obtained from X-ray energy diffraction spectroscopy (EDX) of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H magnetic nanoparticles (Fig. 6) confirm the presence of elements S, C, N, Si, O, Fe in the hybrid nanostructure.The higher intensity of the peak corresponding to the elements Si and S compared to the Fe peak indicates that the Fe 3 O 4 nanoparticles have been covered by SiO 2 layer and -SO 3 H functionalities on the surface of the nanostructure.The terminal ends of the catalyst have a lot of -SO 3 H groups, causing the sulfur have a higher peak intensity.These results provide evidence for the successful synthesis of the core-shell nanostructure (Fe 3 O 4 @ SiO 2 @TAD-G2-SO 3 H).Moreover, the EDX map analysis reveals a good distribution of various elements including Fe (a), N (c), S (d), O (e), and Si (f) throughout the nanostructure.
Thermal gravimetric studies were conducted within the temperature range of 25-800 °C under a N 2 atmosphere, to evaluate the thermal stability of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H (Fig. 7).A weight loss of approximately 4-6% is observed in the temperature range of 25 to 250 °C, which is attributed to the loss of residual solvent and water on the sample surface (physically absorbed) process.Furthermore, a significant weight loss of approximately 40% was observed in 250-650 °C, which can be attributed to the degradation of dendrimer branches and organic moieties, followed by a phase change in the silica nanoparticle groups.The remaining weight (˃650 °C) is attributed to inorganic support which was not decomposed.The magnetization curves of Fe 3 O 4 (a), Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H (b) were measured using the VSM technique at room temperature, within the range of ± 8000 Oe (Fig. 8).The S-like magnetization curves, the coincidence of the hysteresis loop, and the low remanence and coercivity confirm the superparamagnetic properties of these hybrid materials.As seen in Fig. 6, the saturation level for the Fe 3 O 4 sample is 40 emu g −1 , While it is 15 emu g −1 for Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H nanostructure.This decrease in magnetic property indicates the presence of a surface coating on the Fe 3 O 4 nanoparticles, confirming the core-shell structure and the grafting of the dendritic branches to the magnetic nanoparticles.
After the characterization of the Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H catalyst, its catalytic activity was evaluated for the synthesis of benzo[c]acridin-8(9H)-one derivatives (Fig. 1).For this purpose, the reaction of 4-chlorobenzaldehyde (1 mmol), dimedone (1 mmol) and 1-naphthylamine (1 mmol) was used as a model and conducted under different reaction parameters including the catalyst amount, solvent, and temperature (Table 1).The best result was achieved when the reaction took place in the presence of 30 mg of the catalyst, in a polar solvent mixture of H 2 O/EtOH (1:1), and at a temperature of 70 °C (Table 1, entry 9).In continuation, the catalytic activity of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H catalyst was evaluated for the synthesis of benzo[h]indeno[1,2-b]quinolin-8-ones.Interestingly, the best result was achieved in H 2 O/EtOH (1:1) at 70 °C, using 30 mg of the catalyst.After obtaining the best conditions for the reaction, various arylaldehydes including electron-withdrawing and electron-releasing groups were subjected to the reactions.All substituted arylaldehydes effectively reacted and afforded the corresponding products in excellent yields without any side product (Table 2).
A plausible mechanism is shown in Fig. 9.The carbonyl group of the aldehyde is initially protonated using the acidic catalyst.Subsequently, dimedone is enolized in acidic condition and undergoes condensation with activated aldehyde, leading to the formation of an intermediate (I).In the next step, the intermediate (I) is subjected to nucleophilic attack by 1-naphthylamine and followed by tautomerization, resulting in the production of structure (II).The intramolecular cyclization of compound (II) and elimination of water ultimately yields the benzoacridine (4).The catalytic activity of Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H MNPs for the model reaction was also compared with that reported in the literature (Table 3).These data confirm that the Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H nanostructure is a suitable catalyst for synthesizing the desired corresponding product.The absence of the need for extraction with organic solvents not only simplifies the synthesis process but also reduces the environmental impact of the reaction.Overall, these results highlight the potential of this nanostructure as a green and efficient catalyst for other organic transformations.

Catalyst recovery and reuse
The catalyst retrievability plays a crucial role in industrial applications, as well as in promoting environmentally friendly processes.Therefore, we conducted an investigation into the reusability of the Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H catalyst in a sequential reaction involving 4-chlorobenzaldehyde (1 mmol), 1-naphtylamine (1 mmol), and dimedone (1 mmol) in a H 2 O/EtOH (1:1) mixture at 70 °C.After the reaction was completed, the resulting mixture solidified.To dilute it, 10 mL of hot EtOH was added.The catalyst was easily separated using an external magnet, washed with hot EtOH, dried under vacuum, and reused in the next reaction.Each run allowed for the nearly complete recovery of the catalyst, with up to 95% being obtained.The reused catalyst exhibits high efficiency in the synthesis of benzoacridine, as depicted in Fig. 10.The stability of the catalyst is further considered by the FT-IR spectra of the reused catalyst (Fig. 10), which proves the stability of catalyst in reaction condition.

Conclusions
A solid acid catalyst (Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H) which can be easily retrieved using magnets, was successfully synthesized and characterized.This catalyst was created by growing triazine dendrimer on silica-coated magnetic nanoparticles, while also immobilizing sulfonic acid groups.The prepared dendritic nanostructure (Fe 3 O 4 @SiO 2 @TAD-G2-SO 3 H) efficiently catalyzed the synthesis of benzo[c]acridin-8(9H)-one and benzo[h] indeno[1,2-b]quinoline-8-one derivatives in excellent yields (90% to 96%).Grafting of dendrimer increases the active sites on Fe 3 O 4 nanoparticles and decreases their agglomeration.The catalyst can be easily separated from the reaction mixture by employing a magnetic field, allowing for its recycling up to five times with slight loss in its activity (10%).Other advantages of this protocol include the use of aqueous ethanol as a mild reaction media, operational simplicity, high to excellent yields, high atom-economy, easy separation of the catalyst, reusability, and elimination of the need for tedious column chromatography during product isolation and purification.These aspects align with the principles of green and sustainable chemistry, which aim to design chemical products and processes that reduce or eliminate hazardous substances and waste generation.

Figure 10 .
Figure 10.Reusability of the catalyst, and FT-IR spectra of the fresh and reused nanocatalyst.