Dendrons containing boric acid and 1,3,5-tris(2-hydroxyethyl)isocyanurate covalently attached to silica-coated magnetite for the expeditious synthesis of Hantzsch esters

A new multifunctional dendritic nanocatalyst containing boric acid and 1,3,5-tris(2-hydroxyethyl)isocyanurate covalently attached to core–shell silica-coated magnetite (Fe3O4@SiO2@PTS-THEIC-(CH2)3OB(OH)2) was designed and properly characterized by different spectroscopic or microscopic methods as well as analytical techniques used for mesoporous materials. It was found that the combination of both aromatic π–π stacking and boron–oxygen ligand interactions affords supramolecular arrays of dendrons. Furthermore, the use of boric acid makes this dendritic catalyst a good choice, from corrosion, recyclability and cost points of view. The catalytic activity of Fe3O4@SiO2@PTS-THEIC-(CH2)3OB(OH)2, as an efficient magnetically recoverable catalyst, was investigated for the synthesis of polyhydroacridines (PHAs) as well as polyhydroquinolines (PHQs) via one-pot multicomponent reactions of dimedone and/or ethyl acetoacetate, different aldehydes and ammonium acetate in EtOH under reflux conditions. Very low loading of the catalyst, high to quantitative yields of the desired PHAs or PHQs products, short reaction times, wide scope of the substrates, eliminating any toxic heavy metals or corrosive reagents for the modification of the catalyst, and simple work-up procedure are remarkable advantages of this green protocol. An additional advantage of this magnetic nanoparticles catalyst is its ability to be separated and recycled easily from the reaction mixture with minimal efforts in six subsequent runs without significant loss of its catalytic activity. This magnetic and dendritic catalyst can be extended to new two- and three-dimensional covalent organic frameworks with different applications.

MCRs are one-pot reactions that involve more than two substrates demonstrating convergence as well as very high atom efficiency and bond-forming-index (BFI) [88][89][90] . Thus, MCRs are usually a good alternative for the sequential multistep synthesis, especially for useful heterocyclic scaffolds such as Hantzsch esters including 1,4-dihydropyridines (DHPs), PHQs and PHAs in organic synthesis and medicinal chemistry [91][92][93][94][95][96] . Generally known as one of the main groups of nitrogen heterocycles, polyhydroquinolines (PHQs) and polyhydroacridines (PHAs) have become considerably interesting due to their significant therapeutic and pharmacological properties [97][98][99][100] . Indeed, they are used as antimalaria, calcium β-blocker, antioxidant, antimicrobial, antifungal, vasodilator, anticancer, bronchodilator, antiatherosclerotic, geroprotective, hepatoprotective and antidiabetic agents as well as in the production of laser colors, radical reservoirs and safe hydrogen transfer agents 4,101-111 . First introduced by Arthur Hantzsch in 1882, Hantzsch reaction is an MCR that contains the combination of a β-dicarbonyl compound, an aldehyde and a source consisting of ammonia (usually NH 4 OAc) 112 . However, catalytic systems are required to accelerate this multicomponent reaction. Here are some recent reported catalysts in this area: Mn@PMO-IL 103 , vanadium ion doped titania nanoparticles 113 , Lewis acidic mesoporous material (TUD-1) containing Fe 114 , magnetite nanoparticle-supported ceria 41 , silica-coated magnetic nanoparticles with tags of ionic liquid 115

Results and discussion
Characterization of dendritic nanocatalyst containing boric acid and 1,3,5-tris(2-hydroxyethyl)isocyanurate covalently attached to core-shell silica-coated magnetite (Fe 3 O 4 @SiO 2 @ PTS-THEIC-(CH 2 ) 3 OB(OH) 2 , 1). At first, the boric-acid-functionalized-1,3,5-tris(2-hydroxyethyl)isocyanurate attached to the silica-coated SPIONs (Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 , 1) was characterized using different spectroscopic or analytical methods. As it has been shown in FT-IR spectrum (Fig. 1), the absorption bands at around 632 and 572 cm −1 are related to the Fe-O bond vibrations. On the other hand, absorption band of Si-O-Si asymmetric stretching vibrations are apparent at around 1076 cm −1 . Furthermore, the observed signals at 954, 802 and 459 cm -1 are assigned to the symmetric stretching and bending vibrations of Si-O-Si bond 43,57,124 . Also, the absorption band of C=O bond vibrations of the isocyanurate moiety appeared at around 1637 cm −177,120,125 . Furthermore, the signals in range of 1350-1000 cm −1 belong to the C-N bonds vibrations. On the other hand, the absorption band of B-O vibrations appeared at 1510 cm −1 . Furthermore, there is an absorption signal at around 1191 cm −1 which is related to B-O-H bond vibrations. Also, the signal at 563 cm −1 is assigned to O-B-O bond vibrations. It is generally accepted that the broad band centred at 3400 cm −1 is ascribed to the stretching vibrations of O-H bonds 126,127 . All of these data demonstrate that the catalyst 1 has been successfully prepared.
Thermal gravimetric analysis (TGA) and differential thermal analysis (DTA) measurements were carried out under air atmosphere by heating the sample at the rate of 10 °C min −1 up to 800 °C (Fig. 5). The first weight loss under 100 °C is related to the removal of water and organic solvents which have remained in the dendritic catalyst through its preparation processes. On the other hand, the second weight loss about 150 °C can be assigned to the dehydration of boric acid moieties and their condensation. Furthermore, two distinct weight losses about 460 and 510 °C are attributed respectively to the decomposition of aliphatic linkers and 1,3,5-tris(2-hydroxyethyl) isocyanurate moieties in the structure of the dendritic Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 catalyst (1) according to the data obtained by DTA (Fig. 5b).

Investigation of the catalytic activity of dendritic Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 (1) for the synthesis of Hantzsch esters.
After characterization of the dendritic Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 catalyst (1), the Hantzsch reaction for the synthesis of polyhydroacridine and polyhydroquinoline derivatives was chosen to examine the catalytic activity of Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 (1). For this purpose, the condensation of 4-chlorobenzaldehyde (2a, 1 mmol), dimedone (3), NH 4 OAc (4, 1 mmol) and/or ethyl acetoacetate (6, 1 mmol) were selected as the model reactions, for the synthesis of polyhydroacridine 5a and polyhydroquinoline 7a, respectively. The reactions were optimized considering different parameters such as the amount of catalyst loading, solvents and temperature. The results are reported in Table 1. Indeed, the reaction yield for the desired products 9-(4-chlorophenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione (5a) or ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahyd-   www.nature.com/scientificreports/ roquinoline-3-carboxylate (7a) were trace in the absence of any catalyst in EtOH at room temperature (entry 1). However, low yields of the desired products 5a and 7a were obtained under reflux conditions (entry 2) after long times. Interestingly, the yields were improved significantly in the presence of dendritic Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 catalyst (1, entries [3][4][5]. Further optimization of the reaction conditions illustrated that EtOH is the best solvent to promote the reaction with high efficiency for the synthesis of the desired products 5a or 7a (entries 6-12). The results of optimizing of the model reactions demonstrated that the optimal conditions for the reaction are 10 mg catalyst 1 loading in EtOH under reflux conditions. On the other hand, both boric acid and Fe 3 O 4 @SiO 2 @PTS-THEIC, as the components of the catalyst 1, afforded moderate yields of the desired products 5a and 7a at same catalyst loading under optimized conditions (entries 13 and 14). Finally, hot filtration test (the Sheldon test) was performed to prove the heterogeneous nature of the catalyst 1. During this test, the solid catalyst 1 was removed from the mixture of model reaction for producing 7a by filtration after 10 min using an external magnet. Then, the obtained mixture was heated again for 10 min. The result showed that after removal of the magnetic catalyst 1, the model reaction did not proceed significantly. Indeed, only 48% of the desired product 7a was isolated after 1 h (Fig. 8).
After finding the optimal conditions, the catalytic activity of Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 nanocatalyst (1) was further expanded to several other aromatic or heterocyclic aldehydes for the synthesis of other derivatives of PHAs 5a-o and PHQs 7a-u. As it is shown in Tables 2 and 3, the isolated yields of the desired products 6 or 8 were good to excellent in all studied cases under the optimized condition of reaction. In most cases, the products were obtained in similar periods of time and yields compared to the model reaction. Indeed, aldehydes including aromatic carbocyclic or heterocyclic substrates well survived under optimized conditions without formation of any by-products. It is noteworthy that aldehydes bearing electron-withdrawing groups or six-membered heterocycles almost reacted faster than substrates having electron-donating groups or five-membered heterocycles. This trend of reactivity was observed in both symmetric and asymmetric Hantzsch reaction to afford PHAs 5a-o or PHQs 7a-u derivatives, respectively. Furthermore, the α,β-unsaturated cinnamaldehyde (2q) or aliphatic butyraldehyde (2r) reacted in longer reaction times and afforded lower yields. These may be due to resonance and electron-releasing of the double bond and alkyl groups, respectively. All of these findings, led us to purpose a plausible mechanism depicted in Scheme 2.
An important distinguishing feature of this magnetic dendritic nanocatalyst (1) beside easy separation from the reaction mixture is its recyclability. After the reaction was completed, the catalyst was separated and washed by acetone and hexane, respectively. Then, it was dried and reused in the model reactions for the next runs. The obtained results have been summarized in Fig. 9. These results show that this catalyst can be recovered and reused at least for five times in further runs under optimized conditions without a notable loss of its activity. Furthermore, comparison of the FTIR spectra of both fresh dendritic Fe 3 O 4 @SiO 2 @CPTS-THEIC-(CH 2 ) 3 OB(OH) 2 nanocatalyst (1) and the recycled sample after six consecutive runs for the synthesis of 5a demonstrated that their structures are almost similar (Fig. 10). Table 4 contains some of the formerly reported methods and representing their catalytic activity for the synthesis of polyhydroacridines and polyhydroquinolines to compare them with the dendritic Fe 3 O 4 @SiO 2 @ CPTS-THEIC-(CH 2 ) 3 OB(OH) 2 . These data clearly demonstrate that the nanocatalyst 1 is more active than other previously reported catalytic systems in terms of catalyst loading, product yield, required reaction time and avoiding the toxic solvents.  www.nature.com/scientificreports/ Experimental section. General information. All chemicals and reagents were provided by Merck or Aldrich chemical companies and used as received without any further purification, except for benzaldehyde which was used as a fresh distilled sample. FTIR spectra were recorded using KBr pellets on a Shimadzu FT IR-8400S spectrometer. Energy dispersive spectroscopy (EDS) was recorded on a SAMx instrument. The X-ray powder diffraction (XRD) data were collected on an X'Pert MPD Philips diffractometer with Cu radiation source (λ = 1.54050 Å) at 40 kV voltage and 40 mA current. Field emission scanning electron microscopy (FESEM) images were obtained using a MIRA3 instrument of TESCAN Company, Czech Republic. Thermal gravimetric analysis (TGA) and differential thermal analysis (DTA) were performed by means of a Bahr company STA 504 instrument. The BET specific surface area of the catalyst 1 was obtained using an equipment ASAP 2020 Micromeritics. Magnetic susceptibility measurements were taken out by using a Lakeshore VSM, 7410 series. Melting points were determined using an Electrothermal 9100 apparatus and are uncorrected. 1 H NMR (500 MHz) spectra were obtained using a Bruker DRX-500 AVANCE spectrometer in CDCl 3 at ambient temperature. Analytical TLC was carried out using Merck 0.2 mm silica gel 60 F-254 Al-plates and n-hexane: EtOAc, (3:1, v/v %) as eluent. All products are known and their structures were established by comparing the physical constants as well as FTIR and NMR spectroscopic data with authentic samples 120,122,141 .

Preparation of the dendritic Fe 3 O 4 @SiO 2 @PTS-THEIC-(CH 2 ) 3 OB(OH) 2 nanocatalyst (1).
A mixture of Fe 3 O 4 @SiO 2 @CPTS@THEIC (1 g) and 1,3-dibromopropane (d = 1.98 g.cm −3 , 2 ml) was added to toluene (15 ml) and heated at 40 °C for 12 h. The obtained solid was filtered off, washed with toluene (5 ml) and then dried in a vacuum oven at 60 °C for 2 h. The as-prepared solid and H 3 BO 3 (1 g) were mixed in EtOH (30 ml) and the obtained mixture was stirred at room temperature for 18 h. After completion of the process, the obtained brown solid was filtered off and washed with EtOH (5 ml) on a Buchner funnel and then kept in a vacuum oven at 60 °C for 12 h. The complete procedure for the preparation of catalyst 1 has been represented in Scheme 3.

Conclusions.
In conclusion, the multifunctional dendritic nanocatalyst containing boric acid and 1,3,5-tris(2-hydroxyethyl)isocyanurate covalently attached to core-shell silica-coated magnetite (Fe 3 O 4 @SiO 2 @ PTS-THEIC-(CH 2 ) 3 OB(OH) 2 ) was prepared and properly characterized for the first time. It was found that the combination of both aromatic π-π stacking and boron-oxygen ligand interactions affords supramolecular arrays of dendrons. The use of boric acid makes this dendritic catalyst a green choice from corrosion, recyclability and cost points of view. The magnetic dendritic catalyst was used, as a mild and recyclable catalyst, for the one-pot efficient synthesis of polyhydroacridines and polyhydroquinolines through MCR strategy in EtOH as a green solvent. Indeed, very low catalyst loading, short reaction times, mild reaction conditions, high to excellent yields, reusability of the catalyst, ease of separation by an external magnetic field, and the use of nontoxic materials for the preparation of the catalyst are among other advantages of this protocol. Further exploring of this magnetic dendritic magnetic catalyst for other organic transformations is underway in our research lab and would be presented in due course.