One-pot synthesis of 1-(benzothiazolylamino)aryl methyl-2-naphthols and 3-benzothiazolyl 2,3-dihydroquinazolinones using a magnetically recoverable core–shell nanocomposite as catalyst

1 Introduction

Magnetic nanoparticles have attracted much attention in biomedical fields, electronics, and catalytic processes due to their unique features [1], [2]. Catalytic magnetic nanoparticles have the notable advantage to be simply separable from a reaction mixture by application of a magnetic field. Some have been shown to be of advantage in terms of easy synthesis, reusability, high catalytic activity and excellent thermal and chemical stability in various organic solvents and chemical processes [3], [4]. Considering these aspects, magnetic core–shell nanocomposites have attracted much attention in green organic synthesis [5], [6]. These composite systems have shown remarkable potential in practical applications [7], [8]. In particular, various organic/inorganic materials as the shell supported on magnetite (Fe₃O₄) nanoparticles as the core have been synthesized and utilized as catalysts in diverse organic transformations [9], [10], [11], [12], [13], [14], [15], [16].

2-Aminobenzothiazoles are widely used in the formation of a variety of fused heterocyclic compounds, which have gained attention in medicinal and biological chemistry [17]. Benzothiazole derivatives have shown a wide spectrum of pharmacological applications in particular for their antiinflammatory, anticonvulsant, antitumor, and antitubercular activities [18], [19], [20]. Furthermore, they are also commercially important as antioxidants [21], vulcanization accelerators [22], and a dopant in light-emitting organic electroluminescent devices [23].

Various protocols have been developed for the synthesis of functionalized benzothiazoles [24], [25]. Among them, 1-(benzothiazolylamino)aryl-methyl-2-naphthols have two biologically active parts, 2-aminobenzothiazole and aminoalkyl naphthols (Betti Base). Aminoalkyl-2-naphthols have provided convenient access to some useful synthetic building blocks through their amino and phenolic hydroxy functional groups [26].

In the literature, 1-(benzothiazolylamino)arylmethyl-2-naphthols have been synthesized by three-component condensation reactions of 2-aminobenzothiazole, aldehydes and 2-naphthol. Catalysts utilized for these syntheses include maltose [27], heteropoly acids [28], oxalic acid [29], Fe₃O₄@SiO₂-ZrCl₂ [12], imidazolium ionic liquids [30], [31] and magnetic heterogeneous catalysts [32], [33], [34].

Quinazolinone derivatives are of particular value because of their promising biological and pharmacological activities such as anticancer, antidiuretic, anticonvulsant and sedative behavior [35], [36]. Due to these advantages of the quinazoline scaffold, some marketed drugs like Quinethazone, Gefitinib, Fenquizone, Proquazone, Febrifugine and Erlotinib are derived from this structure [37]. A large number of synthetic approaches to dihydroquinazolinones has been advanced [38], [39], [40], [41], [42].

However, it is deemed worthwhile to explore a convenient protocol for the synthesis of 1-(benzothiazolylamino)arylmethyl-2-naphthols and 3‐benzothiazolyl 2,3-dihydroquinazolinones. As a continuation of our interest in catalytic applications of solid acid catalysts in organic synthesis, we herein report the three-component reaction of 2-aminobenzothiazole, aldehydes and 2-naphthol/isatoic anhydride with a magnetite (Fe₃O₄) nanocomposite coated with sulfonated polyethylene glycol (Fe₃O₄@PEG-SO₃H) as a magnetically recoverable heterogeneous catalyst (Scheme 1).

Scheme 1:

Synthesis of 1-(benzothiazolylamino)arylmethyl-2-naphthols 5 and 3‐benzothiazolyl 2,3-dihydroquinazolinones 6.

2 Results and discussion

The magnetite nanoparticles were prepared by the chemical coprecipitation of Fe²⁺ and Fe³⁺ according to a method reported previously [12]. In the next step, the nanoparticles were coated with polyethylene glycol to give Fe₃O₄@PEG. Finally, the surface of these nanoparticles was reacted with chlorosulfonic acid using a procedure modified with respect to the one given in Ref. [14] (Scheme 2). This procedure led to the introduction of SO₃H as a functional group on the Fe₃O₄@PEG nanoparticles in the form of Fe₃O₄@PEG-SO₃H. As it is indicated in Schemes 1 and 2, SO₃H is bound as a sulfuric acid mono ester ROSO₂(OH) to the PEG outer shell. The such prepared magnetic nanocomposite was characterized by energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM) and vibrating sample magnetometry (VSM).

Scheme 2:

Preparation of the core–shell nanocomposite Fe₃O₄@PEG-SO₃H.

As can be seen in Figure 1, EDX analysis of Fe₃O₄@PEG-SO₃H proves that the nanostructure is composed of carbon, oxygen, sulfur and iron and gives some indication for the existence of a PEG-SO₃H shell on the surface of Fe₃O₄.

Figure 1:

EDX spectrum of Fe₃O₄@PEG-SO₃H.

The particle size and morphology of the synthesized Fe₃O₄@PEG-SO₃H nanoparticles was investigated by SEM. The SEM image (Figure 2) shows that the main structure of the nanocomposite has a sphere-like morphology with an average sphere size of about 25 nm.

Figure 2:

SEM image of core–shell Fe₃O₄@PEG-SO₃H.

The magnetization hysteresis of Fe₃O₄@PEG-SO₃H was studied with a VSM. The result is shown in Figure 3. The saturation magnetization value of Fe₃O₄@PEG-SO₃H (∼31.3 emu g⁻¹) is lower than that of Fe₃O₄ nanoparticles (∼59.2 emu g⁻¹), which is in accord with the presence of a diamagnetic outer shell (PEG-SO₃H). Nevertheless, such magnetizations are sufficient to allow the magnetic separation of the catalyst from the reaction mixture.

Figure 3:

The magnetization curve of (a) Fe₃O₄ and (b) Fe₃O₄@PEG-SO₃H.

In order to screen the catalytic activity of the nanocomposite, the reaction of benzaldehyde, 2-aminobenzothiazole, and 2-naphthol was studied as a model reaction under a variety of different conditions. The results are summarized in Table 1. They clearly indicate that the Fe₃O₄@PEG-SO₃H nanocatalyst allows for much shorter reaction times and better yields as compared to the catalysis by nano-Fe₃O₄ or PEG-SO₃H alone or the uncatalyzed reaction.

The amount of Fe₃O₄@PEG-SO₃H catalyst required has been optimized next. The maximum yield of 1-(benzothiazolylamino)phenyl methyl-2-naphthol 4a (95%) was obtained when the reaction was performed with 10 mg of catalyst under ethanol reflux conditions with a reaction time of 15 min (entry 5, Table 1). Further increase of the amount of catalyst gave no pronounced enhancement of the yield.

The effect of different protic and aprotic solvents such as EtOH, H₂O, CHCl₃, DMF, CH₃CN as well as solvent-free conditions were studied next (Table 1, entries 8–12). The results suggest that good product yields are obtained in ethanol under reflux conditions. However, it should be mentioned that the condensation reaction is not effective at room temperature (entry 7).

In order to study the applicability of the three-component reaction catalyzed by Fe₃O₄@PEG-SO₃H various aromatic aldehydes were used. The resulting products are outlined in Table 2. Different aldehydes with electron-donating or electron-withdrawing groups were investigated. The condensation reaction proceeds efficiently under mild conditions to give the corresponding 1-(benzothiazolylamino)aryl methyl-2-naphthols 5a–l in excellent yield in short times (10–15 min) in the presence of 10 mg of Fe₃O₄@PEG-SO₃H nanocomposite. As can be seen, the nature of the aromatic substituents on the ring does not strongly effect the reaction in terms of yields under the selected conditions. Moreover, the condensation of polycyclic aromatic aldehydes such as 1-naphthaldehyde with 2-aminobenzothiazole, and 2-naphthol can also be carried out successfully and the corresponding 1-(benzothiazolylamino)aryl methyl-2-naphthol 5k was obtained in high yield. The direct three-component reaction also works well with thiophene-2-carbaldehyde as a heterocyclic aldehyde (Table 2, 5l). All of the products are known and were characterized using melting point, IR and NMR spectra [27], [28], [29], [30], [31] (see Supplementary material available online).

Table 2:

Synthesis of 1-(benzothiazolylamino)aryl methyl-2-naphthols in the presence of Fe₃O₄@PEG-SO₃H nanocomposite.

Time: 15 min	Time: 15 min	Time: 10 min	Time: 15 min
Yield: 95%	Yield: 94%	Yield: 94%	Yield: 85%
M. p.: 203–204 °C	M. p.: 202–203 °C	M. p.: 207–209 °C	M. p.: 215–216 °C
Ref. [30]	Ref. [27]	Ref. [27]	Ref. [31]
Time: 10 min Yield: 92% M. p.: 206–207 °C	Time: 15 min Yield: 93% M. p.: 189–191 °C	Time: 15 min Yield: 94% M. p.: 205–206 °C	Time: 10 min Yield: 92% M. p.: 190–192 °C
Ref. [27]	Ref. [27]	Ref. [27]	Ref. [12]
Time: 15 min	Time: 15 min	Time: 15 min	Time: 15 min
Yield: 91%	Yield: 88%	Yield: 90%	Yield: 85%
M. p.: 175–176 °C	M. p.: 181–183 °C	M. p.: 207–209 °C	M. p.: 192–194 °C
Ref. [27]	Ref. [12]	Ref. [30]	Ref. [27]

The resulting optimized protocol can be summarized as follows. The reaction can be carried out in a simple manner, just by mixing the three components and Fe₃O₄@PEG-SO₃H in EtOH and heating the mixture at reflux. The products are formed in excellent yield within 10–15 min followed by a simple work-up. After completion of the reactions the catalyst is easily separated by an external magnet. Recyclability and durability are crucial criteria in designing an efficient catalytic system from the viewpoint of green chemistry. The recovered magnetic nanoparticles were washed several times with ethanol, dried at 80 °C under reduced pressure for 2 h and reused in the next cycle. Figure 4 indicates that the catalyst could be reused with good activity even after eight consecutive cycles.

Figure 4:

Reusability of catalyst for the synthesis of 5a.

These good results encouraged us to extend our study to other organic transformations. Accordingly, we attempted the efficient synthesis of 3-benzothiazolyl 2,3-dihydroquinazolinones. With the optimized conditions in hand (10 mg of Fe₃O₄@PEG-SO₃H nanoparticles, ethanol, reflux), the one-pot three-component reaction of 2-aminobenzothiazole, isatoic anhydride and alde-hydes was carried out to afford 3-benzothiazolyl 2,3-dihydroquinazolinones (Table 3). Substrates with various functional groups tolerated the reaction conditions and resulted in good to excellent yields in rather short reaction times.

As can be seen in Table 3, hetero-aromatic aldehydes (such as pyridine-2-carbaldehyde, entry 10) afford the corresponding dihydroquinazolinones without by-products. The reaction is compatible with aliphatic aldehydes such as acetaldehyde and heptanal (entries 11, 12, Table 3).

Based on a literature survey [38], [39], [40], [41], [42], a plausible mechanism for the synthesis of 3‐benzothiazolyl 2,3-dihydroquinazolinones is shown in Scheme 3. The role of the catalyst is believed that the acid groups distributed on the surface of the Fe₃O₄@PEG-SO₃H nanoparticles activate the carbonyl groups of isatoic anhydride and the aldehydes. The first step involves the condensation of the activated isatoic anhydride 4 with 2-aminobenzothiazole 2 followed by decarboxylation to give the corresponding 2-aminobenzamide under the effect of the nanocatalyst. Afterwards, the activated aldehyde 1 reacts with the amino group of 2-aminobenzamide to the imine, which undergoes cyclization and tautomerization to furnish the desired products 6.

Scheme 3:

Proposed mechanism for the synthesis of 3‐benzothiazolyl 2,3-dihydroquinazolinones.

The utility of the current work in comparison to previous studies for the synthesis of 1-(benzothiazolylamino)phenyl methyl-2-naphthol 5a and 3-(2ʹ-benzothiazolyl)-2-phenyl-2,3-dihydroquinazolin-4(1H)-one 6a is summarized in Table 4. The data indicate that the Fe₃O₄@PEG-SO₃H appears to catalyze the reaction more effectively than a number of other reported catalysts, particularly in terms of the reaction time and the obtained yields. Moreover, this synthetic protocol avoids disadvantages of the other procedures, such as difficult preparation of the catalyst, expensive reagents, and tedious separation of the catalyst.

3 Conclusion

In conclusion, nano-magnetite-supported sulfated polyethylene glycol (Fe₃O₄@PEG-SO₃H) as a magnetically recoverable heterogeneous catalyst has been used for the one-pot, three-component reaction of 2-aminobenzothiazole, aldehydes and 2-naphthol/isatoic anhydride resulting in efficient formation of 1-(benzothiazolylamino)arylmethyl-2-naphthol or dihydroquinazolinones derivatives. The significant features of this method include green conditions, operational simplicity, minimizing production of chemical waste, shorter reaction times and good to high yields. Mild reaction conditions, the broad substrate scope, short reaction times, easy performance and good yields make this method versatile and showing its practical synthetic value. The excellent catalytic performance, thermal stability and easy separation and reusability of the catalyst make this green and eco-friendly method a superior alternative to existing protocols.

4 Experimental

5 Supporting information

Spectral data of the products 5a–l and 6a–l are given as supplementary material available online (https://doi.org/10.1515/znb-2021-0010).