Functionalized magnetic nanoparticles with deep eutectic solvents as efficient catalyst for the green synthesis of dihydroquinazolinones

Abstract

In this study, deep eutectic solvents were attached to SiO₂-coated magnetic nanoparticles through a linker. The resulting nanomagnet-immobilized arginine/choline chloride designated as MNP@Arg/ChCl was characterized using FT-IR, XRD, TGA, VSM, and SEM techniques. The catalyst showed an irregular spherical morphology, and the mean particle diameter was determined to be about 39.9 nm. TGA analysis also confirmed that the catalyst remained thermally stable up to approximately 225 °C. MNP@Arg/ChCl demonstrated excellent catalytic activity in the solvent-free synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-one derivatives via a three-component reaction involving isatoic anhydride, amines, and aldehydes. The scope of this method was assessed using various aromatic aldehydes and aromatic amines. The 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-one derivatives were obtained in yields ranging from 85% to 93% within a short reaction time. Due to the magnetization properties of MNP@Arg/ChCl, the catalyst can be easily separated from the reaction mixture and reused several times without significant loss of catalytic activity. This method is particularly attractive in the context of green chemistry due to its high catalytic efficiency, thermal stability, reusability, ease of recovery, and environmentally friendly features.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-23849-4.

Introduction

Over the past two decades, deep eutectic solvents (DESs) have attracted a lot of attention as catalysts and reaction media due to their unique properties, including tunable physicochemical properties, non-toxicity, negligible vapor pressure, simple preparation, nonflammability, high thermal stability, and biodegradability^1,2. In general, DESs are straightforwardly prepared by heating and mixing a hydrogen bond acceptor (HBA) with a hydrogen-bond donor (HBD), facilitated by hydrogen bonding, halogen bonding, π-π interactions, or electrostatic interactions^3,4. Choi, Paiva and co-workers described natural deep eutectic solvents (NADES) derived from natural origins such as alcohols, sugars, carboxylic acids, and amino acids^5,6. NADESs are composed of components that are in our daily food, making them safe, sustainable, and cost-effective⁷. Arginine (Arg) is a naturally occurring, readily available, non-toxic, and biologically active amino acid. It consists of three parts: an alpha-amino group, a carboxyl group, and a guanidine moiety, the latter of which imparts its basic nature and facilitates its participation in various biochemical reactions. The N-H bonds of the guanidine moiety can easily act as hydrogen bond donors⁸.

While DESs have shown considerable promise as solvent and catalyst in organic transformations over the past decade^9–14, their industrial applications remain limited due to the need for substantial quantities of DES, challenges with reusability, and associated high costs¹⁵. To overcome these challenges, DESs are being supported on solid substrates such as metal organic frameworks (MOFs)¹⁶, SBA-15¹⁷, graphene oxide¹⁸, and pectin¹⁹. Heterogeneous catalysis offers significant advantages over homogeneous catalysis in the synthesis of organic compounds²⁰. One key benefit is the straightforward recovery and reuse of the catalyst. Moreover, heterogeneous catalysts are generally more robust and compatible with a broader range of reaction conditions compared to their homogeneous counterparts^21–23. However, the disadvantages of heterogeneous catalysts include their lower selectivity and catalytic activity, which result from poor dispersion and accessibility of heterogeneous catalysts. Recently, DES catalysts supported on magnetic nanoparticles have gained attention due to their high surface area, good stability, straightforward synthesis, ease of operation, and convenient separation using an external permanent magnet^24–29.

The development and synthesis of complex organic molecules through green and sustainable methods is a fundamental goal in organic chemistry³⁰. Multicomponent reactions (MCR) have presented as an attractive technique that allows for the facile synthesis of complex molecules in a one-pot synthesis, without the need to isolate or purify intermediates³¹. Compared to traditional methodologies, MCRs offer several advantages, including shorter reaction times, energy efficiency, cost-effectiveness, and the capability to produce a diverse array of products³². As a result, MCR has profoundly impacted pharmaceutical and chemical synthesis.

2,3-Dihydroquinazolin-4(1 H)-ones are an important class of heterocyclic compounds known for their diverse range of biological activities and pharmacological properties, including, antitumor³³, anti-inflammatory³⁴, antibacterial³⁵, antihistamine³⁶, antidiabetic and antioxidant³⁷, antimalarial³⁸, and antifungal³⁹. Due to the importance of these compounds, considerable efforts have been made to improve the synthesis of 2,3-dihydroquinazolin-4(1 H)-ones through a three-component reaction involving isatoic anhydride, aldehydes, amines, or ammonium salts, utilizing various catalysts, including glutamic acid⁴⁰, carboxymethyl cellulose@MnFe₂O₄⁴¹, Fe₃O₄@SiO₂@Pr-PABA⁴², zinc (II) perfluorooctanoate⁴³, CoFe₂O₄‑Spirulina‑SO₃H⁴⁴, CS-TDI-SSA-Fe₃O₄⁴⁵, MCM-41@serine@Cu(II)⁴⁶, Fe₃O₄/TiCl₂/cellulose⁴⁷, and Co-aminobenzamid@Al-SBA-15⁴⁸. Although the methods described offer considerable benefits, some of them suffer from one or more limitations, including laborious work-up procedures, difficulties in catalyst preparation, high temperatures, the use of toxic solvents and reagents, prolonged reaction times, and low yields.

Building on previous studies focused on the development of new heterogeneous DES catalysts^{16–19,24–29} and continuing our research into green and sustainable methods for synthesizing heterocyclic compounds^49–53, this study presents an environmentally friendly approach for immobilizing NADES on magnetic nanoparticles to synthesize 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-one derivatives, as outlined in Scheme 1. The MNP@Arg/ChCl was designed and synthesized by functionalizing the Fe₃O₄@SiO₂ surface with 3-chloropropyltrimethoxysilane (CPTMS) and arginine/choline chloride. The applicability of the synthesized MNP@Arg/ChCl was assessed as a reusable heterogeneous catalyst in the three-component synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-ones under mild and solvent-free conditions.

Scheme 1.

Synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-one derivatives by MNP@Arg/ChCl.

Results and discussion

Synthesis and characterization of MNPs@Arg/ChCl

MNPs@Arg/ChCl were successfully synthesized through hydrogen bonding interactions between arginine attached to silica-coated magnetite nanoparticles and choline chloride. As illustrated in Scheme 2, the process began with the synthesis of silica-coated nanomagnetite using Fe₃O₄ and tetraethoxysilane (TEOS). Subsequently, the core-shell nanoparticle system was functionalized with 3-chloropropyltrimethoxysilane (CPTMS). The subsequent reaction of arginine with the chloro-functionalized SiO₂ led to the immobilization of arginine on the nanoparticle surface. Finally, choline chloride is added as a hydrogen bond acceptor. The resulting novel MNP@Arg/ChCl was characterized by FT-IR, EDX, element mapping images, FE-SEM, XRD, and TGA.

Scheme 2.

Synthesis route of MNP@Arg/ChCl.

The Fourier-transform infrared spectroscopy (FT-IR) analysis was employed to confirm the structure by identifying the functional groups. The IR spectra of Fe₃O₄@SiO₂, Fe₃O₄@SiO₂@CPTMS, Fe₃O₄@SiO₂@CPTMS@Arg, and MNP@Arg/ChCl are collectively displayed in Fig. 1. The absorption band at 559 cm⁻¹ corresponds to the stretching vibration of the Fe–O bond in Fe₃O₄. Additionally, the Si–O–Si stretching vibrations at 1075 cm⁻¹ indicate the presence of a silica shell surrounding Fe₃O₄ (Fig. 1A). In the spectra presented in Fig. 1B, the Fe–O stretching vibrations are observed at 554 cm⁻¹, and Si–O–Si stretching vibrations at 1066 cm⁻¹. Also, the stretching vibrations at 2985 and 2921 cm⁻¹ pertain to C–H bonds, which result from the presence of the propyl group, thereby demonstrating the successful bonding of CPTMS to Fe₃O₄@SiO₂. The FT-IR spectrum of Fe₃O₄@SiO₂@CPTMS@Arg (Fig. 1C) displays absorption bands in the regions of 3500 –3000 cm⁻¹, as well as at 2927 cm⁻¹ and 2856 cm⁻¹, which are attributed to the stretching vibrations of N-H bonds and O-H bonds and the stretching vibrations of C-H bonds in arginine. The asymmetric COO⁻ stretching vibrations were observed at 1570 cm⁻¹, and the symmetric COO⁻ stretching vibrations at 1414 cm⁻¹. Additionally, the bending vibrations of NH and the stretching vibrations of C = N are noted at 1680 cm⁻¹ and 1610 cm⁻¹, respectively, which are associated with the guanidine functional group⁵⁴. The presence of characteristic peaks of arginine indicates the successful binding of Fe₃O₄@SiO₂@CPTMS with L-arginine. Finally, the alkyl group vibration bands at 1472 cm⁻¹ and the C-N⁺(CH₃)₃ vibrations at 954 cm⁻¹, along with the broadening of the absorption bands in the range of 3600 –2600 cm⁻¹, confirm the successful interaction of choline chloride with Fe₃O₄@SiO₂@CPTMS@Arg (Fig. 1D).

Fig. 1.

FT-IR spectra of (A) Fe₃O₄@SiO₂, (B) Fe₃O₄@SiO₂@CPTMS, (C) Fe₃O₄@SiO₂@CPTMS@Arg and (D) MNP@Arg/ChCl.

Energy dispersive X-ray spectroscopy (EDX) was utilized to confirm the formation of the MNP@Arg/ChCl nanocomposite. The peaks corresponding to Fe, Si, O, C, N, and Cl observed in the EDX spectrum (Fig. 2), along with the quantitative data regarding the elemental composition presented in Table 1, validate the successful synthesis of the MNP@Arg/ChCl nanocomposites. Furthermore, elemental mapping analysis demonstrated a uniform distribution of atoms throughout the structure of the nanocomposites (Fig. 3).

Fig. 2.

EDX spectrum of MNP@Arg/ChCl.

Table 1.

Quantitative results of EDS analysis.

Elemental	Fe	Si	O	C	N	Cl
W%	13.17	4.72	35.01	29.68	16.27	1.16

Fig. 3.

Elemental mapping analysis of MNP@Arg/ChCl.

To investigate the morphology and surface characteristics of the catalyst, scanning electron microscopy (SEM) images of MNP@Arg/ChCl were recorded (Fig. 4). The obtained images revealed that the MNP@Arg/ChCl catalyst exhibits irregular spherical shapes. Furthermore, the SEM micrographs indicate slight aggregation, which may be attributed to interactions between the layers of DES surrounding the nanoparticles. Additionally, the average particle size derived from the histogram indicates a core diameter of approximately 39.9 nm for MNP@Arg/ChCl.

Fig. 4.

SEM images and particle size analysis of MNP@Arg/ChCl.

The crystallinity and phase analysis of magnetic Fe₃O₄ and MNP@Arg/ChCl were examined using X-ray diffraction (XRD). The peaks observed at 2θ = 11.04°, 18.32°, 19.16°, 19.48°, 23.08°, and 27.44° were attributed to L-arginine (Fig. 5), which matched the standard pattern (JCPDS-PDF, No. 00-030-1527)⁵⁵. The XRD patterns of Fe₃O₄ magnetic nanoparticles reveal six prominent diffraction peaks at 2θ values of 30.3°, 35.6°, 43.3°, 53.7°, 57.3°, and 62.8°, corresponding to the (220), (311), (400), (422), (511), and (440) planes, respectively (Fig. 5). This pattern is consistent with the standard XRD data for the crystal structure of Fe₃O₄ (JCPDS card No. 19–0629)⁵⁶. Furthermore, the presence of Fe₃O₄ diffraction peaks indicates that no phase changes occurred in the Fe₃O₄ nanoparticles after the preparation of MNP@Arg/ChCl. Also, using the Scherrer equation, the average crystallite size of the MNP@Arg/ChCl nanoparticles was determined to be 41.1 nm.

Fig. 5.

XRD patterns of (a) Fe₃O₄, and (b) MNP@Arg/ChCl.

The thermal stability of the MNP@Arg/ChCl catalyst was evaluated using thermogravimetric analysis (TGA) over a temperature range of 20 to 800 °C under an argon atmosphere. The TGA curve shows a weight loss of about 8 wt% in the range of 20–180 °C, which is mainly due to moisture loss. This is followed by a weight loss of about 35 wt% in the temperature range of 280–700 °C, attributed to the thermal decomposition of organic components. This suggests the presence of substantial organic layers on the surface of the catalyst (Fig. 6).

Fig. 6.

TGA curve of MNP@Arg/ChCl.

The vibrating sample magnetometer (VSM) analysis was utilized to investigate the magnetic properties of MNP@Arg/ChCl. Based on the magnetic curves shown in Fig. 7, the saturation magnetic values for Fe₃O₄ and MNP@Arg/ChCl were 67.13 and 20.21 emug^− 1, respectively. The observed decrease in magnetic properties with increasing amounts of organic materials loaded on the Fe₃O₄ surface confirms the successful functionalization of the nanoparticles. Furthermore, the catalyst’s magnetization is sufficient to enable its efficient recovery from the reaction using an external magnet.

Fig. 7.

Magnetization curves of Fe₃O₄ and MNP@Arg/ChCl.

Catalytic activity MNP@Arg/ChCl

We initiated our study on the catalytic efficiency of the synthesized MNP@Arg/ChCl in a three-component reaction for the synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-ones. Accordingly, the reaction between isatoic anhydride 1 (0.50 mmol), aniline 2a (0.60 mmol), and 4-chlorobenzaldehyde 3a (0.50 mmol) was investigated as a model reaction.

The effects of various factors such as solvent, reaction temperature, catalyst amount, and type of catalyst, were investigated on the yield and rate of the reaction (Table 2). Initially, the reaction was carried out in the absence of catalyst, under solvent-free conditions, and at reflux in ethanol. After 2 h no product was observed (Table 2, entries 1 and 2). This confirmed that the presence of the catalyst is essential for this reaction. To investigate the effect of solvents, the model reaction was conducted under both solvent-free conditions and in the presence of various solvents, including ethanol, water, acetonitrile, and n-hexane, under reflux conditions (Table 2, entries 3–6). According to the results presented in Table 2, the reaction conducted under solvent-free conditions achieved a high yield in the presence of 30 mg of catalyst at 60 min (entry 7). In the next step, temperature was examined as a parameter to achieve better efficiency. Increasing the temperature to 100 °C enhanced the product yield to 92% and reduced the reaction time (Table 2, entry 8). Also, it should be noted that increasing the temperature to 120 °C did not result in a significant change in either reaction yield or time (Table 2, entry 9). Next, the model reaction was conducted using varying amounts of catalyst. As shown in Table 2, entry 10, reducing the catalyst amount from 30 mg to 15 mg resulted in a decrease in yield, whereas increasing it to 50 mg did not affect the reaction yield (Table 2, entry 11). Model reactions employing ChCl, MNP@Arg, and Fe₃O₄ individually were performed to evaluate the distinct contributions of each catalyst components (entries 12–14). The results indicated that the overall efficiency of the catalyst in the three-component reaction for synthesizing 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-ones is superior to that of its individual components (Table 2, entry 8). The synergistic effect arising from the interaction between ChCl and MNP@Arg, combined with the ionic nature of the deep eutectic solvent, enhanced the catalytic performance of the system. The use of SiO₂-coated magnetic nanoparticles (MNPs) in our catalyst design is justified not only by the ease and speed of catalyst recovery through magnetic separation, but also by the fact that the multifunctional catalyst MNP@Arg/ChCl delivers significantly higher yields than its individual components.

Table 2.

Optimization of the model reaction.

Entry	Solvent	Catalyst	catalyst amount	Temp. (oC)	Time (min.)	Yielda (%)
1	–	–	–	80	120	–
2	EtOH	–	–	reflux	120	–
3	EtOH	MNP@Arg/ChCl	30	reflux	120	72
4	H2O	MNP@Arg/ChCl	30	reflux	120	50
5	CH3CN	MNP@Arg/ChCl	30	reflux	120	70
6	Hexane	MNP@Arg/ChCl	30	reflux	120	25
7	–	MNP@Arg/ChCl	30	80	60	78
8	–	MNP@Arg/ChCl	30	100	30	92
9	–	MNP@Arg/ChCl	30	120	30	93
10	–	MNP@Arg/ChCl	15	100	30	55
11	–	MNP@Arg/ChCl	50	100	30	93
12	–	Fe3O4	30	100	30	35
13	–	MNP@Arg	30	100	30	50
14	–	ChCl	30	100	30	27

Reaction conditions: Isatoic anhydride (0.50 mmol), aniline (0.60 mmol), and 4-chlorobenzaldehyde (0.50 mmol).

^aIsolated yields.

Under the optimal reaction conditions (Table 2, entry 8), the scope and versatility of the three-component reaction involving isatoic anhydride, various substituted amines and aldehydes were investigated. As shown in Table 3, a wide variety of benzaldehydes containing different substituents, including electron-withdrawing groups (− Cl, −Br, −CN, and − NO₂) and electron-donating groups (− OCH₃, −CH₃, and − N(CH₃)₂) successfully reacted. The results indicated that both electron-donating and electron-withdrawing groups at the para position of the benzaldehyde ring had no significant effect on the reaction time and gave products in good to excellent yields (Table 3, entries 1–7). In contrast, ortho-substituted aromatic aldehydes exhibited longer reaction times due to steric hindrance (Table 3, entries 8–10). Notably, the reaction with heteroaryls, such as thiophene and furan carbaldehydes, gave the desired products in a short reaction time and excellent yields (Table 3, entries 11 and 12). Next, we examined a variety of aromatic amine substrates. As shown in Table 3, anilines with electron-withdrawing (-Cl, -Br and -COOH) and electron-donating (-OCH₃ and -CH₃) afforded the desired products in high yields. However, the presence of electron-withdrawing groups led to a slight increase in the reaction times (Table 3, entries 14–18).

Table 3.

Preparation of 2,3-dihydroquinazolin-4(1 H)-one derivatives via a three-component reaction.

Entry	R 1	R 2	Product	Time (min)	Yielda (%)	M.P (˚C)
						Found	Reported
1	4-ClC6H4	C6H5		30	92	223–225	220–22240
2	4-BrC6H4	C6H5		30	91	220–222	221–22340
3	4-NO2C6H4	C6H5		35	90	194–196	196–19840
4	4-CN C6H4	C6H5		35	88	200–202	203–20457
5	4-MeOC6H4	C6H5		35	93	201–204	203–20540
6	4-MeC6H4	C6H5		30	91	212–214	215–21645
7	4-(Me)2NC6H4	C6H5		30	89	187–190	184–18543
8	3-MeOC6H4	C6H5		35	90	186–188	187–18957
9	2-ClC6H4	C6H5		45	85	170–173	174–17640
10	2-MeOC6H4	C6H5		45	80	147–149	144–14658
11	C4H3S	C6H5		35	93	203–206	198–20144
12	C4H3O	C6H5		40	90	139–141	135–13759
13	C6H5	C6H5		30	93	199–203	202–20640
14	C6H5	4-ClC6H4		45	89	207–209	210–21243
15	C6H5	4-BrC6H4		40	91	230–232	228–22957
16	C6H5	4-HOOCC6H4		60	90	237–240	238–24060
17	C6H5	4-MeC6H4		30	91	194–197	196–19943
18	C6H5	4-MeOC6H4		30	93	213–216	209–21143
19	4-ClC6H4	4-MeC6H4		30	90	249–250	251–25345

Reaction conditions: Isatoic anhydride (0.5 mmol), amine (0.6 mmol), and aldehyde (0.5 mmol) in MNP@Arg/ChCl (30 mg) at 100 °C.

^aIsolated yields.

Based on published studies^19,61,62, a plausible mechanism for the synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-one derivatives through one-pot reactions involving aldehydes, isatoic anhydride, and anilines in the presence of MNP@Arg/ChCl is proposed and illustrated in Scheme 3. MNP@Arg/ChCl, as a multifunctional catalyst, activates carbonyl, amine, and imine functional groups through extensive hydrogen bonding. Additionally, Fe₃O₄ nanoparticles act as Lewis acids, enhancing the electrophilicity of aldehydes and imines through coordination with the Fe centers. Moreover, the guanidine groups in arginine serve as basic sites, promoting the deprotonation steps and facilitating the reaction. Initially, the catalyst’s hydrogen-bond donating and accepting abilities, combined with the Lewis acidity of the Fe₃O₄ nanoparticles, facilitate the nucleophilic attack of the aromatic amine on the activated isatoic anhydride. This is followed by decarboxylation, leading to the formation of 2-amino-N-arylbenzamide (2). In the next step, the catalyst activates the reaction between the aldehyde and 2-amino-N-arylbenzamide (2) via hydrogen bonding and coordination with Fe₃O₄ nanoparticles, resulting in the formation of intermediate a. Then, the elimination of a water molecule produces the imine intermediate b, which is activated by the catalyst to undergo an intramolecular nucleophilic reaction forming intermediate c. Proton transfer facilitated by the multifunctional catalyst ultimately leads to the formation of the desired product (4).

Scheme 3.

A plausible mechanism for the synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-ones.

The recyclability and reusability of the magnetic catalyst in the model reaction were evaluated under optimized conditions. After the reaction was completed, the catalyst was easily recovered using an external magnet and washed several times with ethyl acetate. It was then dried in an oven at 80 °C. Based on our experimental findings, the recycled magnetic nanocatalyst can be utilized for five consecutive cycles in the model reaction with no substantial decline in catalytic efficiency (Fig. 8). The catalyst’s stability and recyclability are primarily attributed to the SiO₂ shell covering the nano-Fe₃O₄, which protects it from oxidation during the cycling process. The comparison of the XRD patterns of the recycled catalyst and the fresh catalyst (Fig. 9A) indicates that no phase transformation occurred in the Fe₃O₄ nanoparticles during the recycling process. Additionally, the comparison of the FT-IR spectra of the recycled and fresh catalysts demonstrates that the recycled catalyst retains the characteristic bands, confirming that the nanocatalyst structure remains unchanged after five consecutive reaction cycles (Fig. 9B). SEM images also did not show a significant change in the morphology in the surface of recovered catalyst after the 5th recycles (Fig. 10). EDX analysis was also conducted to confirm the presence of choline chloride in the recycled catalyst. The EDX spectrum clearly displays the chlorine peak, verifying the presence of choline chloride onto recycled catalyst (Figs. 10 and 11).

Fig. 8.

Recycling study of MNP@Arg/ChCl for the model reaction of 4-chlorobenzaldehyde, isatoic anhydrides, and aniline.

Fig. 9.

(A) XRD patterns and (B) FT-IR spectra of (a) MNP@Arg/ChCl, (b) reused MNP@Arg/ChCl.

Fig. 10.

SEM images of (a) fresh MNP@Arg/ChCl and (b) reused MNP@Arg/ChCl after five cycles.

Fig. 11.

EDX analysis of reused MNP@Arg/ChCl.

To assess the heterogeneity of the catalyst and evaluate the stability of MNPs@Arg/ChCl in the reaction medium, a hot filtration test was conducted. For this purpose, the model reaction was performed in ethanol (Table 2, entry 3). Before the reaction was completed (60 min), the catalyst was separated using an external magnet. The reaction mixture was then maintained under the same conditions for one hour. During this time, the reaction did not proceed further (monitored by TLC), indicating that the catalyst remained insoluble in the solvent. (Fig. 12).

Fig. 12.

Time conversion curve for the hot-filtration test (a) after separation of catalyst, and (b) the presence of catalyst.

To evaluate the effectiveness of the MNPs@Arg/ChCl in synthesizing 2,3-diphenyl-2,3-dihydroquinazolin-4(1 H)-one (4q) compared to other catalysts reported in the literature, the results are summarized in Table 4. The results indicate that this method provides the product (4q) in a higher yield and shorter reaction time compared to other methods. Notably, the absence of solvents, metals, toxic reagents, and microwave radiation, combined with the ease of operation and separation, as well as the use of two completely natural and environmentally friendly materials, highlights the significant advantages of the introduced nanocatalyst.

Table 4.

Comparison of the catalytic activity of MNP@Arg/ChCl with selected reported catalysts for the synthesis of 4q.

	Entry	Catalyst	Conditions	Time (min)	Yield	Refs.
	1	Glutamic acid	EtOH/MW	8	85%	40
	2	CCMC@MnFe2O4	EtOH/Reflux	40	90%	41
	3	Fe3O4@SiO2@Pr-PABA	H2O/Reflux	25	85%	42
	4	CoFe2O4-Sp-SO3H	H2O/60 °C	60	93%	44
	5	CS-TDI- SSA-Fe3O4	EtOH/Reflux	23	87%	45
	6	Fe3O4@Sap/Cu(II)	H2O/RT	30	91%	57
	7	N-Bromosaccharin	H2O/Reflux	40	87%	58
	6	[PyPS]3PW12O40 [2]	MW, solvent free/80 °C	15	92%	63
	9	ProMSAa	Solvent free/120 °C	60	91%	64
	10	MNP@Arg/ChCl	Solvent free/100 °C	30	93%	This work

^aProlinium methane sulphonate.

Conclusion

In conclusion, we have developed magnetic deep eutectic solvent as a novel biocompatible nanocatalyst. The nanomagnet-stabilized arginine/choline chloride (MNP@Arg/ChCl) was simply prepared and characterized by FT-IR, XRD, TGA, VSM, and SEM techniques. The synthesized catalyst demonstrated remarkable performance in the synthesis of 2,3-dihydroquinazolin-4(1 H)-one derivatives through three-component reactions involving isatoic anhydride, aniline derivatives, and aldehyde derivatives under solvent-free conditions at 100 °C. The desired products were obtained in yields ranging from 85% to 93% within a short reaction time. Furthermore, the catalyst could be easily separated from the reaction mixture and reused five times without a significant decline in catalytic activity. We believe that this approach can make a valuable contribution to the field of green chemistry for the synthesis of heterocyclic compounds due to its high catalytic efficiency, ease of recovery, reusability, and environmentally friendly properties.

Experimental

The details of the reagents and instruments utilized in this research are presented in Appendix, along with additional supplementary material.

Preparation of Fe₃O₄ nanoparticles

The synthesis of Fe₃O₄ nanoparticles was conducted as described in the literature⁶⁵. A total of 3.78 g of FeCl₃·6H₂O and 2.22 g of FeSO₄·7H₂O were dissolved in 150 mL of deionized water. The resulting solution was stirred under N₂ at 80 °C for 1 h. Subsequently, 20 mL of NH₄OH solution was added, leading to the formation of a black solid. The final mixture was stirred at 80 °C under N₂ for 1 h. The precipitate was separated using an external magnet and washed four times with distilled water and ethanol. Finally, the magnetic nanoparticles (MNPs) were dried in a vacuum oven at 60 °C.

Preparation of Fe₃O₄@SiO₂-CPTMS

An amount of 1.0 g of Fe₃O₄ was dispersed by sonication for 15 min in the mixture of water (6 mL) and ethanol (35 mL). Subsequently, 1.5 mL of tetraethyl orthosilicate (TEOS) was added to the mixture, and sonication was continued for an additional 10 min. Following sonication, 1.4 mL of ammonium hydroxide (NH₄OH, 28%) was gradually added. After stirring at 80 °C for 12 h, the silica-coated magnetic nanoparticles (Fe₃O₄@SiO₂) were separated via a permanent magnet, rinsed several times with deionized water and methanol, and then dried at 25 °C under vacuum⁵⁶. In the second step, 1.0 g of Fe₃O₄@SiO₂ was suspended in dry toluene through sonication for 35 min. Subsequently, 3 mL of 3-chloropropyltrimethoxysilane (CPTMS) was slowly added dropwise to the solution. The mixture was kept at reflux and stirred under an argon atmosphere for 12 h. Afterward, the resulting solid was easily separated using an external magnet, washed with ethanol and acetone, and then dried in a vacuum at 80 °C⁶⁶.

Preparation of MNPs@Arg/ChCl

The synthesized Fe₃O₄@SiO₂-CPTMS (1.0 g) was dispersed in dry toluene over a period of 20 min. Subsequently, 1.5 g of L-arginine and 1.2 mmol of triethylamine were added to the mixture, which was stirred for 48 h at 100 °C. Afterward, the nanoparticles (Fe₃O₄@SiO₂-CPTMS@Arg) were filtered, washed with deionized (DI) water and ethanol, and dried at vacuum oven 100 °C for 12 h⁶⁷. The synthesis of the magnetic DES was carried out according to the procedures described in the literature^27–29. Specifically, 0.419 g of choline chloride (3.0 mmol) was added to 1.0 g of Fe₃O₄@SiO₂-CPTMS@Arg in 30 mL of toluene and the mixture was refluxed for 18 h. Upon completion of the reaction, the resulting catalyst (named as MNPs@Arg/ChCl) was washed with 50 mL of n-hexane and 20 mL of ethanol, and then allowed to air dry.

General procedure for the synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1 H)-ones

A mixture of isatoic anhydride (0.5 mmol), aldehyde (0.5 mmol), aniline (0.6 mmol), and 30 mg of MNPs@Arg/ChCl was stirred at 100°. The progress of the reaction was monitored using TLC with a mobile phase of n-hexane and ethyl acetate (EtOAc) in a 3:1 ratio. Upon completion, ethanol was added and the nanocatalyst was easily separated using an external magnet, and the residue was concentrated to yield the crude product. Finally, recrystallization of the crude product from 5 mL of ethanol resulted in a pure product.

The structures of the products were confirmed by comparing their physical data and ¹H and ¹³C NMR spectra (see Figures S1-S38 Supplementary Information).

Selected data for the products: 2-(4-Chlorophenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (4a): White solid; mp 223–225 °C; ¹H NMR (300 MHz, DMSO-d₆) (ppm): δ 7.74–7.69 (m, 2 H, H_Ar and NH), 7.39–7.21 (m, 10 H), 6.78–6.71 (m, 2 H), 6.34 (d, J = 2.7 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ_C: 162.6, 146.8, 141.0, 140.1, 134.3, 133.3, 129.1, 129.0, 128.8, 128.4, 126.7, 126.6, 118.1, 115.7, 115.3, 72.3.

2-(4-Nitrophenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (4c): White solid; mp 194–196 °C; ¹H NMR (300 MHz, DMSO-d₆) (ppm): δ 8.20 (d, J = 8.7 Hz, 2 H), 7.85 (d, J = 3.3 Hz, 1H, NH), 7.74 (dd, J = 7.8, 1.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2 H), 7.40–7.23 (m, 5 H), 7.26–7.17 (m, 1H), 6.79–6.72 (m, 2 H), 6.51 (d, J = 3.0 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ_C: 162.4, 148.4, 147.8, 140.9, 134.5, 129.2, 128.5, 128.3, 126.7, 126.5, 124.6, 124.1, 118.4, 115.7, 115.4, 72.1.

3-Phenyl-2-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one (4f): White solid; mp 212–214 °C; ¹H NMR (300 MHz, DMSO-d₆) (ppm): δ 7.73 (dd, J = 7.8, 1.5 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H, NH), 7.36–7.25 (m, 7 H), 7.19 (td, J = 6.9, 1.5 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2 H), 6.77–6.69 (m, 2 H), 6.25 (d, J = 2.7 Hz, 1H), 2.30 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d₆) δ_C: 162.7, 147.0, 141.3, 138.1, 134.1, 129.4, 129.1, 129.0, 128.4, 126.9, 126.5, 126.4, 117.9, 115.8, 115.2, 72.8, 21.0.

2-(3-Methoxyphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (4k): White solid; mp 186–188 °C; ¹H NMR (300 MHz, DMSO-d₆) (ppm): δ 7.76 (dd, J = 7.8, 1.8 Hz, 1H), 7.36–7.17 (m, 9 H, H_Ar and NH), 7.00 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 8.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 3.77 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d₆) δ_C: 162.9, 156.4, 147.0, 141.2, 134.1, 130.3, 129.1, 128.3, 128.0, 127.0, 126.8, 126.6, 120.5, 117.8, 115.3, 111.8, 68.6, 56.0.

2-(Thiophene-2-yl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (4n): White solid; mp 203–206 °C; ¹H NMR (300 MHz, DMSO-d₆) (ppm): δ 7.75 (dd, J = 7.8, 1.5 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H, NH),7.41–7.31 (m, 6 H), 7.25 (td, J = 7.2, 1.5 Hz, 1H), 6.97 (dd, J = 5.1, 1.5 Hz, 1H), 6.89 (t, J = 4.2 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.79 (td, J = 7.8, 1.2 Hz, 1H), 6.55 (d, J = 2.7 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ_C: 162.0, 146.8, 145.1, 140.9, 134.3, 129.1, 128.4, 126.9, 126.8, 126.70, 126.3, 118.5, 116.0, 115.7, 69.9.

2-(4-Chlorophenyl)-3-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one (4w): White solid; mp 249–250 °C; ¹H NMR (300 MHz, DMSO-d₆) (ppm): δ 7.72 (dd, J = 7.8, 1.8 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.38 (s, 4 H), 7.29 (td, J = 7.8, 1.8 Hz, 1H), 7.14 (s, 4 H), 6.77–6.70 (m, 2 H), 6.28 (d, J = 2.7 Hz, 1H), 2.27 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d₆) δ_C: 162.6, 146.8, 140.2, 138.4, 135.9, 134.2, 129.6, 128.9, 128.8, 126.6, 118.1, 115.2, 110.2, 72.5, 21.0.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

**Z.V: ** Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. **R.H: ** Writing – review & editing, Supervision, Project administration, Conceptualization. **Y.S: ** Conceptualization, Supervision. **B.M: ** Conceptualization, Validation.

Funding

None.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Declarations

Competing interests

The authors declare no competing interests.

Ethical approval

This work does not contain any studies with human participants or animals performed by any of the authors.