One-pot multicomponent diastereoselective synthesis of indoline spirobicyclics using a recyclable chiral nanomagnetic L-proline catalyst under mild conditions

Abstract

Fe₃O₄@SiO₂-NH-TCT–(trans-4-hydroxy-L-proline)₂ nanoparticles were synthesized as a chiral, magnetically recoverable nanocatalyst. The material was thoroughly characterized by FT-IR, VSM, XRD, TEM, FE-SEM, BET, CHNS elemental analysis, mass spectrometry, and ¹H/¹³C-NMR. The catalyst enabled a one-pot, multicomponent diastereoselective synthesis of indoline spirobicyclic derivatives from anilines, carbon acids, Fischer’s base, and aldehydes under solvent-free conditions at ambient temperature. The method afforded high to excellent yields with excellent diastereoselectivity. Product structures and anti/syn diastereomeric ratios were established by ¹H-, ¹³C-NMR, 2D-ROESY, mass spectrometry, and single-crystal X-ray diffraction.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-40598-0.

Introduction

Catalysts are central to both academic and industrial chemistry, improving energy efficiency and reducing waste. They are broadly classified as homogeneous, heterogeneous, or biocatalysts¹. While homogeneous catalysts often exhibit superior reactivity and selectivity, heterogeneous systems are more easily separated and recycled, making them particularly valuable in large-scale applications^2,3.

Nanoparticles (NPs), with dimensions below 100 nm, offer high surface-to-volume ratios, tunable structures, and enhanced catalytic activity⁴. Metal oxides and carbon-based nanomaterials can mimic enzymatic behavior⁵, and various solid supports such as silica, magnetic materials, and carbon nanotubes have been developed to stabilize active nanoparticles^6,7. Among these, magnetic nanoparticles (MNPs) are especially attractive, as they can be recovered via external magnetic fields. Superparamagnetic Fe₃O₄, often stabilized in a core–shell structure such as Fe₃O₄@SiO₂, has emerged as a robust platform for heterogeneous catalysis^8–12.

In parallel, organocatalysis, which the use of small, low-molecular-weight organic molecules as catalysts, has gained prominence for enabling environmentally benign transformations¹³. Chiral organocatalysts, including bifunctional systems, allow precise stereocontrol through mechanisms involving enamine, iminium, or hydrogen-bonding pathways^14–16. L-proline, often referred to as the “simplest enzyme,” exemplifies this versatility, and its hydroxylated derivative, 4-hydroxy-L-proline, provides enhanced coordination ability as a bidentate ligand¹⁷.

Indoline-based spirobicyclic scaffolds, such as spiroaminals and spiropyrans, are important motifs in biologically active compounds and functional materials^18–21. Despite their significance, few studies have explored the use of recyclable nanomagnetic catalysts for their stereoselective synthesis^22,23.

Herein, we report the synthesis of Fe₃O₄@SiO₂-NH-TCT–trans-4-hydroxy-L-proline nanoparticles and their application as a chiral, magnetically recoverable catalyst for the diastereoselective synthesis of indoline spirobicyclics under mild and green conditions. Emphasis is placed on catalyst reusability and stereocontrol.

Experimental

Chemical, instrumentation and analysis

All chemicals were obtained from Fluka, Merck, Aldrich, and Acros, and solvents were purified using standard protocols. Reaction progress was monitored by thin-layer chromatography (TLC) on silica gel plates (SIL G/UV 254). Products were purified by column chromatography on Merck Kieselgel (70–230 mesh) or by recrystallization, and characterized by melting point determination, FT-IR, ¹H/¹³C-NMR, CHNS elemental analysis, and mass spectrometry.

¹H- and ¹³C-NMR spectra were recorded on Bruker Avance DPX400 and DPX500 spectrometers at 400/500 MHz and 126 MHz, respectively, in CDCl₃ with TMS (δ 0.00 ppm) as the internal reference. FT-IR spectra were obtained on a Shimadzu FT-IR-8300 in the 4000–500 cm⁻¹ range using KBr pellets. X-ray diffraction (XRD) patterns were recorded on a Bruker AXS D8 Advance diffractometer with CuKα radiation (λ = 1.5418 Å). Morphology was examined by FE-SEM (Hitachi S-4160) and TEM (Philips EM208, 100 kV). Mass spectra were collected by EI (20–70 eV, m/z 10–800) using an Agilent 5975 C instrument. Thermogravimetric analysis (TGA) was performed on a PerkinElmer instrument, and magnetic properties were evaluated by a vibrating sample magnetometer (VSM; BHV-55).

Preparation of Fe₃O₄@SiO₂-NH-TCT–(T-4-HLP)₂

Protocol A

Synthesis of Fe₃O₄@SiO₂ (1)

Fe₃O₄ nanoparticles were synthesized by a standard co-precipitation method²⁴. Briefly, FeCl₃·6 H₂O (1.3 g, 4.8 mmol), FeCl₂·4 H₂O (0.9 g, 4.5 mmol), and polyvinyl alcohol (1.0 g, PVA 15,000) were dissolved in deionized water (30 mL) under vigorous stirring. The mixture was heated to 80 °C, and hexamethylenetetramine (HMTA, 1.0 M) was added dropwise until pH 10, yielding black magnetic particles. The precipitate was separated magnetically, washed with EtOH/H₂O (3 × 5mL), and dried at 80 °C for 10 h.

The Fe₃O₄@SiO₂ core–shell nanocomposite was then prepared by a modified Stöber method²⁴. Fe₃O₄ (0.5 g) was dispersed in EtOH (50 mL), H₂O (5 mL), and tetraethoxysilane (TEOS, 200 µL). A NaOH solution (10 wt%, 5 mL) was added dropwise, and the mixture was stirred at room temperature for 30 min. The product was magnetically separated, washed (EtOH/H₂O, 3 × 5mL), and dried at 80 °C.

Synthesis of Fe₃O₄@SiO₂–NH₂ (2)

Fe₃O₄@SiO₂ (1.0 g) was dispersed in EtOH (10 mL) under ultrasonication, followed by addition of 3-aminopropyltriethoxysilane (APTES, 250 µL, 1.0 mmol). The mixture was refluxed for 12 h under stirring. The product was magnetically collected, washed with EtOH/H₂O, and dried at 80 °C for 6 h²⁴.

Synthesis of Fe₃O₄@SiO₂–NH–TCT (3)

Fe₃O₄@SiO₂–NH₂ (1.0 g) was dispersed in THF (10 mL), followed by addition of cyanuric chloride (TCT, 185 mg, 1.0 mmol) and diisopropylethylamine (DIPEA, 170 µL, 1.0 mmol). The reaction was stirred at room temperature for 16 h. The product was magnetically separated, washed with EtOH/H₂O, and dried at 80 °C for 4 h²⁴.

Synthesis of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ (4)

Fe₃O₄@SiO₂–NH–TCT (1.0 g) was dispersed in DMF (5 mL), then treated with trans-4-hydroxy-L-proline (T-4-HLP, 262 mg, 2.0 mmol) and DIPEA (350 µL, 2.0 mmol). The mixture was stirred at 80 °C for 12 h, after which the product was collected magnetically, washed with EtOH/H₂O, and dried at 70 °C for 4 h (Scheme 1).

Scheme 1.

Preparative process of Fe₃O₄@SiO₂-NH-TCT-(T- 4-HLP)₂ (4) via protocol A.

Protocol B

Synthesis of Cl–TCT–(T-4-HLP)₂ (5)

As shown in Scheme 2, T-4-HLP (262 mg, 2.0 mmol) and cyanuric chloride (TCT, 185 mg, 1.0 mmol) were dissolved in THF (10 mL). DIPEA (0.35 mL, 2.0 mmol) was added to neutralize the HCl generated during the reaction, and the mixture was stirred at room temperature for 12 h. Upon completion, Na₂CO₃ solution (0.2 M, 10 mL) was added to dissolve the precipitate. The mixture was extracted with chloroform (15 mL), and the organic phase was concentrated. The crude solid was washed with cold ethanol to afford Cl–TCT–(T-4-HLP)₂ (5) as a white powder in 85% yield.

Scheme 2.

The synthetic process of Fe₃O₄@SiO₂-NH-TCT-(4-HLP)₂ (4) via protocol B.

Synthesis of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ (4)

Cl–TCT–(T-4-HLP)₂ (5) (370 mg, 1.0 mmol) and DIPEA (130 µL, 1.0 mmol) were added to a DMF dispersion (10 mL) of Fe₃O₄@SiO₂–NH₂ nanoparticles (2) (1.0 g). The reaction mixture was stirred at 80 °C for 16 h, and the resulting product was magnetically separated, washed thoroughly with H₂O and EtOH, and dried at 70 °C for 4 h to yield Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ (4) (0.9 g).

General protocol for the synthesis of indoline spiroaminals

Indoline spiroaminals were synthesized via a sequential one-pot multicomponent domino reaction. An aniline derivative (0.5 mmol) and a 1,3-dicarbonyl compound (0.5 mmol) were mixed with Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ (20 mg) under solvent-free conditions. The progress of β-enamino ketone formation was monitored by TLC.

Subsequently, Fischer’s base (0.5 mmol, 0.085 mL) and a benzaldehyde derivative (0.5 mmol) were added, and the mixture was stirred until reaction completion, as determined by TLC. Ethanol (5 mL) was then introduced, and the catalyst was recovered magnetically. The reaction mixture was treated with distilled H₂O, and the resulting precipitate was filtered, washed with H₂O, and recrystallized from ethanol to afford the pure spiroaminal product.

Result and discussions

Identification of Cl-TCT-(T-4-HLP)₂ Organic Part

Mass analysis

The mass spectrum of Cl-TCT-(T-4-HLP)₂ displayed a molecular ion peak at m/z 372.070, along with a characteristic [M + 2] isotopic peak of approximately one-third the intensity of [M⁺]. This isotopic pattern confirms the presence of a single chlorine atom in the structure (Fig. 1).

Fig. 1.

The mass spectrum of synthesized Cl-TCT-(T-4-HLP)₂ (5).

FT-IR analysis of Cl-TCT-(T-4-HLP)₂ (5)

The FT-IR spectrum of the organic moiety in the catalyst exhibited characteristic absorption bands at 1558, 1228, and 782 cm⁻¹, corresponding to C = N stretching [2523], C–N stretching²⁵, and Csp²–Cl vibrations²⁶, respectively. Additional peaks at 3260, 2900, 1627, and 1404 cm⁻¹ were assigned to N–H stretching, Csp³–H stretching²⁷, C = O stretching of carboxylate²⁸, and CH₂ bending²⁶, respectively. These features confirm the immobilization of up to two equivalents of T-4-HLP per cyanuric chloride unit (Fig. 2).

Fig. 2.

FT-IR spectrum of the synthesized Cl-TCT-(T-4-HLP)₂ (5).

¹H-and ¹³C-NMR analysis

The structure of Cl-TCT-(T-4-HLP)₂ was confirmed by detailed NMR analyses. In the ¹H NMR spectrum (500 MHz, DMSO-d₆), signals corresponding to H1 and H4 of T-4-HLP were observed at 4.40 and 4.25–4.35 ppm, respectively (Fig. 3a). Peaks at 3.38 and 3.05 ppm were assigned to the diastereotopic methylene protons H5 and H5′, while H3 and H3′ resonated at 2.20 and 2.02 ppm. The ammonium protons H1 and H1′ appeared as broad signals at 5.5 and 10.0 ppm, respectively.

Fig. 3.

(a) ¹H NMR spectrum (500 MHz, DMSO-d₆) of Cl-TCT-(T-4-HLP)₂. (b) ¹³C NMR spectrum (125 MHz, DMSO-d₆) of Cl-TCT-(T-4-HLP)₂.

Further confirmation was obtained from ¹³C NMR and J-MOD spectra. Strong resonances at 37.8 and 53.5 ppm were attributed to C5 and C3, respectively, while signals at 69.0 and 58.2 ppm corresponded to C4 (adjacent to the hydroxyl group) and C2 (adjacent to the carboxylate group). Additionally, two weak signals at 150.0 and 154.0 ppm were assigned to the ipso carbons C7 and C6 of the triazine ring (Fig. 3b).

The ¹³C J-modulated spin–echo (J-MOD) spectrum was further employed to confirm the carbon multiplicities of Cl-TCT-(T-4-HLP)₂. Unlike DEPT, J-MOD allows simultaneous visualization of quaternary carbons along with methine, methylene, and methyl signals, with quaternary and methylene resonances appearing in opposite phase to methine and methyl signals. Accordingly, the quaternary carbon C-1 and methylene carbons C-3 and C-5 appeared as negative signals at 170, 37.26, and 53.21 ppm, respectively, whereas the methine carbons C-2 and C-4 gave positive signals at 57.87 and 68.75 ppm (Fig. 4).

Fig. 4.

The J-MOD spectrum of synthesized Cl-(NCCl)₃-(4-HP)₂ in DMSO-d₆.

Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ characterization

FT-IR analysis

Figure 5 presents the stepwise FT-IR analysis of Fe₃O₄, Fe₃O₄@SiO₂, Fe₃O₄@SiO₂–NH₂, Fe₃O₄@SiO₂–NH–TCT, and Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ nanoparticles, confirming the successful modification and functionalization of the catalyst. The absorption bands at 1654 cm⁻¹ and 3422 cm⁻¹ correspond to bending and stretching vibrations of surface –OH groups, while a distinct peak at ~ 562 cm⁻¹ is assigned to Fe–O stretching in Fe₃O₄ (Fig. 5a). In Fig. 5b, strong Si–O–Si stretching bands at 1024–1032 cm⁻¹ verify the presence of the Fe₃O₄@SiO₂ core–shell structure. The appearance of peaks at 1120–1250 cm⁻¹ (C–N stretching), 1479 cm⁻¹ (CH₂ bending), 2929 cm⁻¹ (C–H stretching), and 3422–3431 cm⁻¹ (NH₂ stretching) confirms successful surface functionalization with 3-aminopropyl(triethoxy)silane (Fig. 5c). The peak at 1337 cm⁻¹ (aromatic C–N stretching), together with the band at 782 cm⁻¹ attributed to the C–Cl bond, indicates the successful reaction of TCT with Fe₃O₄@SiO₂–NH₂, leading to the formation of Fe₃O₄@SiO₂–NH–TCT nanoparticles (Fig. 5d). Finally, the presence of peaks at 1120–1250 cm⁻¹ (C–N stretching), 1266–1342 cm⁻¹ (aromatic C–N stretching), and 1653 cm⁻¹ (carboxylic C = O stretching) confirms the covalent linkage of T-4-HLP to the nanostructure, evidencing the formation of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ (Fig. 5e). Collectively, these results demonstrate the successful loading of 4-HLP onto the surface of the magnetic nanoparticles.

Fig. 5.

The FTIR spectra of (a) Fe₃O₄, (b) Fe₃O₄@SiO₂, (c) Fe₃O₄@SiO₂-NH₂, (d) Fe₃O₄@SiO₂-NH-TCT and (e) Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂.

XRD Analysis for proving the crystalline structural properties

Using XRD, we investigated the crystalline structural properties of Fe₃O₄, Fe₃O₄@SiO₂, and Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂, with the results presented in Fig. 6. The characteristic diffraction pattern of iron oxide was observed in both Fe₃O₄@SiO₂ and Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ nanoparticles, confirming the successful incorporation of Fe₃O₄ into these nanostructures. Distinct reflections at 2θ = 30.3°, 35.9°, 43.2°, 53.8°, 57.5°, and 63.1°, corresponding to the (220), (311), (400), (422), (511), and (440) planes, respectively, verified the cubic spinel structure of the synthesized magnetic nanoparticles. A decrease in diffraction intensity of the magnetite phase was observed after coating with an amorphous layer of SiO₂ and organic compounds (Fig. 6b). Furthermore, a broad diffraction band between 10° and 25° (Fig. 6b, c) was attributed to the amorphous nature of SiO₂ and the organic moieties anchored onto the Fe₃O₄ surface. The crystallite size (D) of the as-prepared Fe₃O₄ nanoparticles was calculated using Scherrer’s equation:

Fig. 6.

The XRD images of (a) Fe₃O₄, (b) Fe₃O₄@SiO₂ and (c) Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂.

where K = 0.9 (for Cu Kα radiation), λ is the X-ray wavelength, β is the full width at half maximum (FWHM), and θ is the diffraction angle. The mean crystallite size of Fe₃O₄ was calculated to be approximately 15.4 nm.

FE-SEM and TEM analyses

FE-SEM analysis was conducted to confirm the uniform and spherical morphology of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ magnetic nanoparticles. The FE-SEM image (Fig. 7a) revealed an average particle size of approximately 26.6 nm. TEM analysis provided further structural insights, clearly showing the core–shell architecture of the nanoparticles, with a dark magnetic Fe₃O₄ core surrounded by a gray silica layer and an outer organic shell (Fig. 7b).

Fig. 7.

(a) The FE-SEM image of synthesized Fe₃O₄@SiO2-NH-TCT-(T-4-HLP)₂ nanoparticles. (b) The TEM image of synthesized Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ nanoparticles.

TGA analysis

TGA (thermogravimetric analysis) and DSC (differential scanning calorimetry) were employed to investigate the thermal stability and pyrolytic decomposition behavior of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ nanoparticles, with the results presented in Fig. 8. The TGA curve revealed multiple weight-loss steps upon heating. The first weight loss, occurring below 130 °C, was attributed to the removal of surface-adsorbed water and residual solvents. A subsequent weight loss of approximately 20% between 130 and 220 °C corresponded to the decomposition of organic moieties, followed by an additional loss between 220 and 600 °C, associated with the structural degradation of the T-4-HLP amino acid and remaining organic compounds. After heating to 600 °C, only ~ 37% of the total weight had been lost, indicating that the catalyst possesses relatively high thermal stability.

Fig. 8.

Thermogravimetric analysis of Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ nanoparticles.

VSM analysis

Using vibrating sample magnetometry (VSM), we evaluated the magnetic properties of the nanoparticles. The results (Fig. 9) confirmed the superparamagnetic nature of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂, with a saturation magnetization (Ms) of 28.8 emu/g.

Fig. 9.

Magnetization curve of Fe₃O₄@SiO₂-NH-TCT–(T-4-HLP)₂ nanoparticles.

EDX Analysis for calculating the catalyst composition

The synthesized nanoparticles were further characterized by energy-dispersive X-ray (EDX) analysis to evaluate their elemental composition and confirm the uniform distribution of elements on the catalyst surface. EDX spectra were collected from several selected regions on the external surface of the crystals. The presence of characteristic peaks corresponding to Fe, Si, C, N, and O in the spectrum of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ verified the successful preparation of the catalyst (Fig. 10a). In addition, elemental mapping analysis was performed for more detailed structural confirmation. The results demonstrated the homogeneous distribution of Fe, Si, C, N, and O across the entire surface of the nanocatalyst, further supporting its successful synthesis (Fig. 10b).

Fig. 10.

(a) The EDX analysis of catalyst Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ nanoparticles; (b) and elemental mapping of catalyst.

BET analysis

The surface area and porosity of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ nanoparticles were evaluated using Brunauer–Emmett–Teller (BET) and Barrett–Joyner–Halenda (BJH) analyses, with the results summarized in Table 1. The BET surface area was determined to be 42.994 m²/g, while the BJH pore surface area was measured at 50.456 m²/g.

Table 1.

Results of BET and BJH for Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ NPs.

BJH summary
Surface area	50.456 m²/g
Pore Volume	0.2338 cm3/g
Pore Diameter Dv(d)	5.29 nm
BET summary
Surface Area	42.994 m2/g

Zeta potential analysis

The observed negative zeta potential(−21.7 mV) is likely associated with the deprotonation of surface carboxylic acid groups, leading to electrostatic repulsion between particles and improved colloidal stability in aqueous environments Fig 11. 

Fig. 11.

The zeta potential graph of Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂.

Catalytic activity of Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂

We next investigated the catalytic performance of the chiral nanomagnetic L-proline catalyst in the one-pot multicomponent diastereoselective synthesis of indoline spiropyridines and spiropyrans. These heterocyclic compounds are well known for their thermochromic and photochemical properties, as well as their advanced applications in data storage, optical switching, nonlinear optics, and display technologies. As a model system, the multicomponent reaction of aniline, dimedone, benzaldehyde, and Fischer’s base was chosen to optimize key reaction parameters, including solvent, reaction time, catalyst type, and catalyst loading. The corresponding optimization results are summarized in Table 2.

Table 2.

Optimization of reaction conditions for the indoline spiropyridines DR7 as the model product ^[a].

Entry	Temp. (o C)	Catalyst type	Catalyst amount (mg)	Solvent	Time (h)	Yield (%)[b]
1	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	5	Solvent Free	14	43
2	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	10	Solvent Free	14	65
3	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	15	Solvent Free	10	72
4	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	Solvent Free	6	87
5	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	30	Solvent Free	6	85
6	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	MeCN	6	Trace
7	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	CH2Cl2	7	40
8	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	DMSO	6	Trace
9	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	Diethyl ether	8	70
10	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	H2O/EtOH(1:1)	6	60
11	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	Ethyl acetate	9	70
12	R.T.	Fe3O4@SiO2-NH-TCT-(T-4-HLP)2	20	EtOH	6	80
13	R.T.	No Catalyst	20	Solvent Free	16	trace
15	R.T.	Fe3O4@SiO2	20	Solvent Free	6	45
16	R.T.	Fe3O4	20	Solvent Free	6	50
17	R.T.	Acetic acid	20	Solvent Free	6	75
18	R.T.	L(+) Ascorbic acid	20	Solvent Free	6	70
19	R.T.	Nitrilotriacetic acid	20	Solvent Free	6	45
20	R.T.	L-Proline	20	Solvent Free	6	50
21	R.T.	Amino tris(phosphonic acid)	20	Solvent Free	6	45
22	R.T.	Amberlyst (15)	20	Solvent Free	6	50

^[a] Reaction conditions: aniline (0.5 mmol), dimedone (0.5 mmol), benzaldehyde (0.5 mmol) and Fischer’s base (0.5 mmol), catalyst, solvent.

^[b] Isolated yield.

After establishing the optimized reaction conditions—0.5 mmol each of aniline, dimedone, benzaldehyde, and Fischer’s base, along with 20 mg of catalyst under solvent-free conditions—the scope and versatility of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ were further investigated. A variety of substituted anilines, carbon acids, and benzaldehydes were employed to evaluate the general applicability of the method, and the corresponding results are summarized in Table 3.

Table 3.

Employing of Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ catalyst for the diastereoselective synthesis of indoline spiropyridines and spiropyranes^[a].

Entry	ArNH2	Carbon Acid	ArCHO	Product	Time (h)	Yield (%)[b]	Anti/syn[c]
1					6	40	> 99:1
2					5	87	> 99:1
3					4	93	> 99:1
4					6	65	> 99:1
5					5	60	> 99:1
6					6	70	> 99:1
7					6	87	> 99:1
8					8	70	> 99:1
9					6	84	70:30
10					4	86	> 99:1
11					3	95	90:10
12					3	80	> 99:1

[a] Reaction conditions: aniline (0.5 mmol), dimedone (0.5 mmol), aldehyde (0.5 mmol) and Fischer’s base (0.5 mmol), Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ (20 mg) and solvent free.

[b] Isolated yield.

[c] Anti/syn ratio using 1 H NMR analysis.

Most of the reactions afforded the target products in moderate to excellent yields, with the exception of entry 1, where the desired product was obtained in only 40% yield due to the ortho-steric effect of the nitro substituent. FT-IR and 1D 1 H- and 13 C-NMR spectroscopy analyses confirmed that all reactions, except for entries 9 and 11, proceeded with quantitative diastereoselectivity, affording exclusively one diastereomer (the anti-stereoisomer). To establish the absolute configuration of the anti-stereoisomers, single-crystal X-ray diffraction analysis was performed on compound DR-7. The crystallographic data revealed that, in the low-temperature crystal structure of DR-7, all bond lengths and bond angles fell within the expected ranges. The spiro carbon (C5) was identified as an sp³-hybridized carbon with tetrahedral geometry, while the olefinic double bond between C22 and C29 exhibited a bond length of 1.365 Å. The structure also clearly demonstrated the anti-relationship between the phenyl substituent at C7 and the C5–CMe₂ bond (CCDC 011124) (Fig. 12).

Fig. 12.

The single-crystal structure of DR-7 compound.

To gain deeper insight into the structure of the synthesized products and to assign their relative stereochemistry, 1D (¹H and ¹³C NMR), 2D Rotating-Frame Nuclear Overhauser Effect Spectroscopy (¹H–¹H ROESY), and high-performance liquid chromatography (HPLC) analyses were performed, with results provided in the Supporting Information. These studies confirmed the excellent diastereoselectivity observed in entries 1–8, 10, and 12 of Table 3, while revealing distinct features in the spectra of compound DR-9, as discussed below.

The combined ¹H, ¹³C NMR, ROESY, and mass spectrometry data (Figs. 13 and 14) indicated the presence of two stereoisomers of DR-9 in a ratio of ~ 70:30 and 90:10, respectively. The ¹H NMR spectrum of DR-9 displayed two mutually coupled doublets of doublets at 2.31 ppm (dd, J = 13, 6.5 Hz, 1H) and 2.45 ppm (dd, J = 13, 6.5 Hz, 1H), corresponding to the diastereotopic protons of CH₂ group 3. Proton H8, coupled with this CH₂ group, appeared as a doublet of doublets at 4.15 ppm (dd, J = 13, 6.5 Hz, 1H). The vicinal CH₂ group 1 protons were observed as two mutually coupled doublets at 1.76 ppm (d, J = 16.5 Hz, 1H) and 2.06 ppm (d, J = 16.5 Hz, 1H), while CH₂ group 2 protons overlapped to appear as a doublet of doublets at 2.20 ppm (dd, J = 28, 16 Hz, 2 H) (Fig. 13a).

Fig. 13.

(a) The ¹H-NMR spectrum; (b) the ¹³C-NMR spectrum of DR-9.

Fig. 14.

(a) the mass spectrum, and (b) the ROESY spectrum of DR-9.

The existence of weaker duplicate peaks adjacent to major resonances, marked with the same numbering, confirmed the presence of stereoisomeric products. For example, the methoxy group exhibited two singlets at 3.84 ppm (3 H, syn, 30%) and 3.24 ppm (3 H, anti, 70%), consistent with a 70:30 isomer ratio. Similarly, the three methyl groups derived from Fischer’s base showed signals at 2.41, 1.58, and 1.34 ppm (all syn, 30%) for the minor isomer, and at 2.36, 1.59, and 1.35 ppm (all anti, 70%) for the major isomer.

Interestingly, the ¹H NMR spectrum of DR-9 revealed two notable downfield-shifted aromatic signals: H4 at 5.98 ppm (s, 1H) and H33 at 5.80 ppm (d, J = 7.7 Hz, 1H), in contrast to the other aromatic protons, which appeared above 6.7 ppm. These unusual shifts were attributed to anisotropic shielding by the aromatic ring of Fischer’s base (Fig. 14a).

The ¹³C NMR spectrum of DR-9 displayed 32 distinct signals, including 13 aromatic CH carbons, five quaternary aromatic carbons, one carbonyl carbon, two quaternary sp² carbons of double bonds, one quaternary sp³ spiro-carbon center, two additional quaternary sp³ carbons, six methyl carbons, three methylene carbons, and one methine carbon. This confirmed the non-equivalence of nearly all carbons, except for two equivalent pairs (C10/C31 and C11/C32). The conjugated carbonyl carbon of dimedone resonated at a low chemical shift (159 ppm), consistent with strong upfield shielding due to resonance effects with both the double bond and the amino group. Additional small peaks near the major carbon resonances (highlighted with black arrows) further supported the presence of stereoisomers of DR-9 (Fig. 13b).

Mass spectrometry further confirmed the molecular weight of compound DR-9, showing peaks at m/z 506.29 ([M]) and 529.29 ([M + Na]), consistent with the expected molecular formula (Fig. 14a). The ROESY spectrum of DR-9 (Fig. 14b) provided additional stereochemical insight. For the major isomer (70%), a strong cross-peak correlation was observed between the H13 proton of the N–Me group at 2.36 ppm (s, 3 H, anti, 70%) and the H8 proton at 4.15 ppm (dd, J = 13, 6.5 Hz, 1 H). In contrast, for the minor isomer (30%), a correlation was detected between the H13 proton of the N–Me group at 2.41 ppm (s, 3 H, syn, 30%) and the H29 methylene protons of dimedone at 2.20 ppm (dd, J = 28, 16 Hz, 2 H).

Finally, 4-hydroxycoumarin and 4-hydroxy-1-methylquinolin-2(1H)-one were employed as alternative carbon acids in place of dimedone under the optimized conditions, leading to the successful synthesis of the expected indoline spiropyridine derivatives (Scheme 3).

Scheme 3.

The expected indoline spiropyridine products when 4-hydroxycoumarine and 4-hydroxy-1-methyl quinoline-2(1H)-one used in the place of dimedone.

Surprisingly, interpretation of the ¹H- and ¹³C-NMR spectra of the obtained products, particularly the absence of the characteristic peak at 5.7 ppm and the reduced number of Csp²–H aromatic signals, revealed that the aniline component in both reactions did not participate in the course of the reaction and was absent in the structure of the final products. Instead, the reactions yielded the corresponding indoline spiropyrans (Table 3, entries 11 and 12). To further investigate this unexpected result, control reactions were performed between aniline (or anisidine) and 4-hydroxycoumarin or 4-hydroxy-1-methylquinolin-2(1H)-one. TLC monitoring of these reactions confirmed the persistence of the starting materials and the absence of any product formation (Scheme 4).

Scheme 4.

The reaction of aniline with 4-hydroxycoumarine and p-anisidine with 4-hydroxy-1-methyl quinoline-2(1H)-one.

The ¹H-NMR spectrum of DR-11 exhibits two mutually coupled doublets of doublets at 2.58 ppm (dd, J = 14.5, 6 Hz, 1H) and 2.37 ppm (dd, J = 14 Hz, 1H), corresponding to the diastereotopic protons of CH₂ group 1. Additionally, proton H8, which is coupled with this CH₂ group, appears as a doublet of doublets at 4.43 ppm (dd, J = 12.5, 6 Hz, 1H) (Fig. 14). The presence of several minor peaks with lower intensity adjacent to the main signals (marked with arrows) further supports the existence of diastereomeric products. For example, in the ¹H-NMR spectrum of DR-11, the N–Me group appears as two distinct singlets at 3.62 ppm (s, 3 H, syn, 10%) and 3.60 ppm (s, 3 H, anti, 90%), indicating a syn/anti ratio of 10:90. Similarly, the methyl groups of the Fischer’s base fragment are observed at 2.93 ppm (s, 3 H, syn, 10%), 1.47 ppm (s, 3 H, syn, 10%), and 1.11 ppm (s, 3 H, syn, 10%) for the minor isomer, and at 2.96 ppm (s, 3 H, anti, 90%), 1.39 ppm (s, 3 H, anti, 90%), and 1.31 ppm (s, 3 H, anti, 90%) for the major isomer (Fig. 15a).

Fig. 15.

(a) The ¹H-NMR spectrum, (b) the ¹³C-NMR spectrum of DR-11.

The ¹³C-NMR spectrum of DR-11 displays twenty-seven distinct signals: ten aromatic CH carbons, six aromatic quaternary carbons, one carbonyl carbon, two quaternary sp² carbons (double bonds), one quaternary sp³ spiro-carbon, one additional quaternary sp³ carbon, four methyl carbons, one methylene carbon, and one methine carbon. These assignments are consistent with all carbons being non-equivalent, except for the equivalent chemical shifts observed in carbon atom pairs C10/C14 and C11/C13 (Fig. 15b).

Additionally, HPLC analysis confirmed the presence of stereoisomers of the DR-11 compound in the reaction mixture. Each peak in the chromatogram corresponds to a compound with distinct polarity and is labeled with its specific retention time, which reflects the duration required for elution from the HPLC column. The first peak, appearing at approximately 14.02 min, represents the isomer with lower polarity, while the second peak, observed at 15.02 min, corresponds to another isomer with slightly higher polarity. These findings suggest that the two compounds possess nearly identical chemical properties and differ only in their stereochemistry (Fig. 16).

Fig. 16.

The HPLC spectrum of DR-11.

Recoverability and reusability of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂

The recoverability, stability, and reusability of heterogeneous catalysts are key factors in modern green chemistry from both economic and environmental perspectives. To assess these properties, the reusability of Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ was investigated under optimized reaction conditions. After each reaction cycle, the catalyst was magnetically separated from the reaction medium, thoroughly washed with ethanol (3 × 10 mL), and dried at 70 °C under vacuum before being reused in subsequent runs.

The recycling experiments demonstrated that the catalyst could be efficiently reused for up to seven consecutive cycles without any significant loss of catalytic activity or selectivity (Fig. 17). Furthermore, XRD and FT-IR analyses of the recovered catalyst after seven runs (Figs. 18 and 19) showed only negligible changes in comparison to the related spectra of the fresh catalyst in Figs. 5 and 6, confirming that the structural integrity of the nanocatalyst was well preserved throughout the recycling process.

Fig. 17.

The reusability study of Fe₃O₄@SiO₂-NH-TCT-(T-4-HLP)₂ nanocatalyst.

Fig. 18.

XRD pattern of the recovered Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ nanocatalyst after seven runs.

Fig. 19.

FT-IR spectrum of the recovered Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ nanocatalyst after seven runs.

Proposed mechanism

Based on the experimental data, a plausible mechanism is proposed for the Fe₃O₄@SiO₂–NH–TCT–(T-4-HLP)₂ catalyzed one-pot four-component reaction of anilines, benzaldehydes, carbon acids, and Fischer’s base.

Initially, the catalyst activates the carbonyl group of dimedone through intermolecular hydrogen bonding or protonation, facilitating condensation with aniline to form the imine intermediate (A). This imine subsequently tautomerizes to the corresponding enamine intermediate (B).

Concurrently, the proline residue of the catalyst activates the aldehyde via its nitrogen atom, generating the corresponding E/Z-iminium species, with the equilibrium favoring the E-isomer (Scheme 5). Fischer’s base then attacks regioselectively from the Re-face to give the R-configured intermediate (C).

Scheme 5.

Proposed mechanism for the synthesis of Z- and E- iminium forms of the proline catalyst with benzaldehyde.

In the final step, the enamine intermediate (B) undergoes an intramolecular SN2-type attack on intermediate (C), followed by cyclization to furnish the desired spirocyclic product. The catalyst is regenerated at the end of the cycle (Scheme 6).

Scheme 6.

Plausible mechanisms for the preparation of indoline spiropyridines.

Conclusion

In this study, a magnetic chiral nanocatalyst incorporating L-proline as a bioorganic ligand was synthesized via two synthetic strategies and comprehensively characterized by FT-IR, ¹H-NMR, ¹³C-NMR, J-MOD, mass spectrometry, XRD, BET, FE-SEM, TEM, EDX, VSM, and TGA analyses. The catalyst was successfully applied to the solvent-free, sequential multicomponent synthesis of novel indoline spirobicyclic derivatives from anilines, benzaldehydes, carbon acids, and Fischer’s base under ambient conditions.

This methodology offers several advantages: operational simplicity, mild and solvent-free conditions, clean reaction profiles, broad product diversity, high yields with excellent diastereoselectivity, and compatibility with green chemistry principles. Furthermore, the catalyst exhibited high stability, recoverability, and reusability, highlighting its potential for sustainable and scalable applications in synthetic organic chemistry.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Danial Rafipour : Data curation, formal analysis, investigation, resources, validation, visualization, writing original draft; Marzieh Jamali: Formal analysis, investigation, methodology, writing original draft, project administration; Ali Reza Sardarian : conceptualization, supervision, writing-review&editing, funding acquisition; Saeed Davoodi: Formal analysis, validation, investigation.

Data availability

All data are available in the supporting information file.

Declarations

Competing interests

The authors declare no competing interests.