One-pot synthesis of Bis-spiro Piperidines Using Nanocellulose/BF3/Fe3O4 as a Natural Based Catalyst

Moharrami Korblagh, Parisa; Bamoniri, Abdolhamid; Mirjalili, Bi Bi Fatemeh

doi:10.22052/JNS.2026.04.092

One-pot synthesis of Bis-spiro Piperidines Using Nanocellulose/BF3/Fe3O4 as a Natural Based Catalyst

Document Type : Research Paper

Authors

Parisa Moharrami Korblagh ¹

Abdolhamid Bamoniri ¹

Bi Bi Fatemeh Mirjalili ²

¹ Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, I.R.Iran

² Department of Organic Chemistry, College of Science, Yazd University, Yazd, I.R.Iran

10.22052/JNS.2026.04.092

Abstract

Recently, multi-component reactions (MCRs) have been purposeful and they have become a serious area of research in medicinal and chemical science. A highly impressive one-pot multicomponent synthesis of bis-spiro piperidine derivatives has been reported by performing the reaction of formaldehyde, aromatic aniline and dimedone (in ratio of 3:1:2) compounds. This reaction was performed in the presence of nanocellulose/BF3/Fe3O4 as Lewis acid and heterogeneous catalyst in ethanol at room temperature. Nano-cellulose/BF3/Fe3O4 as a Lewis acid catalyst has been synthesized and characterized with Field Emission Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM), Fourier Transform Infrared (FT-IR), Thermal Gravimetry Analysis (TGA), X-ray Diffraction (XRD), X-ray fluorescence (XRF) and (Vibrating sample Magnetometry Measurements (VSM) analysis. The advantages of this protocol are low reaction time, high yield of products, simplicity of operation and reusability of catalyst. The structure of the obtained bis-spiro piperidine derivatives were studied by FT-IR and Nuclear Magnetic Resonance (1H NMR) spectroscopy.

Keywords

Bis-spiro piperidine

Multi-component reactions

Nanocellulose/BF3/Fe3O4

INTRODUCTION
To produce elaborate compounds, multi-component reactions (MCRs) have been purposeful and they have become a serious area of research in medicinal chemistry [1-7]. They are defined as monovalent reactions [8] which at least three components are joined by covalent bonding [9]. Simplicity of reaction [10], single container [11], extraction and treatment hence minimize waste production12. In recent years, piperidine has been established as a significant heterocyclic compound [13-14]. The pharmacological activity of piperidine is well known [15]. Compounds containing piperidine show anticonvulsant [16], antihypertensive [17], anti-HIV [18] and anti-malarial [19] activities. Piperidines are also used as important pharmacological agents in the treatment of viral infections and diabetes [20]. Piperidines is the basic structure of many natural alkaloids [21]. Numerous methods have been reported for the preparation of spiro pipyridines. From the significance of piperidines, spiro-piperidines, which are partly lesser outstanding [22]. The prime spiro-piperidine was created by Bayer in 1900 described as a bicyclic hydrocarbon contiguous by a single carbon [23]. There has been no intention to application acetic acid as a catalyst for the synthesis of spirons [24].
Recently, multitude organic reactions are synthesized using acid catalysts. The use of homogenous catalysts has received little attention [25-27]. So, the search for a cheap [28], readily available [29], and comfortable catalyst is desirable [30]. Nanoparticles are the functional component in different MCR [31], owing to the unique properties that arise from their size [32]. The catalytic activity of a catalyst is mainly resolute by its particle size. Nano-cellulose has specific importance because of its availability [33], high stability and the fact that organic groups can adjoin to its surface with strong connection [34]. Nanocellulose is an unparalleled natural polymer and biological attributes such like as biocompatibility [35-37], biodegradability and low toxicity. In this work, we apply nano-cellulose/BF3/Fe3O4 as a bio-based and magnetic catalyst for the synthesis of bis-spiro substituted piperidines.

MATERIALS AND METHODS
General
The different substrates used in this study were purchased from Sigma Aldrich and Merck . TLC was carried out using silica gel G60 F254 plates (Merck). 1H NMR, 13C NMR spectra were recorded on a Brucker-Avance 400 MHz spectrometer using TMS as an inner standard and DMSO-d6 as a solvent. X-ray diffraction patterns were obtained with a Philips Xpert MPD diffractometer with a Cu Kα anode (k = 1.54 A˚) in the 2Ө range from 10 to 80. Field emission scanning electron microscopy was carried on a Mira 3- XMU, and transmission electron microscopy using a Philips CM120 with a LaB6 cathode and an accelerating voltage of 120 kV. X-ray fluorescence analysis was carried with a Bruker S4 Explorer instrument. Vibrating sample magnetometry measurements were carried by using a vibrating sample magnetometer.

Preparation of nano-cellulose from cotton
3 g of cotton was refluxed with 150 ml of 17.5% NaOH solution for 24 h. The obtained cotton was filtered and washed with distilled water. Then, the cotton was refluxed in solution of 15 ml of sodium hypochlorite and 55 ml of distilled water for 1.5 hours. After that, the cotton fibers were washed with distilled water. For partial acid hydrolysis and obtain nanocellulose, 60 ml of 35% sulfuric acid aqueous solution was added to cotton fibers and refluxed for 5-6 hours. The prepared suspension was diluted with water, then centrifuged at 6000 rpm.

Preparation of nanocellulose/BF3/Fe3O4
0.5 ml of BF3 was added dropwise to a mixture of nanocellulose (0.5 g) in 5 ml of dichloromethane and stirred for 20 minutes at 25 °C. Then the obtained mixture was filtered and washed with dichloromethane and dried at 25°C. After that, under ultrasound irradiation, the resulting nanocellulose/BF3 was dispersed with 5 g of Fe3O4 nanoparticles in 5 ml of dichloromethane at room temperature for 1 hour. Then the resulting suspension was separated and washed with dichloromethane and dried at 25°C to obtain nanocellulose/BF3/Fe3O4 catalyst.

General procedure for the synthesis of bis-spiro piperidines in the presence of nanocellulose/BF3/Fe3O4 as catalyst
In a flask, a mixture of formaldehyde (3 mmol) 1,3-dicarbonyl compound (2 mmol), aniline (1 mmol), 5 mL of EtOH and 0.02 g of catalyst was mixed at room temperature for the stipulated time given in Table 2. The reaction progress was monitored by thin layer chromatography (TLC). After the completion of a reaction, the catalyst was removed from the reaction mixture by an external magnet. The solvent of reaction mixture was evaporated and the solid product was recrystallized in ethanol.

Spectroscopic data of some products
Compound 1a (Table 2, Entry 1): mp: 207-208 ºC; FTIR (KBr) ῡ: 1073, 1223, 1375, 1600-1460, 1725, 2924, 3039 cm-1. 1H NMR (400 MHz, CDCl3, δ ppm): 7.35 (2H, d, 3J=6.8 Hz, ArH), 7.00 (2H, d, 3J =6.8Hz, ArH), 3.43 (4H, s, NCH2), 2.84 (4H, d, 2J =13.6 Hz, COCH2), 2.65 (4H, d, 2J =13.6 Hz, COCH2), 2.50 (2H, s, CH2), 1.02 (6H, s, CH3),1.01 (6H, s, CH3).
Compound 2a (Table 2, Entry 2) mp: 215-217 ºC; FTIR (KBr) ῡ: 767, 1229, 1389, 1593-1450, 1718, 2926, 3039 cm-1. 1H NMR (400 MHz, CDCl3, δ ppm): 7.22 (2H, d, 3J =8.4 Hz, ArH), 7.05 (2H, d, 3J =8.4 Hz, ArH), 3.43 (4H, s, NCH2), 2.85 (4H, d, 2J =13.6 Hz, COCH2), 2.66 (4H, d, 2J =14 Hz, COCH2), 2.51 (2H, s, CH2),1.02 (12H, s, CH3).
Compound 3a (Table 2, Entry 3) mp: 236-238 ºC; FTIR (KBr) ῡ: 1001, 1286, 1376, 1660-1493, 1749, 2955, 3050 cm-1. 1H NMR (400 MHz, CDCl3, δ ppm): 7.30 (1H, d, 3J =8.8 Hz, ArH), 7.13 (1H, d, 3J =2.8 Hz, ArH), 7.02 (1H, dd, 3J =8.8, 2.8 Hz, ArH), 3.44 (4H, s, CH2 ), 2.85 (4H, d, 2J =14 Hz, COCH2), 2.66 (4H, d, 2J =13.6 Hz, CH2), 2.51 (2H, s, CH2), 1.02 (12H, s, CH3).
Compound 4a (Table 2, Entry 4) mp: 250-253 ºC; FTIR (KBr) ῡ: 1248, 1380, 1610-1421, 1718, 3039, 2963 cm-1. 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.05 (2H, d, 3J =8 Hz, ArH), 6.55 (2H, d, 3J =8 Hz, ArH), 3.38 (4H, s, CH2), 2.66 (3H, s, CH3), 2.32 (4H, d, 2J =16 Hz, CH2), 2.10 (4H, d, 2J =16.4 Hz, CH2), 1.74 (2H, s, CH2),1.05 (12H, s, CH3).
Compound 5a (Table 2, Entry 5) mp: 188-190 ºC; FTIR (KBr) ῡ: 1255, 1374, 1596-1417, 1667, 2958, 3015 cm-1. 1H NMR (400 MHz, DMSO-d6, δ ppm): 6.90 (1H, s, ArH), 6.85 (1H, d, 3J =8 Hz, ArH), 6.64 (1H, d, 3J =8 Hz, ArH), 6.54 (1H, t, 3J =8.4 Hz, ArH), 2.57 (3H, s, CH3 ), 3.4 (4H, s, CH2), 2.27 (4H, d, 2J =16.4 Hz, CH2), 2.12 (4H, d, 2J =16.4 Hz, CH2), 1.75 (2H, s, CH2), 1.04 (12H, s, CH3).
Compound 6a (Table 2, Entry 6) mp: 188–190 ºC; FTIR (KBr) ῡ: 3030, 2922, 1731, 1601-1468, 1350, 1264, 1038, 1264 cm-1. 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.05 (2H, d, 3J =6.4 Hz, ArH), 6.75 (2H, d, 3J =7.2 Hz, ArH), 3.66 (4H, s, CH2), 3.33 (3H, s, OCH3), 2.23 (4H, d, 2 J =17.2 Hz, CH2), 2.07 (4H, d, 2J =17.2 Hz, CH2), 1.72 (2H, s, CH2),1.00 (12H, s, CH3).
Compound 7a (Table 2, Entry 7) mp: 220-222 ºC; FTIR (KBr) ῡ: 1263, 1374, 1593, 1677-1418, 1751, 2956, 3030 cm-1. 1H NMR (400 MHz, DMSO-d6, δ ppm): 8.03 (2H, d, 3J =9.6 Hz, ArH), 7.22 (2H, d, 3J =9.6 Hz, ArH), 3.83 (4H, s, NCH2), 2.85 (4H, d, 2J =13.6 Hz, COCH2), 2.75 (4H, d, 2J =13.6 Hz, COCH2), 2.61 (2H, s, CH2), 0.94 (6H, s, CH3),0.92 (6H, s, CH3).
Compound 8a (Table 2, Entry 8) mp: 186–188 ºC; FTIR (KBr) ῡ: 1264, 1375, 1594, 1677-1449, 1751, 2956, 3030 cm-1. 1H NMR (400 MHz, CDCl3, δ ppm): 7.75 (1H, dd, 3J =8.2, 2.0, ArH), 7.59 (1H, dd, 3J =8.2, 2.0 Hz, ArH), 7.42 (1H, t, 3J =8.0 Hz, ArH), 3.57 (4H, s, NCH2), 2.87 (4H, d, 2J =14.0 Hz, COCH2), 2.69 (4H, d, 2J =14.0 Hz, COCH2), 2.56 (2H, s, CH2), 1.04 (6H, s, CH3), 1.03 (6H, s, CH3).
Compound 9a (Table 2, Entry 9) mp: 140–142 ºC; FTIR (KBr) ῡ: 1094, 1238, 1381, 1598-1469, 1698, 2924 cm-1. 1H NMR (400 MHz, DMSO-d6, δ ppm): 7.28-7.37 (4H, m, ArH), 3.35 (4H, s, NCH2), 2.82 (4H, s, COCH2), 2.73 (4H, s, COCH2), 2.04 (2H, s, CH2), 1.00 (6H, s, CH3),0.96 (6H, s, CH3).
Compound 10a (Table 2, Entry 10) mp: 189–191 ºC; FTIR (KBr) ῡ: 1264, 1375, 1594, 1677-1449, 1751, 2956, 3030 cm-1. 1H NMR (400 MHz, CDCl3, δ ppm): 7.86 (1H, s, ArH), 7.59 (1H, t, 3J =8.0 Hz, ArH), 7.48 (1H, t, 3J =8.0 Hz, ArH), 3.62 (4H, s, NCH2), 2.87 (4H, d, 2J =14.0 Hz, COCH2), 2.69 (4H, d, 2J =14.0 Hz, COCH2), 2.59 (2H, s, CH2), 0.96 (12H, s, CH3).
Compound 11a (Table 2, Entry 11) mp: 189–191 ºC; FTIR (KBr) ῡ: 1264, 1375, 1594, 1677-1449, 1751, 2956, 3030 cm-1. 1H NMR (400 MHz, CDCl3, δ ppm): 8.86 (1H, s, OH), 7.86 (1H, d, ArH), 7.59 (1H, d, 3J =8.0 Hz, ArH), 7.48 (2H, t, 3J =8.0 Hz, ArH), 3.62 (4H, s, NCH2), 2.87 (4H, d, 2J =14.0 Hz, COCH2), 2.69 (4H, d, 2 J =14.0 Hz, COCH2), 2.59 (2H, s, CH2), 0.96 (12H, s, CH3).
Compound 12a (Table 2, Entry 12) mp: 208-209 ºC; FTIR (KBr) ῡ: 1073, 1223, 1375, 1600-1460, 1725, 2924, 3039 cm-1. 1H NMR (400 MHz, DMSO, δ ppm) 7.05 (d, J = 8.2 Hz, 1H), 7.00 (s, 1H), 3.35 (s, 2H), 2.82 (s, 2H), 2.72 (d, J = 13.5 Hz, 2H), 0.94 (s, 3H), 0.91 (s, 6H).

RESULTS AND DISCUSSION
Nanocellulose was prepared by partial hydrolysis of cellulose in cotton. Nanocellulose/BF3 was preparate via reaction of BF3.OEt2 with nanocellulose in CH2Cl2. For magnetization of nanocellulose/BF3, the synthesized Fe3O4 was mixed with nanocellulose/BF3 in CH2Cl2 under ultrasonic condition. In result, nanocellulose/BF3/Fe3O4 was obtained as a magnetic brown powder (Fig. 1).
Identification and investigation of nano cellulose/BF3/Fe3O4 structure was done using various methods such as FT-IR, FESEM, XRF, XRD, TGA, VSM, and TEM. The FT-IR spectrum of nano-cellulose shows the stretching vibrations of the OH group at 3339 cm-1 and the stretching vibrations of the C–O group at around 1059 and 1162 cm-1. In the FT-IR spectrum of nano-cellulose/BF3/Fe3O4, in addition to the above-mentioned bands, the stretching vibrations of the Fe/O bond appears at 560 cm-1. The band at 1371 cm-1 displays the stretching vibrations of the B–O bond, indicating that the BF3 is supported on the nano-cellulose (Fig. 2).
XRD diagrams of fresh nanocellulose /BF3/Fe3O4, reused nanocellulose /BF3/Fe3O4 and Fe3O4 are shown in Fig. 3. According to the XRD diagram of nano-cellulose /BF3/Fe3O4 (Fig. 3a), the signals in 2Ө equal to 23 and 13 are attributed to cellulose section of catalyst. The signals 2Ө = 30, 35.5, 43, 53.5, 57 and 62.9 indicate the presence of Fe3O4.
The shape and size of nanocellulose/BF3/Fe3O4 nanoparticles were investigated and evaluated using FESEM and TEM (Fig. 4). The images show that the nanoparticles of nanocellulose /BF3/Fe3O4 are on average about 22 nm.
X-ray fluorescence (XRF) method was used for elemental analysis of nanocellulose/BF3/Fe3O4. To determine the boron: fluorine ratio in the catalyst, the number of kilograms per second of the elements in the catalyst was evaluated with KCPS of the elements in high-purity H3BO3 and NaF (Table 1). The calculated values for boron and fluoride are 3.496 mol and 0.059 mol, respectively. Therefore, the boron:fluorine ratio in the catalyst is approximately 5:1.
The magnetic properties of Fe3O4 and nanocellulose/BF3/Fe3O4 at 300 K were detected using vibrating sample magnetometer (VSM) technique (Fig. 5). According to the residual ring magnetization, there is no residual magnetization and also the coercivity value is zero for both samples, which proves the superparamagnetic property of the samples in room. The findings prove that the binding of cellulose to nanocellulose/BF3/Fe3O4 decreases the saturation magnetization. Despite of this reduction, the catalyst can still be easily separated from the reaction medium using an external magnetic.
Thermogravimetric analysis (TGA) of nanocellulose/BF3/Fe3O4 was done in the temperature range of 35 °C to 770 °C (Fig. 6). The TGA chart of catalyst shows three parts of weight loss. The first weight loss (6%) in range of 95 °C to 150 °C is related to the removal of moisture from the catalyst. The second weight loss (33%) is the range of 263-336 °C is related to the decomposition of cellulose section of catalyst. The char yield of catalyst in 700 °C is 40%.
After identification of the structure properties of nanocellulose/BF3/Fe3O4, we have applied this catalyst for synthesis of bis-spiro piperidine derivatives. The best condition for this synthesis is using dimedone (2 mmol), formaldehyde (3 mmol), aniline derivative (1 mmol), ethanol (5 ml) and catalyst (0.02 g) at room temperature. The synthesized derivatives of bis-spiro piperidine are tabulated in Table 2.

CONCLUSION
In this study, a nanocellulose/BF₃/Fe₃O₄ composite was prepared and applied as a magnetically separable catalyst for the one-pot synthesis of bis-spiro piperidine derivatives. Characterization by FT-IR, XRD, FESEM, TEM, XRF, VSM, and TGA supported the formation of the composite, with an average particle size of approximately 22 nm and superparamagnetic behavior at room temperature. The multicomponent reaction of dimedone, formaldehyde, and aniline derivatives was conducted in ethanol at room temperature using 0.02 g of the catalyst. The combination of a renewable nanocellulose support, ambient-temperature conditions, and straightforward magnetic separation offers practical advantages for preparing these heterocyclic compounds. Further investigations into catalyst recyclability, component leaching, and substrate scope would help establish the long-term performance and broader applicability of this catalytic system.

ACKNOWLEDGEMENT

The authors are grateful to University of Kashan for financial support of this work.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interests regarding the publication of this manuscript.

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