# Mg/Fe-LDH: An efficient promoter for the synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives

Achraf Hibot, Hicham Fadili, Abderrafia Hafid, Jacques Lebreton, Maria Dolors Pujol, Mostafa Khouili

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## ► To cite this version:

Achraf Hibot, Hicham Fadili, Abderrafia Hafid, Jacques Lebreton, Maria Dolors Pujol, et al., Mg/Fe-LDH: An efficient promoter for the synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives. Journal of Saudi Chemical Society, 2024, 28 (4), pp.101895. 10.1016/j.jscs.2024.101895 hal-04830885

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Submitted on 11 Dec 2024

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# Mg/Fe-LDH: An efficient promoter for the synthesis of tetrahydrospiro
[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives

Achraf Hibot<sup>a,b</sup>, Hicham Fadili<sup>a</sup>, Abderrafia Hafid<sup>a</sup>, Jacques Lebreton<sup>c</sup>, Maria Dolors Pujol<sup>b,*</sup>, Mostafa Khouili<sup>a</sup>

<figure><img src="image_3.png" /></figure>

## ARTICLE INFO

### Keywords:

Heterogeneous catalyst

Layered double hydroxides

Heterocyclic

Spiropyrazolones

Green chemistry

## ABSTRACT

The synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives using Mg/Fe-LDH as a heterogeneous catalyst was reported. This methodology used for the condensation of pyrazolones with aldehydes in a basic medium and with the presence of the Mg/Fe-LDH catalyst presents many benefits, such as the fact of using a reusable and low-cost catalyst, environmentally friendly conditions, short reaction times and excellent yields. It has been verified and confirmed that the catalyst is relatively stable and allows its reuse without additional treatment. Condensation has been carried out with different aldehydes and bis-pyrazolone derivatives have been obtained with yields ranging from 71 to 91% of purified product. The stereo impedance of the adduct formed prevents subsequent condensation.

## 1. Introduction

In view of their excellent biological and pharmaceutical properties, the synthesis of spiropyrazolones cover a great importance in synthetic chemistry, and much effort has been devoted to their synthesis in recent years. [1] Various routes of synthesis have been described in the literature to access these heterocyclic compounds. P. Sun et al. [2] reported the development of a novel enantioselective organo-catalytic sequential Michael/ Michael/ Aldol reaction of 1,3-dicarbonyl compounds with unsaturated pyrazolones and α,β-unsaturated aldehydes to provide the spirocyclohexanepyrazolones. In 2014, Lu et al. [3] published a methodology for the synthesis of spiropyrazolones via [4 + 1] cycloaddition catalyzed by chiral phosphines. Additionally, by another method, V. Ceban et al. [4] reported a highly diastereoselective synthesis of spiropyrazolones catalyzed by secondary amines using the Michael-Aldol cascade reaction between methylene pyrazolones and dialdehydes. The spiropyrazolones are obtained with excellent yields, as a single diastereomer having four chiral centers. Later, Hack et al. [5] published the stereoselective one-pot synthesis of spiropyrazolones through Michael asymmetric organo-catalytic addition by reacting pyrazolone and nitroalkene in chloroform at 40 °C in the presence of 1 mol% of a

squaramide derived from dihydroquinine DHQN-SA1 and 3 mol% Ag₂O. Furthermore, the same group developed an asymmetric one-pot multi-component reaction for the synthesis of spiropyrazolones using N-heterocyclic carbene (NHC) as an organo-catalyst, by reacting aldehydes and pyrazolones as substrates via a [3 + 2] addition reaction. [6] Recently, K. Singh et al. [7] developed an interesting and economic approach for the diastereoselective synthesis of highly functionalized carbocyclic spiropyrazolone derivatives having one quaternary and two tertiary stereocenters as well as an exocyclic double linkage, using sequential organo-silver double catalysis.

Over the past few years, a great deal of interest has been focused on layered double hydroxides (LDHs), due to their abundance in nature and their diverse properties. The interest of layered double hydroxides relates to their two-dimensional character and their anion exchange capacity, offering the possibility of elaborating a wide variety of intercalation compounds either by modifying the chemical composition of the hydroxide layer, or modifying the interlamellar domain chemically or structurally. [8] In addition, LDHs have a high specific surface area, a chemical feature that opens up the prospect of their application in a wide range of fields, including catalysis, [9] environment, [10] pharmaceutical area, [11] polymer industry [12] and solid-state

<footnote><sup>a</sup> Molecular Chemistry, Materials and Catalysis Laboratory, Faculty of Sciences and Technologies, Sultan Moulay Slimane University, BP 523, 23000 Beni-Mellal, Morocco</footnote>

<footnote><sup>b</sup> Laboratori de Química Farmacèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain</footnote>

<footnote><sup>c</sup> Faculty of Sciences, CEISAM Laboratory, University of Nantes, UMR CNRS 6230, 2, rue de la Houssinière BP, 92208-44322, Nantes Cedex 3, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: mdpujol@ub.edu (M. Dolors Pujol).</footnote>
electrochemistry. [13] (see Fig. 1).

LDH family material was first synthesized in 1842, and was identified as hydrotalcite, still a reference compound for LDHs. [14] The first exact formula for hydrotalcite, $[Mg_6Al_2(OH)_{16}]CO_3$, $4H_2O$, was presented in 1915 by E. Manasse. Nevertheless, the structure of LDHs was not described until the 1960 s. Since then, interest in LDHs has grown, focusing on the search for new synthetic methods, the study of their anion exchange, electrochemical and magnetic properties, in addition to the structural characterization of these materials. LDHs were structured by successive layers or two-dimensional sheets. Their structure was similar to that of brucite, where each $Mg^{2+}$ ion was bounded by six OH⁻ ions, and the different octahedra share edges to form infinite sheets [15] (Fig. 2). These sheets were laminated to each other and held together by hydrogen bonds, forming a hexagonal stack. [16,17].

These materials are electrostatically neutral have been considered as antacids used in some therapeutically treatment.

In this context, the objectives of the current study are two-fold: (i) the synthesis of a Mg/Fe-LDH material $[Mg_6Fe_2(OH)_{16}]CO_3$, $4H_2O$ using the co-precipitation method at constant pH (pH = 10) with a molar ratio R = Mg/Fe = 3; (ii) design and synthesize a series of spiropyrazolic compounds based on our previous work but using the novel synthesized material as a catalyst to test its effectiveness. The preparation of spiranic derivatives using Mg/Fe-LDH as a catalyst constitutes a novelty that may be of interest in organic synthesis.

## 2. Results and discussion

The Mg/Fe-LDH (3:1) material was prepared from divalent and trivalent metal salts at pH = 10 using direct co-precipitation, and then characterized by different physic-chemical methods, such as X-ray diffraction, infrared, thermogravimetric analysis and BET analysis.

### 2.1. Preparation of Mg/Fe-LDH material

To prepare the Mg/Fe-LDH material, two solutions (A) and (B) are required: Solution (A) containing the bivalent metal salt $MgCl_2·6H_2O$ (200 mg, 0.983 mmol) and the trivalent metal salt $FeCl_3·9H_2O$ (159.5 mg, 0.491 mmol) dissolved in distilled water (75 mL) and solution (B) of sodium carbonate ($Na_2CO_3$) and sodium hydroxide (NaOH) dissolved in a mixture of distilled water and methanol (75 mL) ($V_{MeOH}/V_{H_2O} = 1/4$). These two solutions were slowly added simultaneously (dropwise) to 75 mL of distilled water, kept under vigorous agitation at room temperature

for 1 h. The reaction medium was brought to pH = 10 and then the mixture was heated to reflux for 24 h. Once the reaction was complete, the gel obtained was filtered, washed several times with distilled water until all excess ions in the solid (Cl⁻, Na⁺...etc.) have been removed, then dried inside an oven (80 °C) all night. The resulting solid was ground to a very fine powder (Fig. 3).

### 2.2. Characterization of the prepared Mg/Fe-LDH [18]

#### 2.2.1. X-ray diffraction characterization

The X-ray diffractogram of the Mg/Fe-LDH material shown in Fig. 4 clearly shows that it corresponds to that typical of layered double hydroxide material. The fine X-ray rays reflect the material's enhanced crystallinity. Diffraction rays (00 l) and (11 l) are characteristic of a hexagonal lattice of well-crystallized material. These rays are located in three different regions: at low angles $2\theta < 30°$, the two intense rays of type (00 l) correspond to the (003) and (006) planes, medium angles $30° < 2\theta < 50°$, the three (0kl)-type rays correspond to the (012), (015) and (018) planes and at large angles $2\theta > 50°$, the last three rays of type (hk0) and (hkl), characteristic rays of the $M(OH)_2$ metal layer, remain invariant for the different LDHs. [19].

Based on this series of rays, the mesh parameters are calculated using the following expressions: $c = 3d_{003}$ and $a = 2d_{110}$ where d is the interreticular distance. Table 1 shows the inter-reticular distances and mesh parameters a and c calculated. The results achieved are consistent with those reported in the literature. [18].

The size of the Mg/Fe-LDH material particles can be derived from Scherrer's formula, and can also be calculated from the half-height ray of diffraction d003: $D = 0,9 * \lambda/\Delta (2\theta_0) \cos \theta_0$. (With λ: wavelength used, θ: angle of the principal diffraction peak and Δ(2θ₀): half-height principal peak width (003)). The calculated size of the Mg/Fe-LDH particles for the most intense line (003) was 32.2 nm.

#### 2.2.2. Characterization by infrared spectroscopy

In order to identify the functional groups, present in the Mg/Fe-LDH material, it was analyzed by Fourier transform infrared spectroscopy (FTIR) as shown in Fig. 5.

FTIR spectrum of the Mg/Fe-LDH material shows a broad vibration band around $3280 \text{ cm}^{-1}$ corresponding to the elongation vibration of hydroxyl groups, a band around $1647 \text{ cm}^{-1}$ attributed to angular deformations of water molecules and a band around $1262 \text{ cm}^{-1}$ due to the vibration of carbonate ions $CO_3^{2-}$. In addition, at values below $800 \text{ cm}^{-1}$,

<figure><img src="image_4.png" /><figcaption>Fig. 1. Previous studies of the preparation of the spiroderivatives.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Fig. 2. A schematic representation of the classic structure of Mg/Fe-LDHs [16].</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Fig. 3. Flow chart of the chemical process for the preparation of Mg/Fe-LDH by co-precipitation in aqueous medium.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>Fig. 4. X-ray diffractogram of the Mg/Fe-LDH material prepared.</figcaption></figure>
<table><caption>**Table 1**
Inter-reticular distance and mesh parameters a and c.</caption><thead><tr><th>2θ(°)Ray (003)</th><th>2θ(°)Ray (110)</th><th>d<sub>003</sub> (Å)</th><th>d<sub>110</sub> (Å)</th><th>a(Å)</th><th>c(Å)</th></tr></thead><tbody><tr><td>11,54</td><td>60,80</td><td>7,66</td><td>1,51</td><td>3,02</td><td>22,98</td></tr></tbody></table>

vibration bands of (M–O) at 637 cm⁻¹ and (M–O–M) at 740 cm⁻¹ (Fig. 5).

### 2.2.3. Thermal characterization

Thermal decomposition of Mg/Fe-LDH material was a complex sequence involving dehydration, dehydroxylation and decarboxylation steps. Fig. 6 shows the mass loss as a function of temperature curve and its derivative with regard to time obtained by thermogravimetric analysis of Mg/Fe-LDH. Thermogravimetric analysis was performed on a 33.16 mg sample. The thermogram obtained is shown in Fig. 6, showing a mass loss of around 12% at temperatures below 200 °C. This loss was characterized by an endothermic phenomenon at 100 ± 5 °C and corresponds to the removal of weakly bound water molecules, adsorbed on the outside of the crystals, and to the loss of inter-lamellar water. A secondary mass loss, indicated by an endothermic phenomenon at 360 °C, was observed in the 200–400 °C temperature range. It was attributed to the elimination of the hydroxyl group and decomposition of interlayer carbonate anions.

### 2.2.4. Characterization by BET

Porosity and surface area measurements were carried out at 77.35 K using a Micromeritics ASAP 2010 nitrogen gas adsorption-desorption process. The experimentally measured isotherm for Mg/Fe-LDH is shown in Fig. 7, and its analysis provides information on the porosity of the material. This isotherm reveals the presence of a type VI hysteresis according to the IUPAC classification, confirming the mesoporosity of the material with a high specific surface area. The specific surface area determined by the BET method was 77.52 m²/g, and the pore size was estimated at 4.88 nm (see Fig. 7).

### 2.2.5. Catalytic application of Mg/Fe-LDH in the synthesis of spiropyrazoles derivatives

In previous work, [20,21] the treatment of 3-amino-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1) with different aromatic aldehydes 2 in basic medium (triethylamine) resulted in the formation of the two new spiropyrazole derivatives 3 and 4 as presented in Scheme 1. On the other hand, the use of Mg/Al-LDH as a catalyst in the condensation reaction of 3-amino-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1) with aromatic aldehydes provides the unexpected product 5 (Scheme 1). [22] Moreover, Shojaei et al. [23] succeeded in the synthesis of tetrahydrospiro[pyr-azole-4,5'-pyrazolo[3,4-b]pyridine] derivatives 3 under two different

experimental conditions, in GuHS (guanidinium hydrogen sulfate) as ionic liquid and in Fe₃O₄-GuHS as supported ionic liquid (Scheme 1).

As part of this work, a simple condensation of 3-amino-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1) with the aromatic aldehydes in the presence of Mg/Fe-LDH as an inorganic material catalyst in order to produce new spiropyrazolone derivatives was also studied for the first time in this work.

<figure><img src="image_8.png" /><figcaption>**Fig. 6.** Thermogravimetric diagram of Mg/Fe-LDH material.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**Fig. 7.** Nitrogen adsorption-desorption isotherm on Mg/Fe-LDH material.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**Fig. 5.** FTIR spectrum of Mg/Fe-LDH material.</figcaption></figure>
<figure><img src="image_11.png" /><figcaption>**Scheme 1.** Reactivity of 3-amino-1-phenyl-2-pyrazolin-5-one 1 with aromatic aldehydes under different reaction conditions.</figcaption></figure>

In an initial attempt, the reaction of aminopyrazolone 1 with benzaldehyde 2 in the presence of 5% Mg/Fe-LDH (mass %) in refluxing ethanol for 1 h leads to the formation of a single compound 3 (Scheme 2). Contrary to the previous results, [20,21] the Mg/Fe-LDH catalyst leads to the formation of a single product. On the other hand, and for the purpose of producing compound 3 (Scheme 2), the reaction of

compound 1 with benzaldehyde 2 has been repeated during this time using 1.5 eq and 2 eq of benzaldehyde. Again, under these later conditions only the formation of compound 3 was observed. Therefore, the material used in this study is not suitable to promote the additional cyclization of the compound 3 with the benzaldehyde to form compound 4.

<figure><img src="image_12.png" /><figcaption>**Scheme 2.** Synthetic route to tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives using Mg/Fe-LDH as a heterogeneous catalyst.</figcaption></figure>
As part of this work, first at all, it was tried to optimize the operating conditions of this reaction sequence, by varying the operating conditions to cited: the solvent, the temperature (heat to reflux, room temperature), the catalytic amount (1%, 5%, 10% weight/weight). At the beginning, this condensation with different solvents, such as ethanol (EtOH), methanol (MeOH), tetrahydrofuran (THF), acetonitrile (CH₃CN) and water was experimented. The reaction only showed good yields with ethanol as a solvent (87% - 91%) (entry 3 and 4, Table 2). For MeOH, THF and CH₃CN the yields are low to moderate. Whereas, in water the reaction did not occur because of the insolubility of the starting material 1. Subsequently, these results were enhanced by adjusting the amount of the catalyst used. The synthetic reaction, in the presence of **Mg/Fe-LDH** (5% by weight) as catalyst and stirring under refluxing ethanol for one hour, gave the desired spiro-compound **3** with excellent yield of 91%. By contrast, the increase in the amount of catalytic material used reduces the yield of the spiro-compound formed **3** (entry 13 and 14, Table 2). Following the results obtained, using the reaction conditions of refluxing the mixture in ethanol with 5% (weight/weight) of **Mg/Fe-LDH** afforded the desired compound in excellent yield and adequate reaction time (entry 4, Table 2).

After the optimization of the reaction conditions, the method was generalized to synthesize new spiro heterocyclic molecules from 3-amino-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1) and the addition of different aldehydes. Using the above procedure, several new compounds were isolated in good to excellent yields (Table 3).

Based on the results obtained in this work and others described in the literature, [21–23] the yields obtained using the **Mg/Fe-LDH** material as a catalyst under green and ecological conditions are relatively good comparing to the previous work (Table 4).

In this study, the reuse of the catalyst was also evaluated. The catalyst was recovered by simple filtration of the reaction mixture, washed several times with ethanol and dried. Quality control tests demonstrated that the prepared catalyst could be used for three successive cycles without any significant loss of catalytic activity (Table 5).

After recovered of the catalyst, it was characterized using FTIR and XRD. In the results obtained with FTIR, the presence of the vibrational bonds corresponding to the material described above was demonstrated (elongation of hydroxyl groups at 3300 cm⁻¹, deformation of water molecules at 1644 cm⁻¹, vibration of carbonate ions CO₃²⁻ at 1260 cm⁻¹, and finally (M–O) at 640 cm⁻¹ and (M–O–M) at 742 cm⁻¹) (Figure 24SI) data that coincide with those obtained by the freshly prepared catalyst (Fig. 5). On the other hand, the X-ray diffractogram of recovery material after the reaction shows the presence of the rays that it corresponds to the Mg/Fe-LDH (Figure 25 (SI), data that coincides with that of the freshly prepared catalyst (Fig. 4).

The structural elucidation of the synthesized spiro derivatives was based on their spectral analysis and especially on their NMR spectra of the proton and carbon 13.

According to the ¹H NMR spectrum registered for compound 3a

<table><caption>**Table 2**
Optimization of the conditions for synthesis of compound 3.</caption><thead><tr><th>Entry</th><th>Solvent</th><th>Catalytic amount %</th><th>Condition</th><th>Time (h)</th><th>Yield %</th></tr></thead><tbody><tr><td>1</td><td>EtOH</td><td>1</td><td>r.t</td><td>—</td><td>—</td></tr><tr><td>2</td><td>EtOH</td><td>1</td><td>Reflux</td><td>—</td><td>—</td></tr><tr><td>3</td><td>EtOH</td><td>5</td><td>r.t</td><td>24</td><td>87</td></tr><tr><td>4</td><td><strong>EtOH</strong></td><td><strong>5</strong></td><td><strong>reflux</strong></td><td><strong>1</strong></td><td><strong>91</strong></td></tr><tr><td>5</td><td>MeOH</td><td>5</td><td>r.t</td><td>24</td><td>72</td></tr><tr><td>6</td><td>MeOH</td><td>5</td><td>reflux</td><td>4</td><td>77</td></tr><tr><td>7</td><td>THF</td><td>5</td><td>r.t</td><td>48</td><td>traces</td></tr><tr><td>8</td><td>THF</td><td>5</td><td>reflux</td><td>16</td><td>36</td></tr><tr><td>9</td><td>CH₃CN</td><td>5</td><td>r.t</td><td>24</td><td>41</td></tr><tr><td>10</td><td>CH₃CN</td><td>5</td><td>reflux</td><td>24</td><td>48</td></tr><tr><td>11</td><td>H₂O</td><td>5</td><td>r.t</td><td>—</td><td>—</td></tr><tr><td>12</td><td>H₂O</td><td>5</td><td>reflux</td><td>—</td><td>—</td></tr><tr><td>13</td><td>EtOH</td><td>10</td><td>r.t</td><td>24</td><td>55</td></tr><tr><td>14</td><td>EtOH</td><td>10</td><td>reflux</td><td>24</td><td>68</td></tr></tbody></table>

(Fig. 1, SI), the presence of two singlet at 4.5 and 4.9 ppm corresponding to the H-5 and H-12 protons respectively was noted. The two protons related to NH₂ resound as a singlet at 6 ppm. Therefore, a singlet at 7.9 ppm is observed representing the proton (N–H). Moreover, the signal concerning the pyrazole proton appears as a singlet at 9.75 ppm. The aromatic protons resonate in the range of 6.8–7.75 ppm. The ¹³C NMR spectrum of compound 3a is also presented in (Fig. 2, SI). The ¹³C NMR spectrum of compound 3a highlights the presence of the carbonyl peaks (C-13 and C-7 (Fig. 8)) at 168.6 and 157.2 ppm respectively. Additionally, the signals in the spectrum corresponding to C-5 and C-12 (Fig. 6) appears at 43.9 and 59.6 ppm respectively. In the other hand, the spiro-carbone resonate at 60.8 ppm. The mass spectrum also shows a molecular peak MS ESI (+): *m/z* 525.2 [M + H]⁺ corresponding to the expected mass for compound 3a (Fig. 4, SI).

The chemical mechanism of this reaction was detailed in schema 3. The use of our material as a catalyst enables to facilitate the enolization of the aminopyrazole 1 and to enhance the nucleophilic character of the methylene carbon of 3-amino-1-phenylpyrazolin-5-one 1 through the interaction with the catalyst which acts as a base. That part of the catalyst behaves and facilitate the condensation of Knoevenagel type. In addition, it can increase the electrophilic carbonyl character of benzaldehydes. The reaction of 3-amino-1-phenylpyrazolin-5-one 1 and benzaldehyde 2 according to tandem processes generally occurs in two successive steps as shown in Scheme 3. Firstly, the condensation of Knoevenagel type that is expected between 3-amino-1-phenylpyrazolin-5-one 1 and benzaldehyde leads to the derivative A, Thereafter, Michael addition involves dimerizing two molecules of A gives the spiro compound 3. Due to a high specific surface area, the mesoporous material and the strong basic sites of Mg/Fe-LDH, a strong catalytic activity, greater catalyst efficiency and durability are achieved in the synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives 3.

In conclusion, we have developed a novel and efficient catalyst Mg/Fe-LDH for the synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivatives. Furthermore, in this case the steric hindrance prevents double condensation and only the compound from the monocation condensation was obtained with high yields. This new method presents many benefits such as the possibility to use a low cost and reusable catalyst, environmentally friendly conditions, short reaction times and excellent yields. It has been proven that the catalyst was relatively stable and allows its reuse after obtaining it by filtering the reaction mixture and washing it with ethanol.

### 3. Experimental section

All chemicals were purchased from commercial sources and were used without further purification. The reactions were monitored by Thin Layer Chromatography (TLC) on commercial silica gel 60 GF254 plates and the reactional mixture were examined under UV light (λ = 254 nm). Column chromatography was carried out using silica gel 60 Merck 0.063e0.200 mm. The reaction solvents used are of analytical quality, except that the solvents used in the column chromatography (hexane and ethyl acetate) are distilled before use. All compounds were characterized in solution by ¹H and ¹³C NMR and when appropriated by using deuterated solvent (DMSO-d₆). The NMR spectra were recorded using Bruker Advance 300, 400 and 500 spectrometers operating at 300.13 MHz, 400 MHz and 500.13 MHz for ¹H and 75.47 MHz, 100.6 MHz and 125.76 MHz for ¹³C, respectively, with tetramethylsilane (TMS) as the internal standard.

XRD: PANalytical X'Pert PRO MPD θ/θ powder diffractometer of 240 mm of radius, in a configuration of convergent beam with a focalizing mirror and a transmission geometry with flat samples sandwiched between low absorbing films.

IR spectrums have been performed with FT-IR Perkin Elmer model Spectrum RX I and Thermo Nicolet model avatar 320 FT-IR spectrophotometers. It is noteworthy that only relevant frequencies (expressed in cm⁻¹) have been highlighted.
<figure><img src="image_13.png" /><figcaption>**Table 3**
Synthesis of spiro derivatives 3a-f using 5% of Mg/Fe-LDH under the optimized conditions.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Ar (aldehyde)</th><th>Compounds</th><th>Yield %</th></tr></thead><tbody><tr><td>1</td><td>—</td><td>—</td><td>91</td></tr><tr><td>2</td><td>—</td><td>—</td><td>86</td></tr><tr><td>3</td><td>—</td><td>—</td><td>71</td></tr><tr><td>4</td><td>—</td><td>—</td><td>82</td></tr><tr><td>5</td><td>—</td><td>—</td><td>90</td></tr><tr><td>6</td><td>—</td><td>—</td><td>78</td></tr></tbody></table>
<table><caption>**Table 4**
Comparison of the results obtained with those of previous works.</caption><thead><tr><th>Entries</th><th>Compounds</th><th>Catalyst</th><th>Yield (%)</th></tr></thead><tbody><tr><td rowspan="3">1</td><td rowspan="3">3a</td><td>Fe<sub>3</sub>O<sub>4</sub>-GuHS<sup>*</sup></td><td>62</td></tr><tr><td>Et<sub>3</sub>N<sup>+</sup></td><td>36</td></tr><tr><td><strong>Mg/Fe-LDH</strong></td><td><strong>91</strong></td></tr><tr><td rowspan="3">2</td><td rowspan="3">3b</td><td>Fe<sub>3</sub>O<sub>4</sub>-GuHS<sup>*</sup></td><td>49</td></tr><tr><td>Et<sub>3</sub>N<sup>+</sup></td><td>92</td></tr><tr><td><strong>Mg/Fe-LDH</strong></td><td><strong>86</strong></td></tr><tr><td rowspan="3">3</td><td rowspan="3">3c</td><td>Fe<sub>3</sub>O<sub>4</sub>-GuHS<sup>*</sup></td><td>–</td></tr><tr><td>Et<sub>3</sub>N<sup>+</sup></td><td>96</td></tr><tr><td><strong>Mg/Fe-LDH</strong></td><td><strong>71</strong></td></tr><tr><td rowspan="3">4</td><td rowspan="3">3d</td><td>Fe<sub>3</sub>O<sub>4</sub>-GuHS<sup>*</sup></td><td>68</td></tr><tr><td>Et<sub>3</sub>N<sup>+</sup></td><td>–</td></tr><tr><td><strong>Mg/Fe-LDH</strong></td><td><strong>82</strong></td></tr><tr><td rowspan="3">5</td><td rowspan="3">3e</td><td>Fe<sub>3</sub>O<sub>4</sub>-GuHS<sup>*</sup></td><td>–</td></tr><tr><td>Et<sub>3</sub>N<sup>+</sup></td><td>–</td></tr><tr><td><strong>Mg/Fe-LDH</strong></td><td><strong>90</strong></td></tr><tr><td rowspan="3">6</td><td rowspan="3">3f</td><td>Fe<sub>3</sub>O<sub>4</sub>-GuHS<sup>*</sup></td><td>–</td></tr><tr><td>Et<sub>3</sub>N<sup>+</sup></td><td>95</td></tr><tr><td><strong>Mg/Fe-LDH</strong></td><td><strong>78</strong></td></tr></tbody></table>

* Previous work reported by Shojaei et al. [23].

** Our previous work [21].

<table><caption>**Table 5**
Catalytic cycle considering the loss of activity.</caption><thead><tr><th>Cycle</th><th>Time</th><th>Yield (%)</th><th>% loss</th></tr></thead><tbody><tr><td>1</td><td>1 h</td><td>91</td><td>–</td></tr><tr><td>2</td><td>1 h</td><td>86</td><td>5%</td></tr><tr><td>3</td><td>1 h</td><td>79</td><td>7%</td></tr></tbody></table>

<figure><img src="image_14.png" /><figcaption>**Fig. 8.** Numbered structure of compound 3a.</figcaption></figure>

## 4. General procedure for the synthesis of tetrahydrospiro [pyrazole-4,5'-pyrazolo [3,4-b] pyridine] derivatives (3a-f)

In a round-bottom flask, an amount of Mg/Fe-LDH catalyst (10 mg) was added to 200 mg of 3-amino-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1) (1.14 mmol, 1 eq) and (1.2 eq) of each aromatic aldehyde 2a-f dissolved in 5.0 mL of ethanol. The mixture was refluxed under stirring for 1 h, and the evolution of the reaction was judged by TLC. Once room temperature reached, the reaction mixture was filtered to recover the catalyst and washed several times with cool ethanol. After, the solvent was evaporated and 15 mL of water was added to the reaction residue and extracted with ethyl acetate (3x20 mL). The combined organic layers were dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained products (3a-f) were recrystallized from methanol and were obtained with high degree of purity and high yields.

### 4.1. 3-Amino-1,2',4',6'-tetraphenyl-1',4',6',7'-tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine]-3',5(1H,2'H)-dione (3a)

Yield: 91% (546.3 mg, 1.03 mmol), m.p.: 215–216 °C. **FTIR:** ν = 3500 (NH<sub>2</sub>), 1700 (C = N), 1655 (C = O), 1650 (C = O), 1600 (C = C), 1500 (NH), 1450 (C = Caromatic); ¹H NMR (300 MHz, DMSO-d<sub>6</sub>) δ 9.76 (s, 1H, N-Hpyr), 7.97 (s, 1H, N-H), 7.75 – 7.65 (m, 2H, H-aromatic), 7.5 – 7.47 (m, 2H, H-aromatic), 7.4 – 7.35 (m, 2H, H-aromatic), 7.32 – 7.25 (m, 5H, H-aromatic), 7.31 – 7.26 (m, 4H, H-aromatic), 7.14 – 7.04 (m, 4H, H-aromatic), 7.02 – 6.95 (m, 1H, H-aromatic), 5.98 (s, 2H, NH<sub>2</sub>), 4.94 (s, 1H, H-5), 4.48 (s, 1H, H-12). ¹³C NMR (75 MHz, DMSO-d<sub>6</sub>) δ 168.6, 157.2, 156.9, 139.5(x2), 137.5(x2), 135.4, 135.0, 128.8(x2), 128.5(x2), 128.2(x2), 128.0(x2), 127.8(x2), 127.0(x2), 126.7, 123.7, 122.5, 118.1(x2), 117.4(x2), 82.4, 60.8, 59.6, 43.9. **MS-ESI** (m/z): calculated for C<sub>32</sub>H<sub>26</sub>N<sub>6</sub>O<sub>2</sub> [M-H]<sup>+</sup> 525.6, found 525.2.

### 4.2. 3-Amino-1,2'-diphenyl-4',6'-di-p-tolyl-1',4',6',7'-tetrahydrospiro [pyrazole-4,5'-pyrazolo[3,4-b]pyridine]-3',5(1H,2'H)-dione (3b)

Yield: 86%, (543.7 mg, 0.98 mmol), m.p.: 260–262 °C. **FTIR:** ν = 3490 (NH<sub>2</sub>), 1695 (C = N), 1655 (C = O), 1650 (C = O), 1600 (C = C), 1500 (NH), 1450 (C = Caromatic); ¹H NMR (300 MHz, DMSO-d<sub>6</sub>) δ 9.72 (s, 1H, N-Hpyr), 7.85 (s, 1H, N-H), 7.68 (d, J = 8.1 Hz, 2H, H-aromatic), 7.36 (q, J = 7.4 Hz, 6H, H-aromatic), 7.20 (t, J = 7.8 Hz, 2H, H-aromatic), 7.08 (d, J = 7.4 Hz, 5H, H-aromatic), 6.99 (t, J = 7.4 Hz, 1H, H-aromatic), 6.90 (d, J = 7.8 Hz, 2H, H-aromatic), 5.92 (s, 2H, NH<sub>2</sub>), 4.87 (s, 1H, H-5), 4.42 (s, 1H, H-12), 2.19 (d, J = 7.0 Hz, 6H, 2xCH<sub>3</sub>). ¹³C NMR (75 MHz, DMSO-d<sub>6</sub>) δ 168.9, 163.6, 157.2, 139.5(x2), 137.6(x2), 135.5, 132.5, 132.0, 128.6(x2), 128.5(x2), 128.4(x2), 128.3(x2), 127.9 (x2), 127.6(x2), 123.6, 122.5, 118.0(x2), 117.4(x2), 82.6, 60.5, 59.6, 43.5, 20.6, 20.6. **MS-ESI** (m/z): calculated for C<sub>34</sub>H<sub>30</sub>N<sub>6</sub>O<sub>2</sub> [M + H]<sup>+</sup> 555.65, C<sub>34</sub>H<sub>30</sub>N<sub>6</sub>O<sub>2</sub> [M + Na]<sup>+</sup> 577.6, found 555.3, [M + Na]<sup>+</sup> 577.2.

### 4.3. 3-Amino-4',6'-bis(3-nitrophenyl)-1,2'-diphenyl-1',4',6',7'-tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine]-3',5(1H,2'H)-dione (3c)

Yield: 71%, (499 mg, 0.8 mmol), m.p.: 230–232 °C. **FTIR:** ν = 3500 (NH<sub>2</sub>), 1700 (C = N), 1655 (C = O), 1650 (C = O), 1600 (C = C), 1500 (NH), 1450 (C = Caromatic); ¹H NMR (300 MHz, DMSO-d<sub>6</sub>) δ 10.19 (s, 1H, N-Hpyr), 8.38 – 8.32 (d, J = 18.1 Hz, 1H, H-aromatic), 8.1 – 8.0 (m, 4H, H-aromatic), 7.84 (s, 1H, N-H), 7.76 – 7.51 (m, 4H, H-aromatic), 7.4 – 7.36 (m, 3H, H-aromatic), 7.25 – 6.93 (m, 6H, H-aromatic), 6.27 (s, 2H, NH<sub>2</sub>), 5.25 (s, 1H, H-5), 4.68 (s, 1H, H-12). ¹³C NMR (75 MHz, DMSO-d<sub>6</sub>) δ 167.9, 156.5, 147.2, 146.9, 139.4, 137.5, 136.9, 135.8, 134.9, 128.7, 128.5, 128.4, 128.1, 118.2, 117.5, 59.6 (low solubility in organic solvents). **MS-ESI** (m/z): calculated for C<sub>32</sub>H<sub>24</sub>N<sub>8</sub>O<sub>6</sub> [M + H]<sup>+</sup> 617.59, C<sub>32</sub>H<sub>24</sub>N<sub>8</sub>O<sub>6</sub> [M + Na]<sup>+</sup> 639.59, found 617.2, [M + Na]<sup>+</sup> 639.2.

### 4.4. 3-Amino-4',6'-bis(4-hydroxyphenyl)-1,2'-diphenyl-1',4',6',7'-tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine]-3',5(1H,2'H)-dione (3d)

Yield: 82%, (522.2 mg, 0.934 mmol), m.p.: 240–242 °C. **FTIR:** ν = 3495 (NH<sub>2</sub>), 3450 (OH), 1700 (C = N), 1655 (C = O), 1650 (C = O), 1600 (C = C), 1500 (NH), 1450 (C = Caromatic); ¹H NMR (500 MHz, DMSO-d<sub>6</sub>) δ 9.36 (s, 1H, N-Hpyr), 9.03 (s, 1H, N-H), 7.61 (2 s, 2H, 2xOH), 7.30 (d, J = 7.8 Hz, 4H, H-aromatic), 7.20 (d, J = 8.2 Hz, 2H, H-aromatic), 7.15 (t, J = 7.4 Hz, 2H, H-aromatic), 7.04 – 6.85 (m, 5H, H-aromatic), 6.6 – 6.5 (m, 3H, H-aromatic), 6.40 (d, J = 7.8 Hz, 2H, H-aromatic), 5.78 (s, 2H, NH<sub>2</sub>), 4.70 (s, 1H, H-5), 4.27 (s, 1H, H-12). ¹³C NMR (126 MHz, DMSO-d<sub>6</sub>) δ 169.7, 161.2, 157.9, 156.4, 140.2, 140.2, 138.2, 130.2, 129.7, 129.7, 129.0, 128.9, 128.6, 125.8, 124.1, 118.6, 115.1, 114.4, 60.9, 60.6, 59.0, 56.5, 43.9 (low solubility in organic solvents). **MS-ESI** (m/z): calculated for C<sub>32</sub>H<sub>26</sub>N<sub>6</sub>O<sub>4</sub> [M + H]<sup>+</sup> 559.6, C<sub>32</sub>H<sub>26</sub>N<sub>6</sub>O<sub>4</sub> [M + Na]<sup>+</sup> 581.6, found 559.2, [M + Na]<sup>+</sup> 581.2.
Step 1

<figure><img src="image_15.png" /></figure>

Step 2

<figure><img src="image_16.png" /><figcaption>Scheme 3. Plausible mechanism for the formation of 3 using the LDH catalyst.</figcaption></figure>

4.5. 3-Amino-4',6'-bis(4-chlorophenyl)-1,2'-diphenyl-1',4',6',7'-tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine]-3',5(1H,2'H)-dione (3e)

Yield: 90%, (611 mg, 1.026 mmol), m.p.: 232–234 °C. **FTIR**: ν = 3500 (NH₂), 1695 (C = N), 1655 (C = O), 1650 (C = O), 1600 (C = C), 1500 (NH), 1400 (C = C<sub>aromatic</sub>); **¹H NMR (500 MHz, DMSO-d₆)** δ 9.83 (s, 1H, N-Hpyr), 7.94 (s, 1H, N-H), 7.61 (d, *J* = 8.1 Hz, 2H, H-aromatic), 7.41 (d, *J* = 8.5 Hz, 2H, H-aromatic), 7.33–7.28 (m, 4H, H-aromatic), 7.26 (d, *J* = 8.1 Hz, 2H, H-aromatic), 7.17 (dd, *J* = 10.5, 5.6 Hz, 4H, H-aromatic), 7.12 (d, *J* = 8.5 Hz, 2H, H-aromatic), 7.02–6.98 (m, 1H, H-aromatic), 6.97–6.94 (m, 1H, H-aromatic), 6.00 (s, 2H, NH₂), 4.90 (s, 1H, H-5), 4.41 (s, 1H, H-12). **¹³C NMR (126 MHz, DMSO-d₆)** δ 168.8, 157.4, 157.3, 139.9, 137.8(x2), 134.8, 134.6, 133.6, 131.9, 131.2(x2), 130.9(x2), 129.1(x2), 129.0(x2), 128.4(x2), 127.6(x2), 124.6, 123.2, 118.7(x2), 118.0(x2), 82.8, 60.5, 59.9, 43.6, **MS-ESI (m/z)**: calculated for C₃₂H₂₄Cl₂N₆O₂ [M-H]⁻ 595.4, found 593.1.

4.6. 3-Amino-4',6'-bis(4-methoxyphenyl)-1,2'-diphenyl-1',4',6',7'-tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine]-3',5(1H,2'H)-dione (3f)

Yield: 90%, (602 mg, 1.026 mmol), m.p.: 232–234 °C. **¹H NMR (400 MHz, DMSO-d₆)**: δ 9.63 (s, 1H, N-Hpyr), 7.81 (s, 1H, N-H), 7.66 (d, *J* = 8.1 Hz, 2H, H-aromatic), 7.40–7.34 (m, 4H, H-aromatic), 7.34–7.30 (m, 2H, H-aromatic), 7.2–7.16 (m, 2H, H-aromatic), 7.12–7.07 (m, 2H, H-aromatic), 7.06–7.02 (m, 1H, H-aromatic), 6.99–6.95 (m, 1H, H-aromatic), 6.83–6.80 (m, 2H, H-aromatic), 6.66–6.61 (m, 2H, H-aromatic), 5.90 (s, 2H, NH₂), 4.84 (s, 1H, H-5), 4.38 (s, 1H, H-5), 3.65 (s, 3H, OCH₃), 3.62 (s, 3H, OCH₃). **¹³C NMR (100.6 MHz, DMSO-d₆)**: δ 168.9, 163.6, 159.1, 157.9(x2), 157.2, 157.1, 139.6, 137.6, 129.8(x2), 129.2, 128.4(x2), 128.2(x2), 127.3, 126.9, 123.6, 122.4, 118.1(x2), 117.4(x2), 113.2(x2), 112.4(x2), 82.6, 60.2, 59.7, 54.9, 54.8, 43.2, **MS-ESI (m/z)**: calculated for C₃₄H₃₀N₆O₄ [M-H]⁻ 585.65, found 585.2.

CRediT authorship contribution statement

**Achraf Hibot:** Writing – review & editing, Writing – original draft, Investigation. **Hicham Fadili:** Investigation. **Abderrafia Hafid:** Investigation. **Jacques Lebreton:** Formal analysis. **Maria Dolors Pujol:** Writing – review & editing, Supervision, Investigation. **Mostafa Khouili:** Supervision.

Declaration of competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Thanks are due to the Sultan Moulay Slimane University of Beni-Mellal for its partial support to this work. The authors also would like to thank the National Center for Scientific and Technical Research (CNRST)-Morocco for the funding the characterization analysis. We thank both the University of Beni-Mellal (Morocco) and the University of Barcelona (Spain) for the financial support to carry out this scientific work and to the UB scientific services for the characterization of these compounds.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jscs.2024.101895.
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