C3-methylation of imidazopyridines via C(sp2)-H activation using magnetic Cu-MOF, and DMSO as solvent and Methyl source

Abstract

In this study, we introduce a protocol for the methylation of the C–H bond at the C₃ position in imidazo[1,2-a]pyridine scaffolds, employing magnetic def./Cu-MOF for the activation of C(sp2)-H bonds. The term ‘def’ refers to strategically induced defects in the Metal-Organic Framework (MOF), which are designed to improve its catalytic efficiency. These defects are generated using specific agents, with benzoic acid serving as the defect-promoting agent, leading to controlled structural imperfections within the MOF. This approach offers an efficient and reliable method for the methylation of imidazopyridines, showcasing excellent compatibility with various functional groups, high site selectivity, and outstanding product yields. Additionally, dimethyl sulfoxide acts as both the solvent and the source of methyl groups in the reaction, further streamlining the process.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-025-14556-1.

Introduction

Imidazopyridine derivatives are crucial building blocks in many pharmacologically active molecules^1–3. The widespread presence of imidazopyridine cores in the design of various pharmacological compounds further underscores their importance in drug discovery (Fig. 1)^4–7. The continuous exploration of new methodologies for their synthesis and functionalization remains an exciting area of research. Over the past few decades, the synthesis of imidazopyridine derivatives has been extensively studied, with significant efforts dedicated to developing novel functionalized imidazopyridines. For instance, in 2000, Gueiffier et al. introduced a Suzuki-type cross-coupling reaction for the synthesis of 3-arylimidazo[1,2-a]pyridines from 3-iodoimidazo[1,2-a]pyridines⁸. In 2012, Lee et al. reported a copper-catalyzed decarboxylative three-component reaction for synthesizing imidazo[1,2-a]pyridines from 2-aminopyridines, aldehydes, and alkynecarboxylic acids⁹. In 2013, Jiang and colleagues developed a rapid method for converting pyridine to imidazo[1,2-a]pyridines through copper-catalyzed aerobic dehydrogenative cyclization with oxime esters¹⁰. Additionally, in 2018, Kumar et al. reported the regioselective functionalization of imidazoheterocycles under metal-free conditions¹¹. In 2019, Cui and coworkers reported visible-light-promoted sulfonylmethylation of imidazopyridines¹².

Fig. 1.

Imidazo[1,2-a]pyridine derivatives with medicinal properties.

According to the other reports, some synthetic procedures for synthesizing 3-methyl-2-arylimidazo[1,2-a]pyridines have also been reported, including (i) oxidative cyclization reaction of ketoxime acetates, pyridine, and ammonia¹³; (ii) the reaction of 2-aminopyridine and N-tosylhydrazones¹⁴; (iii) the reaction of 2-aminopyridine, aldehyde, and propiolic acid¹⁵; (iv) denitration reaction of 2-aminopyridines with 2-methylnitroolefines¹⁶, and finally (v) the reaction of calcium carbide, 2-aminopyridines, and aromatic aldehydes¹⁷. In addition, iodine mediated annulation of triethylamine, aldehydes and 2-aminopyridines for the synthesis of 3-formyl-imidazo[1,2-a]pyridines was reported by Zhang and coworkers (Fig. 2)¹⁸.

Fig. 2.

A comparative overview of the previous work and the current study.

In recent decades, significant attention has been devoted to C-H bond activation, particularly the catalytic functionalization of inert C-H bonds^19–22. This approach offers a straightforward method for the functionalization of relatively inert C-H bonds, which is often challenging or impossible through other means, such as the methylation of an inert bond. The addition of a simple methyl group can significantly alter the biological and physical properties of a molecule²³²⁴,. Given these advantages, catalytic methods have been developed to introduce various substituents, including methyl groups, to inert C–H bonds, thereby facilitating the functionalization of imidazopyridines and enabling the creation of derivatives with enhanced biological and physical properties^25–27.

Despite the advances in previous reports, several significant drawbacks remain in the available methods, such as the use of commercially unavailable starting materials, unstable alkyne sources, expensive metals and catalysts, high temperatures, long reaction times, and generally harsh reaction conditions (please refer to Fig. 2). In contrast, our method offers the advantage of using readily available materials and provides a more efficient and milder reaction setup. The preparation of the magnetic def./Cu-MOF catalyst involves a multi-step process, making it time-consuming, labor-intensive, energy-demanding, and costly. However, a key advantage of this method is the ability to produce the catalyst on a large scale without requiring complex purification steps, which distinguishes it from other approaches. The use of DMSO as both solvent and methyl source poses several challenges. Its high boiling point (189 °C) complicates removal during scale-up, leading to longer purification times and increased costs. Additionally, DMSO can undergo side reactions under certain conditions, generating impurities that reduce overall yield. Some substrates may also be incompatible with DMSO, adversely affecting reaction efficiency. From a safety perspective, DMSO’s ability to penetrate the skin necessitates careful handling and disposal procedures. In this publication, we present a new method for the C–H bond methylation of imidazo[1,2-a]pyridine scaffolds at the C3 position, utilizing magnetic def/Cu-MOF via C(sp2)-H bond activation under relatively mild reaction conditions. This C(sp2)-H activation provides a practical approach to synthesizing 3-methyl-2-arylimidazo[1,2-a]pyridines, which are well-established as important building blocks in various pharmacological molecules.

Results and discussion

Catalyst preparation

Figure 3 illustrates the catalyst preparation procedure briefly. The synthesis of Magnetic Polyacrylic Acid (magnetic PAA) was carried out as follows: Fe3O4@SiO2@MPS nanoparticles were first prepared by dissolving 0.5 g of Fe3O4@SiO2@MPS in 30 mL of double-distilled water, followed by adding 3 mL of acrylic acid in a round-bottom flask. After degassing the mixture with nitrogen gas, 10 mg of azobisisobutyronitrile was added, and the mixture was refluxed in an oil bath for 24 h. The resulting nanoparticles were then collected using an external magnet, washed with double-distilled water and methanol, and dried under vacuum conditions at 60 °C for 24 h. Next, the synthesis of the copper-based magnetic metal-organic framework (magnetic def/Cu-MOF) was carried out as follows: In a round-bottomed flask, 1 g of magnetic PAA, 3.75 g (20 mmol) of copper nitrate, 3.32 g (20 mmol) of terephthalic acid, and 122 mg (5 mol %) of benzoic acid as a modifier were mixed with 20 mL of dimethylformamide and stirred for 2 h. The mixture was then placed in an autoclave at 120 °C for 24 h. Afterward, dimethylformamide was separated from magnetic def/Cu-MOF by centrifugation, and the synthesized sample was immersed in chloroform for 2 days to exchange the solvent. Finally, the Magnetic def/Cu-MOF was placed in a vacuum oven at 180 °C for 24 h to dry and activate the pores of the metal-organic framework. The prepared catalyst has been structurally identified using BET, XRD, TEM, FE-SEM, and FT-IR analysis.

Fig. 3.

Preparation of magnetic def/Cu-MOF composite.

Catalyst characterization

FT-IR spectroscopy

Figure 4 shows the FT-IR spectrum of the Magnetic def./Cu-MOF catalyst²⁸. The peaks in the area of 570 and 676 cm⁻¹ show the stretching and bending vibrations of the metal-oxygen bond. The peaks appearing in the region of 1000–1200 cm⁻¹ are related to the C–O stretching vibrations of terephthalic acid and benzoic acid ligands. The peaks in the region of 700–1000 cm⁻¹ are attributed to the in-plane and out-of-plane C-H bending vibrations of the ligands. The peaks at 1398 cm⁻¹ and 1623 cm⁻¹ correspond to the vibrational peaks of the carboxylate groups (COO⁻) and the C = C stretching vibrations of the aromatic rings in the ligands. In addition, the peak at 1666 cm⁻¹ describe the vibrations of the C = O group of carboxylic acids. The absorption peak in the area of 2932 cm⁻¹ shows the stretching vibration of C-H groups.

Fig. 4.

FT-IR spectrum of magnetic def/Cu-MOF.

XRD analysis

The X-ray diffraction pattern of the prepared catalyst is shown in Fig. 5. The diffraction peaks at angles of 2θ = 10.18°, 12.08°, 13.59°, 16.87°, 17.14°, 17.76°, 20.45°, 24.82°, 34.10°, 42.08° were observed that they were in the good accordance with the another Cu-MOF reported in the literatures. This pattern confirms the successful synthesis of def/Cu-MOF composite²⁹.

Fig. 5.

The XRD pattern of magnetic def/Cu-MOF.

Morphology study

The morphological structure, BET surface area analysis, and acid-base properties of the magnetic def/Cu-MOF catalyst were investigated to understand their impact on the catalyst’s efficiency in promoting the C-H methylation reaction. The FE-SEM and TEM images revealed that the catalyst exhibits a cubic morphology with high porosity, which likely provides a large number of active sites for reactant adsorption. The layered structure observed in some areas of the framework may also enhance the accessibility of these active sites, further promoting the reaction (Fig. 6). The EDX pattern and elemental mapping images shown in Fig. 7confirm the homogeneous distribution of key elements, including C, Cu, Fe, O, and Si, across the catalyst. This uniform distribution suggests that the metal-organic framework (MOF) is well-integrated, which is beneficial for the uniform activation of reactants during the reaction. The BET surface area analysis showed a surface area of 474.68 m²/g, indicating a significant number of available active sites that could facilitate the adsorption and activation of reactants in the C-H methylation reaction. The pore size of 9.27 nm suggests that the catalyst has a favorable pore structure for accommodating reactants and intermediates, which could increase its catalytic efficiency. Additionally, a quantitative analysis of the acid/base sites on the magnetic def/Cu-MOF catalyst was conducted following established methods from the literature^30[,31. In this procedure, 250 mg of the catalyst was mixed with 100 mL of a standard NaOH solution (0.00848 M) at room temperature. After controlling the pH, a more concentrated NaOH solution (0.0848 M) was added to adjust the pH, which was initially around 6 after 24 h. After allowing the mixture to equilibrate for 4 h, the pH reached approximately 11. The catalyst was then filtered, and the remaining NaOH was titrated with a 0.001 M standard hydrochloric acid solution in the presence of phenolphthalein until the purple color disappeared. Based on the titration results, it was calculated that the catalyst released 4.52 mmol of protons per gram of catalyst in water, indicating a significant presence of acidic sites. These acid sites are likely crucial for activating reactants, especially in reactions like C-H methylation.

Fig. 6.

The FE-SEM images of magnetic def/Cu-MOF (a–c), and the TEM image of magnetic def/Cu-MOF (d).

Fig. 7.

(a) The elemental mapping images of magnetic def/Cu-MOF (b) the EDX pattern of magnetic def/Cu-MOF.

The Cu concentration in the magnetic def./Cu-MOF was determined using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The Cu content was found to be 28.7%, measured at a wavelength of 327.395 nm. This high copper content further supports the catalyst’s role in facilitating the activation of reactants, particularly in reactions requiring metal-centered catalysis like the C-H methylation reaction.

In the next step, the catalytic properties of magnetic def/Cu-MOF were evaluated in the C(sp2–H methylation of imidazo[1,2-a]pyridines. To obtain the optimal conditions, 2-arylimidazo[1,2-a]pyridine (1a), dimethylsulfoxide (2) and different catalysts were used to test the effect of various reaction conditions. It is important to note that the reaction was initially performed at 120 °C for 1 h to ensure the formation of the desired radicals (Table 1, entry 1). Upon investigating the effect of temperature, it was found that the highest efficiency was achieved at 70 °C (Table 1, entries 4–6). It was observed that the reaction did not yield any product in the absence of the catalyst, even with an extended reaction time. (Table 1, entry 8). To optimize catalyst loading for maximum efficiency, we evaluated the performance of 3, 5, and 10 mg of the def/Cu-MOF catalyst. Although 3 mg resulted in a comparable yield (88%) to that of 5 mg (92%), we selected 5 mg for subsequent experiments due to its superior and more consistent performance. To further assess the effect of reaction time, we extended the duration from 4 to 6 h using 3 mg of the catalyst at 70 °C. However, this adjustment did not lead to a significant improvement in the yield of the desired product (entry 7). Similarly, increasing the catalyst amount to 10 mg did not result in a noticeable enhancement in yield (Table 1, entry 5). Copper acetate and copper nitrate catalysts produced the desired product, but their low yield was due to lower efficiency and porosity. In contrast, the magnetic def./Cu-MOF catalyst, with higher porosity (as confirmed by BET), showed significantly better performance. (Table 1, entries 9–12). The best results were achieved using 5 mg of magnetic def/Cu-MOF as the catalyst, at 70 °C with 4 h of stirring (Table 1, entry 4).

Table 1.

Screening the optimal reaction conditions. ^aReaction conditions: reaction of 2-arylimidazo[1,2-a]pyridine (1a, 0.5 mmol), DMSO (2, 3 mL) in the presence of different catalyst. ^bAfter purification by column chromatography on silica gel. ^cSynthesis of 2-(2-chlorophenyl)-imidazo[1,2-]pyridine-3-carbaldehyde (4a) was carried out by increasing the reaction time to 10 h and under atmosphere.

Entrya	Time (h)	Temp. (°C)	Catalyst (mg)	Yield b(%)
1	4	120	def/Cu-MOF, 5 mg	90 (3a)
2	4	100	def/Cu-MOF, 5 mg	90(3a)
3	4	80	def/Cu-MOF, 5 mg	92(3a)
4	4	70	def/Cu-MOF, 5 mg	92(3a)
5	4	70	def/Cu-MOF, 10 mg	92(3a)
6	4	70	def/Cu-MOF, 3 mg	88(3a)
7	6	70	def/Cu-MOF, 3 mg	89(3a)
8	24	70	-	-
9	4	70	Cu2(OAc)2, 3 mg	18(3a)
10	4	70	Cu2(OAc)2, 10 mg	20(3a)
11	4	70	Cu2(NO3)2, 3 mg	14(3a)
12	4	70	Cu2(NO3)2, 10 mg	16(3a)
13c	10	70	def/Cu-MOF, 5 mg	70 (4a)

In the next step of the synthetic work, with the optimal reaction conditions established, the generality of the substrates was explored (Table 2). Most functional groups were tolerated, and the reaction was successfully carried out with various substituents on the aromatic ring of the imidazopyridines. In addition to electron-withdrawing and electron-donating groups, thiopyran also gave successful results. Overall, both electron-withdrawing and electron-donating substrates, as well as thiopyran, provided excellent yields of the final products. The structures of the final products were characterized using NMR, mass spectrometry (Supporting information, Figure S1), and elemental analysis (Supporting information, Table S1).

Table 2.

Generality of Substrate Scope^a. ^aReaction conditions: reaction of 2-arylimidazo[1,2-a]pyridine (1a-3s, 0.5 mmol), DMSO (2, 3mL) in the presence of def/Cu-MOF (5 mg). ^bAfter purification by column chromatography on silica gel. ^cReaction of 2-arylimidazo[1,2-a]pyridine (1a, 0.5 mmol), DMSO-d6 (3mL) in the presence of def/Cu-MOF (5 mg). ^dThe reaction time was 10 h.

Control experiments and mechanism

To prove the source of the methyl group in the final products, an isotopic test was performed using hexadeuterodimethyl sulfoxide (DMSO-d₆) under optimal reaction conditions, which led to the formation of the deuterated products (Fig. 8a). In the next step, (CH₂)₃(CMe₂)₂NO (TEMPO) was added to the reaction as a radical inhibitor and it was found that the reaction was completely inhibited (Fig. 8b). Hence, based on the results obtained, a mechanism for the methylation reaction can be proposed, as shown in Fig. 9. The reaction initiates with a single electron transfer (SET) facilitated by the copper catalyst³². The copper acts as a key electron acceptor, enabling the activation of the C–H bond through coordination with the substrate, which enhances the efficiency of the methylation process³³. The final product is then formed by the recombination of the resulting radicals.

Fig. 8.

Control experiments.

Fig. 9.

The proposed mechanism.

Recyclability test

The recyclability of the Magnetic def/Cu-MOF catalyst was tested under optimized reaction conditions. After each run, the catalyst was collected using an external magnetic field, washed with methanol and water, dried in an oven, and then prepared for the next cycle. The catalyst demonstrated excellent recyclability, maintaining its activity without loss in performance. In the third run, the product yield remained at 92%. The catalyst could be easily recovered using a magnet, visible to the naked eye. Additionally, the turnover frequency (TOF) for this model reaction under optimized conditions was calculated to be 22.8 h⁻¹.

Conclusion

In this publication, we describe the development of an efficient procedure for the C–H methylation of imidazo[1,2-a]pyridine scaffolds at the C3 position, using magnetic def/Cu-MOF as the catalyst through C(sp2)-H bond activation. This method successfully addresses the challenges of selective functionalization by offering a straightforward approach that utilizes an easy-to-handle MOF-based catalytic system. The starting materials are readily available, and the protocol is compatible with a broad range of substrates, enabling the synthesis of a variety of methylated imidazopyridine derivatives. The simple procedure, mild reaction conditions, and excellent functional group compatibility make this method highly accessible and efficient. These characteristics make it an attractive strategy for the synthesis of imidazo[1,2-a]pyridine derivatives, which are well-established as significant building blocks in numerous pharmacological molecules, including potential drug candidates. This work provides a promising alternative for the development of these bioactive compounds, with potential applications in medicinal chemistry and drug discovery.

Experimental section

General procedure for the Preparation of 3-methyl-2-aryl-imidazo]1,2-[α-pyridines catalyzed by magnetic def/Cu-MOF

In a test tube, dimethyl sulfoxide (3 mL) and Magnetic def/Cu-MOF catalyst (5 mg) were mixed and stirred at 70 °C for 1 h. Then, 2-aryl-imidazo[1,2-α]pyridine (0.5 mmol) was added to the reaction mixture, and the reaction was allowed to proceed for 4 h until completion, as monitored by thin-layer chromatography (TLC). Afterward, the reaction mixture was separated using dilute ethyl acetate, and the catalyst was recovered using an external magnet. The product was extracted with ethyl acetate (3 × 10 mL), and the organic layer was dried over sodium sulfate. Following evaporation of ethyl acetate under vacuum, the product was purified by chromatography using a solvent mixture of ethyl acetate/hexane (40/50). Finally, the synthesized derivatives were characterized by ¹H NMR and ¹³C NMR spectroscopy.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

F.M.M. devised the project and the main conceptual ideas. A.J. devised the project, performed the experiments, and analyzed spectra. P.Y.P. performed experiments and analyzed spectra. B.A. wrote the main manuscript text, performed the experiments, and analyzed spectra.

Funding

This research receive grant from Sharif University of Technology Research Council.

Data availability

All data generated or analyzed during this study are included in this article [and its Supplementary Information files].

Declarations

Competing interests

The authors declare no competing interests.