One-Pot Synthesis of Imidazo[1,2-a]pyridines via Groebke–Blackburn–Bienaymé Reaction ^†

Abstract

The imidazo[1,2-a]pyridine (IMP) scaffold has attracted considerable attention due to its photophysical properties and their applications in medicinal chemistry and material sciences. Isocyanide-based multicomponent reactions (I-MCRs), particularly the Groebke –Blackburn–Bienaymé reaction (GBBR), are considered election synthetic one-pot processes for synthesis of IMP analogs. Herein we described a novel ultrasound assisted one-pot green synthesis of IMPs via GBBR using water as solvent. The approach aligns with the principles and metrics of green chemistry and enables the efficient synthesis of highly fluorescent molecules. These compounds show potential applications in chemical sensing, optoelectronic devices, and bioimaging.

1. Introduction

Imidazo[1,2-a]pyridines (IMPs) are recognized as valuable structural frameworks in medicinal chemistry due to their diverse biological activities, such as antifungal, antiviral, anticancer, antibacterial, anti-inflammatory, anthelmintic, analgesic, antitubercular, antipyretic, and antiepileptic. Particularly, IMPs scaffolds have attracted attention due to their versatile pharmacological and photophysical properties. Fluorescent chemical sensors are highly effective for analyzing various biological, industrial, and environmental analytes. Their strong selectivity, high sensitivity, fast photoluminescence response, cost-efficiency, and ability to detect low concentrations make them particularly useful, even for bioimaging applications [1]. These qualities make them highly promising chromophores for applications in chemosensors, bioimaging, and optoelectronics, as they can absorb light at specific wavelengths and emit fluorescence (Figure 1) [2].

The synthesis of new chemosensors for detecting heavy and transition metal ions is a research field that is constantly growing. This is due to the significant impact these metal ions—such as cobalt, copper, or zinc—have on the environment and human health, and because they are crucial for various bodily functions and industrial applications; however, abnormal levels can pose health risks. Therefore, regulating their concentrations is vital to minimizing harmful effects [3].

The synthesis of IMPs has been reported by several strategies, such as transition metal-catalyzed reactions, condensation processes, cyclization reactions, heteroannulation, and photocatalytic methods. However, these techniques often require harsh conditions, such as high temperatures, and solvents that are not environmentally friendly; in addition, they can lead to undesirable side products, long reaction times, high costs, and a limited scope, often resulting in low yields [4]. In this context, multicomponent reactions (MCRs) are considered the most efficient synthetic tools for organic synthesis due to advantages such as high overall yields and atomic economy, short reaction time, convergence, and compatibility with a wide range of substrates with different structural characteristics resulting in a broad scope [5]; in particular, the isocyanide multicomponent reaction (IMCR), specifically the Groebke–Blackburn–Bienaymé reaction (GBBR), is the best methodology to synthesize imidazo[1,2-a]pyridine-3-amines (IMPs) [6].

Our research line group is a pioneer in the innovation and development of novel one-pot GBBR protocols using alternative energy sources (AES) that allow chemical activation accelerating reactions. Particularly, the ultrasonic irradiation (USI) occurs through the formation of bubbles and undergoes vigorous collapse by a cavitation process generating energy, enhancing solubility, selectivity, and reducing reaction times [7].

Following our research line focused on the design and development of novel sonochemical IMCR one-pot synthesis of fluorescent IMP analogs [8,9]. (Scheme 1) [10].

Herein we report the first ultrasound assisted one-pot synthesis of potential IMPs chemosensors by GBBR.

2. Results and Discussion

Initially the synthesis of a furan-imidazo[1,2-a]pyridine-3-amine analog 5a was attempted by furfural 1a (1 mmol), 2-aminopyridine 2a (1 mmol), and cyclohexyl isonitrile 3a (1 mmol) in the absence of a catalyst and solvent under USI; after 4 h any product was observed (

Table 1. Screening conditions for the synthesis of 4a.

Entry [a]	Catalyst [b]	Solvent [1.0 M]	Time (h)	Yield [e]
1	---	---	4	---
2	---	H2O	4	traces
3 [c]	NH4Cl	H2O	4	32
4	NH4Cl	H2O	4	50
5	PBA	H2O	4	65
6 [d]	PBA	H2O	4	86

^[a] Furfural (1a, 1.0 equiv.), 2-aminopyridine (2a, 1.0 equiv.), and cyclohexyl isocyanide (3a, 1.0 equiv.); ^[b] 10 mol%; ^[c] 5 mol%, ^[d] 60 °C; ^[e] Isolated yields.

, Entry 1). Next H₂O was employed, such as green solvent; unfortunately only traces were identified (Entry 2). Encouraged by this we decided to use NH₄Cl as a catalyst in 5 to 10% mol, affording the desired product in 32 -50% of yield (Entries 3–4). Then PBA was used, such as catalyst, affording the desired product with 65% of yield (Entry 5). To increase yield. the reaction was conducted at 60 °C, giving the desired product 5a in 86% (Entry 6).

With optimized conditions, we explored the scope of the methodology through variations of aminopyridine reagents. The respective imidazo[1,2-a]pyridine (5a–d, Figure 2) were synthesized under sonication in moderate-to-good yields (67–86%).

3. Experimental Section

3.1. General Information, Instrumentation, and Chemicals

The ¹H and ¹³C NMR spectra were recorded using Bruker Avance III spectrometers (Billerica, MA, USA) operating at 500 MHz. Deuterated chloroform (CDCl₃) was used as a solvent. Chemical shifts were reported in parts per million (δ/ppm), with tetramethylsilane (TMS) at 0.0 ppm as the internal reference. Coupling constants (J) are reported in Hertz (Hz). The multiplicity is reported using the following standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). Spectral data were processed using MestreNova software version 10.0.1–14719. High-resolution mass spectrometry (HRMS) were obtained using electrospray ionization (ESI) via the time-of-flight (TOF) method. Ultrasonic-assisted reactions were carried out in 10 mL sealed vials immersed in a Branson 1510 ultrasonic bath (Danbury, CO, USA) operating at 42 kHz ± 6%. Reactions were monitored by thin-layer chromatography (TLC), and spots were visualized under UV light (254 or 365 nm). Purification of the products was achieved by flash column chromatography on silica gel (230–400 mesh) using a gradient of hexanes with EtOAc (v/v) as the mobile phase. All reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without aditional purification. Chemical structures and nomenclature were generated by ChemBioDraw Ultra 13.0.2.3020 software package.

3.2. General Procedure (GP)

Aldehyde (1, 1.0 equiv.), 2-aminopyridine (2, 1 equiv.), and the appropriate isocyanide (3, 1 equiv.) were added in a sealed vial (10 mL), PBA (10% mol) was dissolved in H₂O (1M), and the resulting mixture was sonicated (42 kHz ± 6%) at room temperature for 4 h. The reactions were monitored by TLC; furthermore, the reactions were extracted with ethyl acetate, and the crude reaction was purified by flash chromatography to afford the corresponding imidazo[1,2-a]pyridine.

3.3. Spectral Data

Characterization of N-cyclohexyl-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine (5a) was synthetized according to the general procedure using 2-aminopyridine, furfural, and cyclohexyl isocyanide. It was obtained as an oil in 86% yield. ¹H NMR (500 MHz, CDCl₃) δ ¹H NMR (500 MHz, CDCl₃) δ 7.97 (dd, J = 6.9, 0.8 Hz, 1H), 7.41 (dd, J = 6.5, 0.7 Hz, 2H), 7.02 (dd, J = 8.4, 7.3 Hz, 1H), 6.78 (d, J =3.2, 1H), 6.69 (t, J =6.5, 1H), 6.49–6.46 (m, 1H), 3.53 (s, 1H), 2.91–2.85 (m, 1H), 1.83–1.79 (m, 2H), 1.67–1.63 (m, 2H), 1.54–1.50 (m, 1H), 1.23–1.10 (m, 5H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 150.4, 141.8, 141.3, 128.1, 125.5, 123.8, 122.7, 117.2, 111.5, 111.4, 106.3, 57.0, 34.1, 25.7, 24.9 ppm. HRMS (ESI-TOF) m/z calcd. for C₁₇H₂₀N₃O⁺ [M + H]⁺ 282.1601, found 282.1616.

Characterization of 6-Chloro-N-cyclohexyl-2-(furan-2-yl)imidazo[1,2-a]pyridin-3-amine (5b) was synthetized according to the general procedure using 2-amino-5-chloropyridine, furfural and cyclohexyl isocyanide. It was obtained as an oil in 86% yield. ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 9.5 Hz, 1H), 7.00 (dd, J = 9.5, 2.0 Hz, 1H), 6.79 (d, J = 3.4 Hz, 1H), 6.46 (dd, J = 3.4, 1.8 Hz, 1H), 3.53 (s, 1H), 2.89 (t, J = 9.8 Hz, 1H), 1.81 (d, J = 10.7 Hz, 2H), 1.75–1.62 (m, 2H), 1.61–1.45 (m, 1H), 1.17 -1.12 (m, 5H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 150.1, 141.9, 140.3, 129.5, 126.0, 125.4, 120.8, 120.2, 117.8, 111.7, 107.0, 57.2, 34.2, 25.8, 25.1 ppm. HRMS (ESI-TOF) m/z calcd. for C₁₇H₁₉ClN₃O [M + H]⁺ 316.1211, found 316.1214.

Characterization of 3-(Cyclohexylamino)-2-(furan-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile (5c) was synthetized according to the general procedure using 2-amino-5-cyanopyridine, furfural, and cyclohexyl isocyanide. It was obtained as an oil in 67% yield. ¹H NMR (500 MHz, CDCl₃) δ 8.39 (s, 1H), 7.48–7.44 (m, 2H), 7.12 (d, J = 9.2 Hz, 1H), 6.85 (s, 1H), 6.49–6.48 (m, 1H), 3.58 (s, 1H), 2.90 (t, J = 10.3 Hz, 2H), 1.81 (d, J = 11.5 Hz, 3H), 1.68 (d, J = 9.0 Hz, 3H), 1.57–1.56 (m, 2H), 1.26–1.11 (m, 9H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 149.4, 142.5, 140.9, 130.5, 129.2, 126.3, 123.7, 118.2, 117.2, 111.9, 108.1, 97.8, 57.5, 34.2, 25.7, 25.1 ppm. HRMS (ESI-TOF) m/z calcd. for C₁₈H₁₉N₄O⁺ [M + H]⁺ 307.1553, found 307.1509.

Characterization of 3-((4-Methoxyphenyl)amino)-2-(5-methylfuran-2-yl)imidazo[1,2-a] pyridine-6-carbonitrile (5d) was synthetized according to the general procedure using 2-amino-5-cyanopyridine, 5-methylfurfural, and 4-methoxyphenyl isocyanide. It was obtained as an oil in 80% yield. ¹H NMR (500 MHz, CDCl₃) δ 8.17 (s, 1H), 7.58 (d, J = 9.3 Hz, 1H), 7.21 (dd, J = 9.3, 1.4 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 3.2 Hz, 1H), 6.46 (d, J = 8.9 Hz, 2H), 5.98 (d, J = 3.0 Hz, 3H), 5.50 (s, 3H) ppm. ¹³C NMR (126 MHz, CDCl₃) δ 154.5, 153.6, 146.0, 141.9, 137.3, 133.6, 128.8, 124.7, 119.7, 118.4, 116.8, 115.5, 115.5, 110.6, 108.1, 98.41, 55.8, 13.9 ppm. HRMS (ESI-TOF) m/z calcd. for C₂₀H₁₇N₄O₂⁺ [M + H]⁺ Calcd for 345.1346, found 345.1362.

4. Conclusions

The main contribution of this work is the multicomponent one-pot synthesis via GBBR toward IMPs incorporating the furan moiety as potential chemosensors. The one-pot GBB synthesis used water as a green solvent, aligning with the principles of green chemistry. The scope of the development strategy will be reported at this time.