Metal-free oxidative coupling of aminopyridines with nitroolefins to imidazo[1,2-a]pyridine in the presence of I₂–TBHP–pyridine

1 Introduction

Metal-catalyzed coupling reactions have provided powerful tools for the formation of carbon–carbon bonds and carbon–heteroatom bonds to a wide range of compounds in many areas [1–4]. Coupling reactions have been extensively studied to develop innovative and greener approaches. Metal-free coupling is an important and increasingly trendy highlight that has attracted much attention in recent years [5–7]. Although traditional metal-catalyzed coupling reactions have been proven effective in many industrial applications, they are also generating harmful metal waste and much other organic waste. In addition, some metal catalysts are moisture and/or air sensitive. Owing to mild conditions, low cost, and good efficiency, metal-free catalysts could be candidates for many green processes in both academic and industrial research.

Imidazo[1,2-a]pyrimidines are important heterocyclic compounds [8]. They are prominent among nitrogen-containing fused heterocycles and are known for a plethora of biological and pharmacological properties [9], such as antidepressant [10], anticancer, antiviral, antiparasitic, and anti–human immunodeficiency virus activities. Furthermore, they are also the core structure of some currently marketed drugs, such as zolimidine, zolpidem, loprinone, and alpidem. Therefore, much interest has been drawn to develop the imidazo[1,2-a]pyridine preparation.

Traditionally, coupling of 2-aminopyridines with α-halocarbonyl compounds provides a practical method to imidazo[1,2-a]pyridine [11–13]. This protocol was also extended to similar α-functionalized ketones [14, 15]. Other methods included (i) the condensation of 2-aminopyridines and aromatic ketones [16–18]; (ii) one-pot condensations of 2-aminopyridines, aldehydes, and isonitriles [19–22]; (iii) three-component reactions of 2-aminopyridines, aldehydes, and alkynes [13–25], or oxidative cross-coupling/cyclization between 2-aminopyridines and terminal alkynes [26]; (iv) condensation of 2-aminopyridines with 1,3-dicarbonyl compounds [27, 28]; and (v) condensation of 2-aminopyridines with chalcones [29, 30]. (vi) Moreover, recently, Yan and co-workers have developed a CuBr-catalyzed method for the preparation of imidazo[1,2-a]pyridines from aminopyridines and nitroolefins [31]. Subsequently, FeCl₂ [32] and FeCl₃ [33, 34] were developed to promote the construction of imidazo[1,2-a]pyridine from in situ–generated or as-prepared nitroolefins. However, there are very few reports on metal-free catalysts for this route [35, 36]. In the former example, the authors found that Bu₄NI–TBHP (t-butyl hydroperoxide) was an efficient catalytic system [35]. In the more recent example, a new protocol was presented in which the cycloaddition of N-aminopyridines and β-nitroolefins to substituted pyrazolo[1,5-a]pyridines had been developed [36]. Thus, a mild, green protocol for the synthesis of imidazo[1,2-a]pyridine is still desirable. Encouraged by the previous reports and as a part of our continuing study on metal-free/catalyst-free reactions in green chemistry [37, 38], we wish to report herein a metal-free I₂–TBHP–pyridine combination mediated by the formation of imidazo[1,2-a]pyridine via Michael addition and oxidative coupling.

2 Results and discussion

To begin with our study, the reaction of 2-aminopyridine and β-nitrostyrene was chosen as a model reaction to screen the conditions (Table 1). The reaction occurred at room temperature, resulting in poor yield (Table 1, entry 1). Even at an elevated temperature, the material could not be consumed completely. Inspired by I₂–TBHP in the C–N oxidative coupling [29, 39], the catalytic system was also tested for the model reaction. Fortunately, a good yield was achieved (Table 1, entry 2). When a catalytic amount of pyridine was added to the reaction mixture, the material was consumed in shorter time with comparative yield (Table 1, entry 3). When the loading of I₂ was increased to 0.2 equiv, a better yield was given (Table 1, entry 4). Similarly, less TBHP gave poor yield (Table 1, entry 5). It is shown that it may be due to the synergistic effect in the catalytic system of I₂–TBHP–Py [40]. However, the model reaction under the optimal condition without any solvent gave a negative result (Table 1, entry 6). Besides these trials, other candidates were also investigated, but they could not lead to better results (Table 1, entries 7–12).

Table 1

Optimization of reaction conditions.^a

Entry	Catalyst	Solvent	Temp. (°C)	Reaction time (h)	Yieldb (%)
1	I2	CH3CN	r. t.	24	36c
2	I2–TBHP	CH3CN	80	20	80d
3	I2–TBHP–Py	CH3CN	80	12	81e
4	I2–TBHP–Py	CH3CN	80	12	90f
5	I2–TBHP–Py	CH3CN	80	12	66g,c
6	I2–TBHP–Py	Solventless	80	24	16f,c
7	TBHP	CH3CN	r. t.	24	– h
8	TBHP	CH3CN	80	24	– h
9	I2–Py	CH3CN	80	12	71i
10	TBHP–Py	CH3CN	80	24	80j
11	I2–30 % H2O2	CH3CN	80	12	52k
12	KI–TBHP	CH3CN	80	17	65l

^aReaction condition: 2-aminopyridine (1.0 mmol), nitroolefin (1.05 mmol), solvent (10 mL), temperature means the oil bath temperature; ^bisolated yields; ^cI₂ (0.2 mmol) was used, and the materials were not consumed completely; ^dI₂ (0.1 mmol) and TBHP (2.0mmol) were added; ^eI₂ (0.1 mmol), pyridine (0.62 mmol), and TBHP (2.0 mmol) were added; ^fI₂ (0.2 mmol), pyridine (0.62 mmol), and TBHP (2.0 mmol) were added; ^gI₂ (0.2 mmol), pyridine (0.62 mmol), and TBHP (1.0 mmol) were added; ^hno reaction, and TBHP (2.0 mmol) was used; ⁱI₂ (0.2 mmol) and pyridine (0.62 mmol) were added; ^jTBHP (2.0 mmol) and pyridine (0.62 mmol) were added; ^k30 % H₂O₂ (1 mL) was used; ^lKI (0.2 mmol) and TBHP (2.0 mmol) were added.

The substrate scope then was investigated under the optimized reaction conditions (Table 2). In most cases, the reaction proceeded smoothly in moderate to good yield. It was observed that some functional groups, such as amino, nitro, halo, and methoxy, were tolerable in the catalytic system. Generally speaking, 2-aminopyridine resulted in better yields than 3-methyl 2-aminopyridine. It was reported that ortho-substituted nitroolefins did not give the desired imidazo[1,2-a]pyridines in the presence of Bu₄NI–TBHP [35]. It is noteworthy that fairly moderate yields were achieved for ortho-substituted nitroolefins under our catalytic system (Table 2, 3e, 3m). It was interesting that the catalytic system was effective even at room temperature in some cases (Table 2, 3d–i, 3k, 3m, 3o). Based on TLC analysis, a reaction at room temperature gave fewer spots than those at elevated temperature in these cases. Finally, the scope was extended to other substrates (Table 3). As for a heterocycle-substituted nitroolefin, it produced a complex mixture (Table 3, entry 1). It was the same when (E)-(2-nitroprop-1-en-1-yl)benzene was used instead of β-nitrostyrene (Table 3, entry 2). The reaction of β-nitrostyrene with acetylated 2-aminopyridine did not occur (Table 3, entry 3). It might be due to reduced activity of an amino in the presence of an acetyl group. If the amino was replaced with a benzyl group, only a poor yield could be obtained. It was more interesting that the benzyl was removed in the reaction process (Table 3, entry 4).

Table 2

Synthesis of imidazo[1,2-a]pyridines.^a

3a, 80 °C, 90 %b	3b, 80 °C, 85 %	3c, 80 °C, 87 %	3d, r. t., 69 %
3e, r. t., 40 %	3f, r. t., 71 %	3g, r. t., 70 %	3h, r. t., 78 %
3i, r. t., 48 %	3j, 100 °C, 46 %	3k, r. t., 58 %	3l, 80 °C, 71 %
3m, r. t., 47 %	3n, 100 °C, 46 %	3o, r. t., 65 %

^aReaction conditions: 2-aminopyridine (1.0 mmol), nitroolefin (1.05 mmol), I₂ (0.2 mmol), pyridine (0.62 mmol), and TBHP (2.0 mmol) were added in CH₃CN (10 mL). The reaction time was 12 h. Temperature means the oil bath temperature. ^bIsolated yields.

Table 3

The trials on extension of scope under the present catalytic system.

Entry	1	2	Product (yield)	Temp. (°C)
1			Complex mixture	80
2			Complex mixture	100
3			No reaction	100
4			3a (20 %)	100
5			No reaction	100
6			No reaction	100
7			No reaction	100
8			No reaction	100

^aReaction conditions: 2-aminopyridine (1.0 mmol), nitroolefin (1.05 mmol), I₂ (0.2 mmol), pyridine (0.62 mmol), TBHP (2.0 mmol), and CH₃CN (10 mL). Temperature means the oil bath temperature. The reaction time was 12 h. ^bIsolated yields.

We have also attempted to construct new fused thiazoles and imidazoles by this protocol. Structures similar to 2-aminopyridine, such as 2-aminobenzimidazole and 2-aminobenzothiazole, were chosen as candidates (Table 3, entries 5 and 6). However, neither of them took part in the reaction. It was also observed that 4-aminopyridine does not undergo the Michael reaction with β-nitrostyrene under the catalytic condition (Table 3, entry 7). Activated alkene, 2-(2-fluorobenzylidene) malononitrile, which was suggested as a Michael addition acceptor, did not proceed as well in the reaction (Table 3, entry 8). Thus, this method showed good selectivity.

Based on the above results and previous reports [31, 35, 40], a plausible mechanism is put forward (Scheme 1). On the one hand, “outer complex” 4 was formed from pyridine and iodine. In the presence of TBHP, intermediate 5 was generated, which split into two kinds of radicals, 6 and 7. The radicals 6 or 7 resulted in PyHI 8 or TBHP after activating the intermediate 12, which would be illustrated in the following step. PyHI 8 and HI were oxidized by TBHP to “outer complex” 4. Thus, the catalytic cycle was achieved.

Scheme 1:

Proposed mechanism.

On the other hand, intermediate 9 was produced from β-nitrostyrene and 2-aminopyridine via Michael addition. The intermediate 9 was oxidized to imine 10, from which enamine 11 equilibrated. The intermediate 12, generated by one-electron oxidation, was abstracted of hydrogen by radicals 6 or 7 to intermediate 13. After intramolecular nucleophilic addition occurred, the final product was obtained by proton elimination of intermediate 14.

3 Conclusions

In summary, we have successfully developed a metal-free catalytic system for the synthesis of 3-nitro-2-arylimidazo[1,2-a]pyridine derivatives. The component in this system shows a synergistic effect for catalysis. It is simple and environmentally benign.

4 Experimental section

All materials were obtained from commercial suppliers and were used without further purification unless otherwise noted. The nitroolefins were prepared by the Henry reaction. All solvents were reagent grade. Flash chromatography was performed with silica gel (200–300 mesh). The nuclear magnetic resonance (NMR) spectra were measured on an AVANCE 400 spectrometer at 400 MHz for ¹H and 100 MHz for ¹³C in CDCl₃ solution with trimethylsilyl as an internal standard. Chemical shifts (δ) are given in parts per million and coupling constants (J) in Hertz. High-resolution mass spectroscopy (HRMS) spectra were recorded on an LTQ-Orbitrap mass spectrometer [(+)-ESI].

5 Supporting Information

General experimental information, spectroscopic data, and spectra of compounds 3a–3o are summarized as Supporting Information available online (DOI: 10.1515/znb-2015-0171).