Heterogeneously copper-catalyzed oxidative synthesis of imidazo[1,2-a]pyridines using 2-aminopyridines and ketones under ligand- and additive-free conditions

Abstract

An efficient and mild heterogeneously CuCl₂/nano-TiO₂-catalyzed aerobic synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and ketones has been developed using air as the oxidant in the absence of any ligands and additives. This strategy was compatible with a large range of substrates, including unactivated aryl ketones and unsaturated ketones and went through the C–H bond functionalization mechanism instead of I⁻-assisted Ortoleva-King reaction to provide the corresponding imidazo[1,2-a]pyridines in good yields with low catalyst loading (0.8 mol%). Moreover, the heterogeneous catalyst can be successfully employed in gram-scale synthesis and reused many times without the significant loss of catalytic activity.

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Introduction

Due to increasing concern about environmental and economic issues, significant effort has been made to develop new catalytic methods, which minimize pollution and are suited for application in industrial processes, such as heterogeneous catalysis.¹ Compared with homogeneous catalysis, its heterogeneous counterpart has practical advantages in catalyst handling, recyclability and separation of the catalyst from products, which results in its wide applications in industrial environments.^2–6 Furthermore, heterogeneous catalysis meets the requirements of green chemistry because it employs recycled catalysts and ligand-free conditions generally.^4,6 Therefore, it is highly desirable to explore economic and eco-friendly heterogeneous catalytic systems for organic synthesis.

Imidazo[1,2-a]pyridines are valuable motifs and exhibit many important biological activities, like antibacterial,⁷ antiviral,⁸ antitumor⁹ and anti-inflammatory properties.¹⁰ Therefore, imidazo[1,2-a]pyridines are widely present in a number of best-selling pharmaceuticals,¹¹ such as zolimidine,¹² zolpidem,¹² alpidem,¹³ olprinone,¹⁴ necopidem,¹⁵ saripidem.¹⁵ Traditionally, imidazo[1,2-a]pyridines were obtained by condensations between 2-aminopyridines and per-functionalized carbonyl compounds under various conditions (Scheme 1, eqn (1)).¹⁶ Recently, Lei's group discovered a silver-mediated oxidative coupling/cyclization using 2-aminopyridines and terminal alkynes to provide imidazo[1,2-a]pyridines (Scheme 1, eqn (2)).¹⁷

Scheme 1 Previous methods for synthesis of imidazo[1,2-a]pyridines.

In 2013, Hajra's group reported a Fe-catalyzed method using 2-aminopyridines and nitroolefins (Scheme 1, eqn (3)).¹⁸ Subsequently, several homogeneous CuI or Cu/ZnI-catalyzed oxidative methods using 2-aminopyridines and unactivated methyl ketones in the presence of ligands or additives were reported, respectively, by Hajra, Adimurthy, Ji and Kumar's group at almost the same time (Scheme 1, eqn (4)).¹⁹ Most recently, Su and co-workers discovered a homogeneous CuI/O₂ system for the synthesis of imidazo[1,2-a]pyridines by a reaction between 2-aminopyridines and unactivated methyl ketones and disclosed an iodine-promoted Ortoleva-King reaction rather than the previously reported C–H functionalization, which was involved in this transformation most probably (Scheme 1, eqn (4)).²⁰ In the course of investigating applications of heterogeneous catalysts in our research group,^4a,e,21 we proposed a simple heterogeneous system for the synthesis of imidazo[1,2-a]pyridines from unactivated ketones and 2-aminopyridines via metal-catalyzed aerobic C–H functionalization under ligand-, additive- and iodine-free conditions, which would be a useful complement to the previous methodologies.²²

Here, we wish to describe a heterogeneous CuCl₂/nano-TiO₂-catalyzed aerobic synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and readily available ketones using air as the oxidant under iodine-, ligand- and additive-free conditions (Scheme 2). The catalytic system tolerates a variety of substrates and could be employed in the synthesis of zolimidine on a gram-scale. More importantly, the heterogeneous catalyst can recycle three times without the loss of activity.

Scheme 2 Heterogeneous catalytic synthesis of imidazo[1,2-a]pyridines.

Results and discussion

Initially, a series of bimetallic heterogeneous catalysts which are successfully used in the aerobic synthesis of 1,2,4-triazoles^4e were employed for the catalytic synthesis of imidazo[1,2-a]pyridines in DCB (1,2-dichlorobenzene) under air at the indicated temperatures (Table 1, entries 1–7). Although the desired product was obtained in very low yield only at 130 °C for 24 h using Cu–Zn/nano-TiO₂, most experiments did not proceed well. Then, we focused on a copper-based solid-supported catalyst and delightedly found that CuCl₂/nano-TiO₂ (0.8 mol%, Cu = 3.16 wt%) could catalyze the cyclization efficiently while copper hydroxide and oxide were both inferior at 130 °C for 24 h (Table 1, entries 9, 10, 14 and 15).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Temp. (°C)	Yield^b (%)
a Reaction conditions: 2-aminopyridine (0.6 mmol), acetophenone (0.5 mmol), heterogeneous catalyst (12 mg, 0.8 mol%), solvent (0.6 mL), air, 24 h.b Isolated yields.c 10 mol% of CuCl2-2H2O was used.d 12 mg of nano-TiO2 was used.e 10 mol% of CuCl2-2H2O and 12 mg of nano-TiO2 were used.
1	Cu–Zn/Al–Ti	DCB	100	0
2	Cu–Zn/Al–Ti	DCB	130	<5
3	Cu–Mn/Al–Ti	DCB	120	0
4	Fe–Zn/Al–Ti	DCB	120	0
5	Cu–Zn/nano-TiO2	DCB	130	8
6	Cu–Ni/nano-TiO2	DCB	130	<5
7	Ni–Zn/nano-TiO2	DCB	130	0
8	Cu–Fe/OMS-2	DCB	130	<5
9	Cu(OH)x/OMS-2	DCB	130	<5
10	CuCl2/nano-TiO2	DCB	130	88
11^c	CuCl2	DCB	130	12
12^d	Nano-TiO2	DCB	130	0
13^e	CuCl2 + nano-TiO2	DCB	130	15
14	Cu(OH)x/nano-TiO2	DCB	130	23
15	CuOx/nano-TiO2	DCB	130	0
16	Ru/nano-TiO2	DCB	130	0
17	Pt/nano-TiO2	DCB	130	0
18	CuCl2/nano-TiO2	DMSO	130	16
19	CuCl2/nano-TiO2	DMF	130	<5
20	CuCl2/nano-TiO2	o-Xylene	130	12
21	CuCl2/nano-TiO2	Dioxane	100	65
22	CuCl2/nano-TiO2	MeNO2	100	<5
23	CuCl2/nano-TiO2	THF	60	<5
24	CuCl2/nano-TiO2	EtOH	70	87

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The supported Cu(OH)_x on manganese oxide-based octahedral molecular sieve (Cu(OH)_x/OMS-2), which is an excellent heterogeneous catalyst for biomimetic homo-coupling of terminal alkynes,^23a and basic Cu(OH)_x/nano-TiO₂, which can successfully catalyze Huisgen [3 + 2] cycloaddition,^23b are not efficient for this cyclization, although the latter gave 23% yield (Table 1, entries 9 and 14). On the other hand, the copper oxide does not have catalytic activity at all in the experiment (Table 1, entry 15). More experiments showed that no reaction proceeded or low yield was obtained in the presence of nano-TiO₂ powder alone or the catalyst precursor of CuCl₂-2H₂O (Table 1, entries 11 and 12). Moreover, the catalytic activity of a mixture of CuCl₂-2H₂O and nano-TiO₂ was much lower than that of the CuCl₂/nano-TiO₂ (Table 1, entry 13), which means that the highly dispersed copper species are effective for this cyclization. Specifically, CuCl₂ can catalyze the reaction while nano-TiO₂ does not have any catalytic activity; therefore, nano-TiO₂ probably plays a role of an appropriate support for the heterogeneous catalyst because of its large surface area, small particle size and the interaction between Cu species and TiO₂.²⁴ To improve the yield of reaction, other metal oxides were used, such as Ru and Pt, although the results were negative (Table 1, entries 16 and 17). Next, we found that the solvent could affect the reaction significantly (Table 1, entries 18–24). Specifically, polar organic solvents, like DMF and DMSO, hardly assisted with the reaction while only dioxane brought about moderate yield of the desired product among other examined solvents (Table 1, entries 18–23). Surprisingly, the best result was obtained by using protic EtOH as a solvent under mild conditions (Table 1, entry 24).

After confirming the catalytic transition metal, a lot of supports were examined for optimization as well (Table 2). In Table 2, we used the impregnation method to load CuCl₂ on various solid supports and ran the cyclization under the established reaction conditions: EtOH as a solvent at 70 °C under air for 24 h. As a consequence, nano-size Al₂O₃, ZrO₂ and CeO₂ were not efficient supports, although they catalyzed the reaction slightly (Table 2, entries 2–4). SiO₂, OMS-2 (manganese oxide-based octahedral molecular sieve), activated carbon and ATP (attapulgite) gave traces to approximately 10% yield (Table 2, entries 5–7 and 9) while CuCl₂/Al–Ti gave moderate yield of the desired product (Table 2, entry 8). Finally, it was proven that nano-TiO₂ is the best support for the heterogeneous catalyst under mild ligand- and additive-free conditions (Table 2, entry 1).

Table 2 Optimization of the heterogeneous catalyst^a

Entry	Catalyst (0.8 mol%)	Isolated yield (%)
a Reaction conditions: 2-aminopyridine (0.6 mmol), acetophenone (0.5 mmol), heterogeneous catalyst (12 mg, 0.8 mol%), EtOH (0.6 mL), 70 °C air, 24 h.
1	CuCl2/nano-TiO2	87
2	CuCl2/nano-Al2O3	15
3	CuCl2/nano-ZrO2	26
4	CuCl2/nano-CeO2	10
5	CuCl2/SiO2	8
6	CuCl2/OMS-2	11
7	CuCl2/C	<5
8	CuCl2/Al–Ti	34
9	CuCl2/ATP	<5

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To verify whether the observed catalysis is derived from the solid catalyst CuCl₂/nano-TiO₂ or the leached copper species, the cyclization of 1a and 2a was carried out, and then the catalyst was removed after filtering a totally converted reaction mixture (acetophenone as a substrate). Next, 1.0 equiv. of a different ketone (2-acetylpyridine) was added as an additional substrate to the filtrate, and then the filtrate was treated with the remaining amount of 2-aminopyridine (>1.2 equiv.). Consequently, only trace amounts of another product 3u was discovered, while 66% yield of 3u was obtained, if the fresh CuCl₂/nano-TiO₂ was added to the filtrate (Scheme 3). ICP-AES was used to analyze the filtrate that was removed by CuCl₂/nano-TiO₂, which confirmed that no copper species was detected in the filtrate (Cu: below 0.001%). These results indicated that the catalysis is from the solid catalyst rather than the leached metal species, and the catalyst is unambiguously heterogeneous in nature.

Scheme 3 The test of the heterogeneous system.

After the cyclization was completed, CuCl₂/nano-TiO₂ was easily retrieved from the reaction mixture by centrifugation and filtration. The retrieved catalyst could be reused at least three times with a slight decrease in catalytic ability (Table 3).

Table 3 Recycling of the CuCl₂/nano-TiO₂ catalyst^a

Cycle	1	2	3	4
a Reaction conditions: 2-aminopyridine (0.6 mmol), acetophenone (0.5 mmol), CuCl2/nano-TiO2 (12 mg, 0.8 mol%), ethanol (0.6 mL), air, 70 °C, 24 h.
Isolated yield of 3b (%)	87	79	72	53

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With the optimized conditions in hand, we sought to define the scope of the aryl ketones using 2-aminopyridine 1a as the substrate. As shown in Table 4, electron-rich and -poor aryl ketones could undergo cyclizations with 2-aminopyridine successfully, including sensitive NO₂-substituted acetophenone. Specifically, electron-poor ketones could give the corresponding products in excellent yields, while electron-poor ketones offered relatively low yields of imidazo[1,2-a]pyridines. Moreover, steric hindrance could influence the reaction, which made ortho-substituted aryl ketones give moderate yields of the desired products (Table 4, 3d, 3j and 3p). Interestingly, the ester group and N,N-dimethyl-substituted ketones also performed smoothly (Table 4, 3m and 3q). Remarkably, cyano was tolerated in the cyclization chemoselectively and offered excellent yield of imidazo[1,2-a]pyridine rather than 1,2,4-triazole under Cu-catalyzed aerobic oxidative conditions (Table 4, 3r).²⁵ Finally, heteroaromatic ketones, such as furan, thiophene, pyridine and thiazole, were effective substrates and provided good yields respectively (Table 4, 3s–v).

Table 4 The scope of the cyclization between 2-aminopyridne and aryl-substituted acetophenones^a

a Reaction conditions: 1a (0.6 mmol), 2 (0.5 mmol), CuCl2/nano-TiO2 (0.8 mol%, 12 mg), EtOH (0.6 mL), air, 70 °C, 24 h, isolated yields.

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Next, more efforts were made to further explore the scope of the heterogeneous cyclization. In Table 5, alkenyl-substituted imidazo[1,2-a]pyridine, which was obtained with difficulty by previous methods,^16m,n was synthesized by this simple heterogeneous method using α,β-unsaturated ketone (Table 5, 4a). Furthermore, propiophenone was also a successful substrate for the reaction (Table 5, 4b). Subsequently, various substituted 2-aminopyridines were investigated and provided moderate to good yields (Table 5, 4c–h), including CF₃- and multi-substituted 2-aminopyridines. Unfortunately, nitro substituted 2-aminopyridine could not participate in the cyclization (Table 5).

Table 5 The scope of the synthesis of imidazo[1,2-a]pyridines^a

a Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), CuCl2/nano-TiO2 (12 mg, 0.8 mol%), EtOH (0.6 mL), 70 °C, 24 h, air, isolated yields.

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To demonstrate the operational simplicity and broad generality of this heterogeneous protocol, a gram-scale reaction was carried out using 2-aminopyridine and 4-methylsufonyl acetophenone under slightly modified reaction conditions (Scheme 4). The synthesis of the marketed drug zolimidine 5 was achieved on a gram-scale with 56% isolated yield under heterogeneous CuCl₂/nano-TiO₂-catalyzed ligand- and additive-free conditions.

Scheme 4 Heterogeneous one-step synthesis of zolimidine on gram scale.

Finally, some control experiments were conducted to further understand the mechanism of this heterogeneous copper-catalyzed oxidative cyclization (Scheme 5). The cyclizations were carried out under different atmospheres and results showed that the products were obtained under air or O₂, while it failed to yield the desired product efficiently under N₂, which indicated that the oxygen plays a role of an oxidant in the synthesis of imidazo[1,2-a]pyridines (Scheme 5, eqn (1)). According to the previous methods of homogeneous Cu-catalyzed synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and ketones,¹⁹ especially Su's latest work on CuI-catalysis,²⁰ it is reasonable that the reaction mechanism of the previous copper-catalysis involved a catalytic Ortoleva-King reaction^16g more probably rather than the copper-catalyzed C–H functionalization because of the use of iodine in the previous methods.^22g,26 To prove this proposal, the cyclizations were conducted directly using I₂ without any copper source (Scheme 5, eqn (2)). Interestingly, the cyclizations preformed smoothly no matter how much I₂ was used in the reaction, which means that a-iodoacetophenone rather than imine is formed firstly for further Ortoleva-King reaction and copper does not play a crucial role when the cyclization is catalyzed by CuI or Cu/ZnI systems. More importantly, when the imine formed from 2-aminopyridine and acetophenone was employed as a starting substrate, the desired product was obtained in 78% yield under a heterogeneous CuCl₂/nano-TiO₂ system. On the other hand, the reaction failed when a catalytic amount of I₂ was used as a catalyst (Scheme 5, eqn (3)). Under our optimized conditions, the absence of iodine anion rules out the possibility of the Ortoleva-King reaction in terms of mechanism.

Scheme 5 Control experiments.

Based on the observations and summary from control experiments and the works of Su and Han's group,^20,27 a plausible mechanism involving oxidative C–H functionalization is postulated in Scheme 6.¹⁹ Firstly, imine A was generated via the condensation of 2-aminopyridine and acetophenone. Then, enamine B was formed by tautomerization of imine A.²⁸ Subsequently, intermediate C was formed via oxidative addition between Cu(II) species and enamine B under the present conditions.²⁹ After reductive elimination, the desired product imidazo[1,2-a]pyridine was given along with the reduced Cu(I) species, which was oxidized by oxygen to finish the catalytic cycle.

Scheme 6 The Proposed mechanism of the reaction.

Conclusions

In summary, we have developed a heterogeneous copper-catalyzed synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and unactivated ketones in the absence of iodine anion, ligands and additives. The heterogeneous catalytic system which uses air as an efficient oxidant can tolerate a large range of substrates under mild conditions and provide desired products in good yields. Moreover, the present heterogeneous method can be applied in one-step synthesis of zalimidine on a gram scale and the heterogeneous catalyst can be recycled many times. With respect to the mechanism, the cyclization more likely undergoes a Cu-catalyzed oxidative C–H bond functionalization instead of the previously reported iodine anion catalyzed Ortoleva-King reaction under these heterogeneous conditions. Further studies to fully understand the mechanism of the reaction and the application of the CuCl₂/nano-TiO₂ in other transformations are in progress in our lab.

Experimental

General

All reagents were purchased from commercial suppliers and used without further purification. Metal salts and catalyst supports were commercially available and were directly used. All experiments were carried out under air. Flash chromatography was carried out using Merck silica gel 60 (200–300 mesh). Analytical TLC was performed using Merck silica gel 60 F254 plates, and the products were visualized by UV detection. ¹H NMR and ¹³C NMR (400 and 100 MHz respectively) spectra were recorded in CDCl₃. Chemical shifts (δ) are reported in ppm using TMS as an internal standard, and spin–spin coupling constants (J) are given in Hz.

Preparation of CuCl₂/nano-TiO₂^23b

Support nano-TiO₂ powder (1 g, anatase, particle size ≤ 30 nm, BET surface area ≥ 120 m² g⁻¹) was added to a 50 mL round-bottom flask. A solution of CuCl₂-2H₂O (0.108 g) in acetone (10 mL) was added to nano-TiO₂ powder, and additional acetone (10 mL) was added to wash down the sides of the flask. Then the flask was submerged into an ultrasound bath for 3 h at room temperature and stirred for further 20 h at room temperature. Furthermore, the acetone was distilled under reduced pressure on a rotary evaporator at 50 °C for more than 2 h. Finally, a dried pale green powder was obtained. The inductively coupled plasma optical emission spectrum (ICP-OES) showed the Cu content to be 3.16 wt%.

General procedure for CuCl₂/nano-TiO₂-catalyzed cyclization

CuCl₂/nano-TiO₂ (12 mg, 0.8 mol%), 2-aminopyridine (0.6 mmol), ketone (0.5 mmol) and EtOH (0.6 mL) were added to a flask with a bar. The flask was stirred at 70 °C for 24 h under air. After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered. The filtrate was removed under reduced pressure to get the crude product, which was further purified by silica gel chromatography (petroleum : ethyl acetate = 3 : 1 as an eluent) to yield the corresponding product. The identity and purity of the products was confirmed by ¹H and ¹³C NMR spectroscopic analysis.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra03299c

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