A copper-catalyzed multi-component reaction accessing fused imidazo-heterocycles via C–H functionalization

Abstract

An efficient synthesis of fused imidazo-heterocycles is described using Cu(OTf)₂ in [bmim]BF₄ by the multi-component reaction of pyridin-2(1H)-one or thiazol/benzo[d]thiazol-2(3H)-ones with O-tosylhydroxyl amine and acetophenones under microwave irradiation. The present method is very rapid and the product formation occurs via a C–H functionalization/tandem addition-cyclization process. The ionic liquid containing copper triflate is recovered and reused four times.

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Transition-metal-catalyzed direct functionalization of C–H bonds towards the C–N bond formation is of great interest and application of these strategies to build azaheterocycles has attracted intensive attention. In particular, the synthesis of fused imidazo-heterocycles (IHs) have received considerable attention because of their diverse biological and pharmaceutical activities¹ such as antiviral, antitumor, antimicrobial, herbicidal, antiulcer agents and immunosuppressive agents. It has wide application as selective cyclin-dependent kinase inhibitors,² calcium channel blockers,³ b-amyloid formation inhibitors,⁴ benzodiazepine receptor agonists⁵ and liver X receptor agonists.⁶ Some of the drug⁷ molecule like zolpidem (1), alpidem (2) and zolimidine (3) also contain imidazo[1,2-a]pyridine (IP) moieties. In addition to this 2-arylimidazo[2,1-b][1,3]benzothiazole derivative (YM-201627) (4) was found to be a potent and orally active antitumor agent and useful for treatment of solid tumors,⁸ in particular, ¹¹C-labeled imidazo[2,1-b]benzothiazole⁹ (5) has been shown to be a superb fluoroprobe in PET analysis of Alzheimer's disease. Several synthetic protocols exist in the literature for the construction of IPs and its derivatives (Scheme 1). The condensation between 2-aminopyridines and per-functionalized carbonyl compounds under various conditions was the most convenient method for the synthesis of IPs (Scheme 1, Route A).¹⁰ Subsequently other alternative methods also reported which includes silver-catalyzed oxidative coupling/cyclization of 2-aminopyridines with terminal alkynes (Scheme 1, Route B),¹¹ and Fe-catalyzed method using 2-aminopyridines and nitroolefins to obtain IPs (Scheme 1, Route C).¹² Another method involves Cu-catalyzed oxidative coupling of 2-aminopyridines and unactivated methyl ketones in the presence of ligands or additives were reported (Scheme 1, Route D).¹³ In addition to this several homogeneous Cu-catalyzed methods using pyridines with N-(alkylidene)-4H-1,2,4-triazol-4-amines (Scheme 1, Route E),¹⁴ acetophenone oxime acetates (Scheme 1, Route F),¹⁵ and vinyl azides (Scheme 1, Route G)¹⁶ were accomplished to give IPs. Though the reported methods are satisfactory for the synthesis of these compounds, it encounter some drawbacks like high catalyst loading, harsh reaction conditions, long reaction times and low yield of the products and limited applications. Therefore, there is a scope to develop a general, efficient and high yield method by addressing the shortcomings of reported methods to afford IH derivatives (Fig. 1).

Scheme 1 Various methods for accessing imidazo[1,2-a]pyridines.

Fig. 1 Imidazo-heterocycle-containing drugs.

In recent years technology plays major role in synthetic organic chemistry, one such technology involves microwave heating. Operational simplicity, high yields, purity of products, and enhanced reaction rates are the important features of microwave.¹⁷ On the other hand ionic liquids are a peculiar class of reaction media with the potential to improvement in organic chemistry.¹⁸ They are environmentally benign and are recyclable. In many reactions they are known to accelerate the rate of reaction. Among the ionic liquids, the more intensively investigated are 1,3-dialkylimidazolium salts. They are stable to air water and are compatible with various organic compounds. In the synthesis of IP derivatives, 2-aminopyridines are usually employed as starting materials. As 2-aminopyridines are derived from pyridin-2(1H)-ones,¹⁹ the direct use of pyridin-2(1H)-ones to build desired IP would be of great advantage. To the best of our knowledge there is no report for the synthesis of IHs using pyridin-2(1H)-one/benzo[d]thiazol-2(3H)-ones.

In continuation of our research in the area of C–H activation under microwave,^20a–d and ionic liquid assisted reactions,^20e–h herein we wish to disclosed a novel and an efficient protocol for the synthesis of functionalized fused imidazo-heterocycles in presence of Cu(OTf)₂ in [bmim]BF₄ by the multi-component reaction of pyridin-2(1H)-one/benzo[d]thiazol-2(3H)-ones, acetophenones and O-tosylhydroxylamine under microwave conditions in good to high yields (Scheme 2). In this protocol, we synthesized different fused imidazo-heterocycles via C–H functionalization followed by addition and cyclization process.

Scheme 2 Cu(II) catalyzed C–H functionalization.

Results and discussions

We have selected pyridin-2(1H)-one 1a, simple acetophenone 2a, and O-tosylhydroxylamine 3 as starting materials for the optimization of reaction. Initially the reaction of pyridin-2(1H)-one 1a (1 mmol) with simple acetophenone 2a (1 mmol) and O-tosylhydroxylamine (2 mmol) in presence of 10 mo1% Cu(OTf)₂ at 70 °C under microwave irradiation for 5 min gave 2-phenylimidazo[1,2-a]pyridine 4a in 10% yield (Table 1, entry 1). The structure of obtained product was confirmed by means of ¹H NMR, ¹³C NMR, IR and mass spectrometry analysis. We presumed that the formation of fused IHs occurred may be via C–H functionalization followed by two C–N bond formations. As the ionic liquids are known to accelerated the rate of reaction, the same reaction was performed in ionic liquid (1-butyl-3-methyl imidazolium tetrafluoroborate [bmim]BF₄) under MW in 5 min. We were pleased to observe the remarkable improvement in the yield of desired product (45%) (Table 1, entry 2). During experiment it was noticed that increase in the MW irradiation time 10 min. gave more yield of the product (52%) (Table 1, entry 3). Later to improve the yield, the reaction was carried out at different temperatures. It was noticed that there was a gradual increase in the yield (62%), when the temperature raised from 70 °C to 110 °C (Table 1, entry 5). Further increase in the temperature (120 °C) did not improve the yield (Table 1, entry 6). Next we examined the effect of the catalyst by performing the reaction with different ratio (15 mol% and 20 mol%) of catalyst. After screening, 20 mol% of catalyst was found suitable for maximum conversion (85%) (Table 1, entry 8). The same reaction in presence of other copper salts CuBr₂, CuCl and CuI gave different degree of conversion (Table 1, entries 9–11).

Table 1 Optimization of the reaction conditions for the synthesis of 2-phenylimidazo[1,2-a]pyridine^a

Entry	Catalyst (mol%)	Ionic liquid	Temp (°C)	Time (min) microwave	Yield^b
a Reaction conditions pyridin-2(1H)-one 1a (1 mmol), acetophenone 2a (1 mmol), O-tosylhydroxylamine 3 (2 mmol), catalyst, and ionic liquid (2 mL) in microwave vial (10 mL) sealed and placed in MW reactor.b Isolated yield.
1	Cu(OTf)2 (10)	—	70	5	10
2	Cu(OTf)2 (10)	[bmim]BF4	70	5	45
3	Cu(OTf)2 (10)	[bmim]BF4	70	10	52
4	Cu(OTf)2 (10)	[bmim]BF4	100	10	57
5	Cu(OTf)2 (10)	[bmim]BF4	110	10	62
6	Cu(OTf)2 (10)	[bmim]BF4	120	10	60
7	Cu(OTf)2 (15)	[bmim]BF4	110	10	70
8	Cu(OTf)2 (20)	[bmim]BF4	110	10	85
9	CuBr2 (20)	[bmim]BF4	110	10	35
10	CuCl (20)	[bmim]BF4	110	10	40
11	CuI (20)	[bmim]BF4	110	10	50
12	Cu(OTf)2 (20)	[bmim]PF6	110	10	42
13	Cu(OTf)2 (20)	[Hbim]BF4	110	10	40
14	Cu(OTf)2 (20)	[emim]BF4	110	10	40

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Later we tested the same reaction in various ionic liquids such as 1-n-butylimidazolium tetrafluoroborate [Hbim]BF₄, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim]PF₆, and 1-ethyl-3-methylimidazolium tetrafluoroborate [emim]BF₄ and found that there is no improvement as compared to [bmim]BF₄ (Table 1, entry 12–14). From this study, the optimum conditions described for the present protocol was 20 mol% Cu(OTf)₂ as the catalyst in [bmim]BF₄ ionic liquid under MW irradiation at 110 °C temperature in 10 min. The same reaction requires 3 h for completion in pre-heated (110 °C) conventional oil bath. This observation indicated that the effect is from not thermal but it is because of MW.

To make the present protocol general, various substituted pyridin-2(1H)-ones 1 and acetophenones 2 were examined under optimized conditions. The results are summarized in Scheme 3. A wide variety of acetophenones participated well in this conversion to afford corresponding imidazo[1,2-a]pyridines (4) in good to high yields. The electronic effects of substituted acetophenones studied in detail, and found that substituents on the acetophenones have influence on rate of reaction. In general, acetophenones bearing electron-withdrawing groups reacted faster and furnished high yields of the products (Scheme 3, 4b, 4c, 4d, 4f, 4g, 4k, 4l, 4m, 4p, and 4s) whereas acetophenones bearing electron-donating groups reacted slowly and gave comparatively less yields of the products (Scheme 3, 4h, 4i, 4n, 4o and 4r). It may be presumed that electron-donating substrates were unfavorable for the nucleophilic addition step proposed in Scheme 3. It is worthy to mention that 4-methyl pyridin-2(1H)-one (1b) and 5-methyl pyridin-2(1H)-one (1c) underwent reaction with simple acetophenone (2a) and O-tosylhydroxylamine (3) in same reaction conditions to furnish corresponding products in high yields (Scheme 3, 4e and 4j).

Scheme 3 Scope of pyridin-2(1H)-ones and acetophenones^a.

Encouraged by the results obtained from the reactions of acetophenone derivatives with pyridin-2(1H)-ones, we extended our efforts to study the reaction of acetophenone derivatives with thiazol/benzo[d]thiazol-2(3H)-ones under similar reaction condition. Likewise, the electronic effects of acetophenones studied, acetophenones bearing electron-withdrawing groups reacted faster and gave the products in excellent yields (Scheme 4, 6d, 6e, 6g, 6h, 6i and 6j) whereas acetophenones bearing electron-donating groups reacted slowly gave comparatively less yields of the products (Scheme 4, 6b, 6c, 6k and 6l). In this method the reactions proceeded smoothly to form three C–N bonds and therefore it should provide a novel and efficient strategy for the synthesis of nitrogen containing heterocycles.

Scheme 4 Scope of thiazol/benzo[d]thiazol-2(3H)-ones and acetophenones^a.

A putative mechanism for this Cu(OTf)₂ catalyzed, microwave promoted synthesis of imidazo[1,2-a]pyridines 4 by the reaction of pyridin-2(1H)-one, acetophenone, and O-tosylhydroxylamine is outlined in Scheme 5. Initially the reaction of simple acetophenone 2a and O-tosylhydroxylamine 3 gave acetophenone oxime tosylate A. Then the isomerization of A provided enamine B, coordination of the copper catalyst (Cu(OTf)₂) to B furnished complex D via C–H functionalization, at the same time the in situ generated pyridin-2(1H)-ylidene oxonium ion C from pyridin-2(1H)-one 1a attacked the inter mediate D to produce the species E with the elimination of TsOH. And intramolecular cycloaddition of E yields F with the regeneration of the catalyst Cu(OTf)₂. Finally, the isomerization of E by the elimination of water lead to the formation of the desired imidazo[1,2-a]pyridines 4.

Scheme 5 Plausible mechanistic pathway for the formation of substituted imidazo[1,2-a]pyridines.

The recovery and recyclability parameter of ionic liquid containing copper catalyst was applied for four model products, such as 4e, 4o,6c, and 6g. After completion of the reaction in ionic liquid [bmim]BF₄ containing with copper triflate the reaction mixture was extracted with ether (3 × 15 mL), activated at 80 °C under reduced pressure and then subjected to the next run with the same substrates and the same reaction time. We reused Cu(OTf)₂/[bmim]BF₄ up to four cycles and did not notice any substantial loss in the catalytic activity of Cu(OTf)₂/[bmim]BF₄. These results are summarized in Fig. 2. We believe that the present protocol is favouring the formation of only one desired product. The ease of recovery and reuse of this reaction media may contribute to the development of green strategy for the preparation of fused IHs.

Fig. 2 Reusability data for Cu(OTf)₂/[bmim]BF₄.

Conclusion

In summary, we have developed a novel multi-component reaction for the synthesis of IH derivatives using Cu(OTf)₂/[bmim]BF₄ through C–H functionalization under microwave irradiation. The reaction is very rapid, simple and convenient. This novel method involves the formation of three new C–N bonds in a cascade pathway. The present reaction provides an excellent alternative over earlier methods in terms of high yields, operational simplicity and mild conditions. Moreover, the recovery and reusability of ionic liquid containing catalyst makes the procedure environmental friendly.

Acknowledgements

The authors G. S. K. and A. S. K. thank CSIR for the award of a fellowship and S. P. R. thank to Dr A. Kamal, Outstanding scientist and Head of the MCP Division, for his support and encouragement. The authors also thank CSIR, New Delhi for financial support as part of XII Five Year plan programme under title ACT (CSC-0301).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra09025c

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