Cu(I)-catalyzed double C–H amination: synthesis of 2-iodo-imidazo[1,2-a]pyridines

Abstract

An iodine/CuI mediated double oxidative C–H amination reaction has been developed for the synthesis of 2-iodo-imidazo[1,2-a]pyridines. The salient features of this methodology are mild reaction conditions and high regioselectivity. The designed compounds e.g. 2-iodo-imidazo[1,2-a]pyridines (3e) may serve as active pharmaceutical ingredients (APIs) of marketed drugs like saripidem and nicopidem. Further saripidem was synthesised by using 3e as an intermediate.

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Heteroaromatic scaffolds containing bridgehead nitrogen atoms such as imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine are found in many biologically active molecules.¹ A number of imidazo[1,2-a]pyridine derived analogues have been successfully used for various biological activities such as antiviral, antibacterial and anti-inflammatory.² Top selling drugs like alpidem (as an anxiolytic agents),³ zolpidem (used in the treatment of insomnia),⁴ nicopidem & saripidem (as an anxiolytic agents),⁵ minodronic acid (used for the treatment of osteoporosis),⁶ and optically active GSK812397 drug (HIV infection)⁷ are derived from imidazo[1,2-a]pyridine scaffold (Fig. 1).

Fig. 1 Imidazo[1,2-a]pyridine derived drugs.

Therefore, synthesis of imidazo[1,2-a]pyridine derivatives remain an active area of research in organic synthesis because of above said biological importance and scaffold of marketed drug. In the recent years, various metal-catalyzed⁸ and metal free⁹ synthetic methods for synthesis of imidazo[1,2-a]pyridine have been reported, the general approach used for the synthesis of imidazo[1,2-a]pyridine is based on the intermolecular cyclization of 2-aminopyridine and other precursor such as phenylacetaldehyde, α-bromoaldehyde, bromo-ketones, iodonium salt, and bromoalkyne.^1,10,11 In addition to above halogenated hetero-aromatic scaffolds have always been a centre of attraction in medicinal chemistry because they can be easily modified by classical coupling reaction such as Suzuki,¹² Heck¹³ and Sonogashira reaction¹⁴ during structure activity relationship (SAR) study.

A careful survey of the literature revealed that the synthesis of 2-halo-substituted imidazo[1,2-a]pyrimidines has been rarely explored. Zhao's group¹⁵ designed a catalyst copper supported on manganese oxide-based octahedral molecular sieves OMS-2 (CuOx/OMS-2) for the synthesis of 3-iodoimidazo[1,2-a]pyridines from acetophenones whereas Jiang's group¹⁶ developed copper-catalyzed method for the synthesis of 2-haloimidazopyridines with aminopyridines and haloalkynes via intermolecular oxidative cyclization (Scheme 1). The substrate 1-haloalkyne used in the Jiang's method, the main disadvantage of this method is that synthesis of 1-haloalkyne requires special halogenating reagents and tedious workup processes. To overcome the drawback, we developed an efficient and simple one-pot Cu-catalyzed protocol for the synthesis of 2-iodo-imidazo[1,2-a]pyridine by using alkynes, 2-aminopyridine, and iodine in presence of O₂.

Scheme 1 Synthesis of 2/3-haloimidazo[1,2-a]pyridine.

Initially, reaction was performed between 2-aminopyridine (1a, 1 eq.) and phenylacetylene (2a, 1.5 eq.) in optimizing the reaction conditions (Table 1) by using Cu(OTf)₂ and I₂ (1 eq.) in CH₃CN at 80 °C in open air condition (Table 1, entry 1), but product formation was not observed. However, the desired 2-iodo-3-phenylimidazo[1,2-a]pyridine (3a) was observed in 50% yield (Table 1, entry 2) under O₂ atmosphere. The spectral data for 3a was found in accordance with literature.^16,17

Table 1 Optimization of the reaction condition^a

Entry	Catalyst	Solvent	Iodine source	Yield
a n.r.: no reaction.
1	Cu(OTf)2	CH3CN	I2	n.r.
2	Cu(OTf)2	CH3CN	I2	50
3	Cu(OTf)2	DMF	I2	25
4	Cu(OTf)2	Dioxane	I2	40
5	Cu(OTf)2	Toluene	I2	Trace
6	CuI	CH3CN	I2(1)	60
7	CuI	CH 3 CN	I 2 (1.5)	80
8	CuI	CH3CN	I2(2)	70
9	CuI	CH3CN	NIS	Trace
10	CuI	CH3CN	I2	Trace
11	CuI	DMSO	I2	Trace
12	CuBr	CH3CN	I2	45
13	CuBr2	CH3CN	I2	55
14	CuCl	CH3CN	I2	50
15	CuCl2	CH3CN	I2	60
16	Cu(OAc)2	CH3CN	I2	35
17	CuI	CH3CN	—	n.r.
18	—	CH3CN	I2	n.r.

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Subsequently, a number of solvents such as DMF, 1,4-dioxane, toluene were investigated but CH₃CN was found most suitable reaction medium in terms of yield (Table 1, entries 2–5). A series of other copper catalyst such as CuI, CuBr, CuBr₂, CuCl, CuCl₂ and Cu(OAc)₂ were also examined for improving the yield (Table 1, entries 6–16). The higher yield was obtained when the reaction was carried out with CuI (10 mol%) and I₂ (1.5 equiv.) in CH₃CN under O₂ atmosphere (Table 1, entry 7) at 80 °C. The yield of 3a was slightly decreased when increasing the ratio of I₂ (2.0 equiv.) (Table 1, entry 8), which may be due to oxidative behaviour of I₂.¹⁸ The other source of iodine like NIS was also examined (Table 1, entry 9), the result revealed that I₂ is better source than NIS in this reaction condition. The control experiments, were also carried out without CuI or I₂ (Table 1, entries 18 and 17) under same reaction conditions but no reaction happened in both case. To avoid unstability of iodoalkyne & minimization of homocouple formation, initially all reaction were carried out at room temperature by stirring for 10 min. There after the temperature was raised gradiently upto 80 °C. In this optimised reaction condition better results were obtained. The synthesis of 2-iodo-imidazo[1,2-a]pyridines via 1-iodoalkyne was carried out with another controlled reaction. 1-Iodoalkyne & 2-aminopyridine were reacted in which with I₂ or without I₂. In result we observed same desired product in both conditions with dimmer of terminal alkyne as expected this prove I₂ is just playing a role for synthesis of iodoalkyne and also observed homocoupled of 1-iodoalkyne in the presence of O₂ (Scheme 2).

Scheme 2 Controlled experiment.

The scope of the reaction was further explored by using various substituted 2-amino pyridines and substituted acetylenes (involving 10 mol% of CuI and 1.5 equiv. of I₂ in CH₃CN under O₂ at 80 °C). The designed 2-iodoimidazo[1,2-a]pyridines (3a–3p) were obtained in moderate to good yields (Table 2). In general, substituted phenylacetylene that contained either electron-donating or electron-withdrawing group reacted smoothly with 2-aminopyridine in 60–80% yield. The electron deficient alkynes were more favourable such as 1-ethynyl-4-fluorobenzene yielded product (3c, 70%) comparatively alkynes with electron donating group such as OMe or t-butyl yielded (3b, 65%) and (3d, 65%) respectively. Various 2-aminopyridines with different substituent's were found suitable partner for the synthesis of 2-halo-substituted-imidazo[1,2-a]pyridines. 2-Aminopyridines with methyl or halo group at different position (3- and 5- position) were successfully transformed into corresponding products in good yield (3f–3o, 60–85%). In case of 2-amino-6-methylpyridine no reaction proceed may be due to steric hindrance could play the role in the formation of desired product (3p). It was observed 2-aminopyridine with electron donating group at various position is favourable for the synthesis of 2-halo-substituted-imidazo[1,2-a]pyridines (3k–3o, 65–85%), compare to 2-amino-pyridine with halo substitution (3f–3h, 60–75%). A halo substituted imidazo[1,2-a]pyridine (3f–3j) at 2 and 6 position can open a window for further modification. Recently Chioua¹⁹ and Zhu²⁰ reported synthesis of the anxiolytic saripidem and nicopidem by imidazo[1,2-a]pyridin-3-yl-methanol. With these background, the transformation of benzyl protected propargyl alcohol under same reaction condition with substituted 2-aminopyridine, gave the corresponding compound (3e, 3h, 3m and 3o) in good yield that can be convert to active pharmaceutical ingredients (APIs) of marketed drugs like saripidem and nicopidem.

Table 2 Synthesis of 2-iodoimidazo[1,2-a]pyridines^a

a All reaction were carried out using 1a (1.0 eq.) and 2a (1.5 eq.),with CuI (10 mol%) catalyst, in CH₃CN 80 °C under O₂ atmosphere, reaction time 8–12 h.

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On the basis of controlled experimental and literature evidence,^19–21 a postulated reaction mechanism for the synthesis of 2-iodo-imidazo[1,2-a]pyridine analogue via CuI/I₂ promoted oxidative cyclization is displayed in Scheme 3. As initially reaction of substituted acetylene with CuI/I₂ gives crude adduct 1-iodoalkynes 5via Cu(I) phenylethyne 4, characterized by mass and ¹H NMR spectroscopic analysis.¹⁶ Then the triple bond of 5 is activated by the coordination with Cu(I) and react with 2-aminopyridine could initially form complex 6. Then migratory insertion of haloalkyne occurred and provide reactive Cu(III) intermediate 7 after deprotonation and oxidation.²¹ Finally the reductive elimination of 7 give desired cyclised compound 3a.

Scheme 3 Proposed mechanism.

Halogenated aromatics are known to convert into the corresponding aryl, alkenyl or alkynyl group under cross-coupling condition. To investigate the scope in coupling reaction, we further functionalized 2-iodo-imidazo[1,2-a]pyridines in some important analogues 8, 9, and 10 in excellent yields through Suzuki, Heck, and Sonogashira reaction respectively (Scheme 4).

Scheme 4 Synthetic utility of the 2-iodoimidazo[1,2-a]pyridine.

The utility of synthesised APIs, was confirmed by using 2-iodo-imidazo[1,2-a]pyridines (3e) in the synthesis of anxioltic saripidem (Scheme 5). Suzuki reaction of intermediate 3e with p-chlorophenylboronic acid gave the intermediate 11 in 90% yield. Debenzylation of 11 with BCl₃ at −78 °C afforded alcohol in good yield that was further converted in intermediate 12 by reaction of butyronitrile in the presence of H₂SO₄. Finally saripidem was obtained by methylation of 12 in the presence of NaH via reported method in excellent yield.¹⁹

Scheme 5 Total synthesis of saripidem from 3e.

In summary, we have developed an efficient one-pot process for synthesis of 2-iodo-imidazo[1,2-a]pyridine analogues via CuI/I₂ promoted oxidative cyclization of 2-aminopyridine. This procedure is general and diverse array of designed 2-iodo-imidazo[1,2-a]pyridine derivatives were synthesized with challenging substitution. Further saripidem was synthesised successfully by using the key intermediate 3e obtained through our develop method. This prove that important heterocycles can be used as advanced intermediate for marketed drugs like nicopidem and saripidem.

Acknowledgements

D. D.; K. R. R. And S. K. R thank to CSIR and ICMR, New Delhi, India for their research fellowship, respectively. This research work was financially supported by CSIR-New Delhi (BSC 0108) IIIM communication no. IIIM/1814/2015.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra02953a

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