Highly regioselective C–H bond functionalization: palladium-catalyzed arylation of substituted imidazo[1,2-a]pyridine with aryl chlorides

Abstract

We have developed an efficient Pd-catalyzed regioselective arylation of substituted imidazo[1,2-a]pyridines with aryl chlorides, which is rarely reported. This methodology has been successfully applied to the synthesis of a variety of substituted imidazo[1,2-a]pyridine core π systems which exhibit a wide range of biological activities in many drugs.

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Bicyclic heteroarenes are one of the most important classes of organic compounds because of the abundance of the bicyclic heterocycle structural motif in natural products, and many pharmaceutically relevant and biologically active compounds.¹ Thus, the development of efficient transition metal-catalyzed cross-coupling reactions to construct bicyclic heteroarenes is one of the current concerns in chemical transformations that drives increasing interest.²

Organic chemists have sought to develop new and more efficient aryl–aryl bond-forming methods during the past decade and significant advances to this field have been successfully supplanted by transition-metal-catalyzed direct C–H activation/functionalization.³ Among the metal catalysts, the palladium-,⁴ copper-,⁵ rhodium-,⁶ ruthenium-,⁷ nickel-catalyzed⁸ C–H bond functionalization of heterocycles are the most important and efficient methods to form complex bicyclic heterocycles molecules. However, aryl bromides or iodides were used as substrates in most of these arylations, and there have only been rare examples for the arylation using less expensive aryl chlorides. Recently, elegant arylations of aryl chlorides as a substrate were reported in such reactions using palladium in the presence of a phosphine ligand with good yields.⁹ Thus, we hope to develop a convenient arylation reaction of substituted imidazo[1,2-a]pyridine with aryl chlorides via Pd-catalyzed highly regioselective C–H bond functionalization.

The imidazo[1,2-a]pyridine moiety is present in a large number of heterocyclic compounds¹⁰ and has been found as a key structural unit in many important pharmaceuticals such as zolpidem (hypnotic), alpidem (anxiolytic), and zolimidine (antiulcer).¹¹ Due to their wide range of biological activities,¹² it is still essential to design and develop new methods for the synthesis of these biological compounds. Herein our interest is to develop a highly regioselective direct arylation of the imidazo[1,2-a]pyridine moiety, which is rarely reported.

At the outset of our studies, we focused on identifying the catalytic system and reaction conditions for C–H arylation of 2-methylimidazo[1,2-a]pyridine (1a) with chlorobenzene (2a) and the results were summarized in Table 1. A variety of palladium catalysts in conjunction with different ligands, bases, solvents and temperatures were screened. As shown in Table 1, we were pleased to find that treatment of 1a with 2a in the presence of 2.5 mol% of Pd(OAc)₂ and 10 mol% PPh₃, gave the corresponding product 3aa in 25% yield (Table 1, entry 1). Other palladium catalysts, such as PdCl₂, Pd(dba)₂, were also tested, and none showed better activities than Pd(OAc)₂ (entries 2–3). Next, we investigated the effects of ligands. Although some literatures have reported that ligand-free Pd(OAc)₂ is found to efficiently catalyze C–H activation/arylation, it is not true for this reaction (entry 4). When the reaction was carried out in absence of ligand, only a trace amount of arylation product 3aa was detected by GC-MS. Interestingly, among the ligands examined, such as PBu₃, BuAd₂P, PCy₃ and 1,10-phenanthroline (phen), BuAd₂P was the best, giving 3aa in 76% yield (entries 5–8). Subsequently, different bases were also employed and the results indicated that Cs₂CO₃ was found to be a superior base compared with K₂CO₃, K₃PO₄, t-BuOK (entries 9–11). In addition, solvent effects were also investigated in the following tests (entries 13–15). It was found that the rate of the arylation reaction was significantly improved and the best yields were obtained in NMP (entry 14). When toluene and DMA were employed, the product 3aa was also obtained in moderate to good yields. Furthermore, the temperature also affected the rate of the reaction. It was indicated that 120 °C was the best condition for this arylation. Therefore, the optimal reaction conditions involved in using Pd(OAc)₂ as the catalyst are: BuAd₂P as the ligand, NMP as the solvent at 120 °C for 24 h.

Table 1 Condition screening for the palladium-catalyzed direct arylation reaction of 1a with 2a^a

Entry	Catalyst	Ligand	Base	Solvent	T (°C)	Yield (%)^b
a Reaction conditions:1 (0.5 mmol), aryl chlorides (0.7 mmol), Pd-catalyst (2.5 mol%), base (1.5 mmol), ligands (10 mol%), solvent (2 mL), rt–140 °C, 24 h. b GC yields.
1	Pd(OAc)2	PPh3	K2CO3	DMF	100	25
2	PdCl2	PPh3	K2CO3	DMF	100	24
3	Pd(dba)2	PPh3	K2CO3	DMF	100	29
4	Pd(OAc)2	—	K2CO3	DMF	100	trace
5	Pd(OAc)2	PBu3	K2CO3	DMF	100	30
6	Pd(OAc)2	BuAd2P	K2CO3	DMF	100	76
7	Pd(OAc)2	PCy3	K2CO3	DMF	100	53
8	Pd(OAc)2	Phen	K2CO3	DMF	100	8
9	Pd(OAc)2	BuAd2P	Cs2CO3	DMF	100	78
10	Pd(OAc)2	BuAd2P	K3PO4	DMF	100	41
11	Pd(OAc)2	BuAd2P	t-BuOK	DMF	100	32
12	Pd(OAc)2	BuAd2P	CsOAc	DMF	100	75
13	Pd(OAc)2	BuAd2P	Cs2CO3	Toluene	100	64
14	Pd(OAc)2	BuAd2P	Cs2CO3	NMP	100	82
15	Pd(OAc)2	BuAd2P	Cs2CO3	DMA	100	80
16	Pd(OAc)2	BuAd2P	Cs2CO3	NMP	120	88
17	Pd(OAc)2	BuAd2P	Cs2CO3	NMP	140	85
18	Pd(OAc)2	BuAd2P	Cs2CO3	NMP	80	56
19	Pd(OAc)2	BuAd2P	Cs2CO3	NMP	rt	—

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Under optimized reaction conditions, the scope with respect to substituted imidazo[1,2-a]pyridine 1 and aryl chlorides 2 was investigated and the results were presented in Table 2. As shown in Table 2, the optimized reaction conditions could be applied to a wide variety of substrates. As expected, a series of functional groups on the phenyl ring of aryl chlorides, such as CH₃, C₂H₅, F, Cl, CN and C(CH₃)₃, were compatible under this transformation, and the corresponding products 3aa–3al were isolated in moderate to good yields. However, the corresponding products (3am, 3an, 3ao) were not detected when aryl chlorides with strong electron-withdrawing and electron-rich groups were used in the reactions, such as 2-chlorothiophene, 1-chloro-4-nitrobenzene and 1-chloro-4-methoxybenzene. From the results in Table 2, it was clearly indicated that this protocol was general and applicable for the arylation of electron-rich and electron-withdrawing groups on the phenyl of aryl chlorides. Meanwhile, functional groups including electron-rich and electron-withdrawing groups in para and meta positions to the chloride were also well tolerated in arylation reactions. Notably, the sterically hindered aryl chloride also proceeded smoothly, giving the desired arylation products 3af, 3ai in 72% and 83% yields respectively. Unfortunately, the corresponding products were not detected, when the reaction carried was out in optimal conditions and 1-chloro-4-nitrobenzene was used as substrate. After a broad scope of electrophiles was established, we were particularly interested in the effect of the group at the imidazo[1,2-a]pyridine for the arylation process. Substituted imidazo[1,2-a]pyridines, such as 6-chloro-2-methylimidazo[1,2-a]pyridine (1b), 2-(trifluoromethyl)imidazo [1,2-a]pyridine (1c), ethyl 5-methylimidazo[1,2-a]pyridine-2-carboxylate (1d), were also employed and coupled with aryl chlorides to afford the corresponding arylation products in good yield. It was worth noting that the electron-withdrawing groups, such as CF₃, CO₂Et, at the C-2 of imidazo[1,2-a]pyridine also well worked in the transformation.

Table 2 Palladium-catalyzed direct arylation of substituted imidazo[1,2-a]pyridine with aryl chlorides ^a

a Reaction conditions: 1 (0.5 mmol), 2 (0.7 mmol), Pd(OAc)2 (2.5 mol%), Cs2CO3 (1.5 mmol), NMP (2 mL), 120 °C, 24 h. b Isolated yields. c No desired products.

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In an endeavour to expand the scope of the methodology, this catalytic system was applied to 2-phenylimidazo[1,2-a]pyridine. To our delight, 2-phenylimidazo[1,2-a]pyridine 1e and aryl chlorides exclusively afforded the corresponding products in moderate to excellent yields (80–85%) via regioselective C–H bond functionalization under the optimized reaction conditions. Significant steric and electronic effects of the substituents on the reactivity were observed. The results revealed that an electron-withdrawing (3ec, 3ed) and electron-rich group (3ea, 3eh, 3ei, 3em) in the aryl chlorides favored the coupling reactions. It also indicated that steric hindrance (3ei) in the aryl chlorides had no influence on the arylation reaction. This process represented the general method for C-3 regioselective arylation of 2-phenylimidazo[1,2-a]pyridine to form a variety of functionalized 2-phenylimidazo[1,2-a]pyridine core π systems. The highly regioselective results observed in Table 2 are possibly because the Ph– at the 2-postition is beneficial to make intermediate B (Scheme 1) stable.

Scheme 1 Possible mechanism.

A plausible mechanism of the direct arylation is described in Scheme 1. An analogous mechanism has been proposed by Miura,¹³ Daugulis^9a and Gevorgyan¹⁴ for the arylation of heterocycles with aryl halides. We believe that it involves an electrophilic attack by intermediate A on 1 to generate the intermediate B. The deprotonation of intermediate B with Cs₂CO₃ has been taken place to give intermediate C, which then undergoes reductive elimination to form the corresponding arylation products and release the Pd catalyst.

In summary, a facile and robust method has been developed for the regioselective arylation at the C-3 position of substituted imidazo[1,2-a]pyridine with aryl chlorides by Pd(II)-catalysis. This protocol easily forms a π-conjugated imidazo[1,2-a]pyridine derivative which is a useful structural motif in both academic and industrial research. Further studies for the construction of other heterocyclic ring systems as well as development of novel drug templates using this method are underway.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2ra20366a

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