Palladium(II)-catalyzed intermolecular oxidative C-3 alkenylations of imidazo[1,2-a]pyridines by substrate-contolled regioselective C–H functionalization

Abstract

An efficient and highly regioselective palladium(II)-catalyzed oxidative C-3 alkenylation of imidazo[1,2-a]pyridines with acrylate, acrylonitrile, or vinylarenes has been developed by using oxygen as an oxidant. Substrates such as acrylate and acrylonitrile tended to form β-product, while vinylarenes tended to form the sole α-products.

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The metal-catalyzed Heck reaction which received the Nobel Prize in 2010 has become one of the most widely used methods in chemical synthesis.¹ This approach offers the possibility for catalytic transformation of unactivated C–H bonds into diverse functionalities. Currently, direct oxidative alkenylation of heterocycles has already achieved widespread acceptance within the organic synthetic fields, because of its capacity to utilize simpler and cheaper precursors for the preparation of functionalized molecules. Consequently, the discovery of efficient methods for the assembly of carbon–carbon bonds has attracted attention in this field, which avoided synthesis of complex and expensive starting substrates. Since the pioneering Fujiwara and co-workers² have first described a wealth of palladium- and rhodium-catalyzed oxidative alkenylations. Many elegant direct oxidative alkenylations³ have been achieved without the need for prior halogenation or metallization in this field. Despite of several methods have been reported during the last decades, there is still an intrinsic need for open new routes to synthesize of diverse heterocycles molecules.

Imidazo[1,2-a]pyridines are extremely important chemicals that exhibit a wide range of biological activities⁴ and are used as antiviral,⁵ antiulcer,⁶ antibacterial,⁷ antifungal,⁸ antiprotozoal,⁹ antiherpes,¹⁰ anti-inflammatory.¹¹ Since the wide application of imidazo[1,2-a]pyridines in pharmaceutical research and drugs including Alpidem, Zolpidem, Necopidem, Olprinone, Divalpon and Zolimidine are available in the market, the development of efficient methods to synthesize imidazo[1,2-a]pyridines has continuously attracted the attentions of many chemists.¹² We have recently developed facile C–H transformation for the preparation of imidazo[1,2-a]pyridine¹³ and other heterocyclic compounds. In this context, our attention is focused on the development alkenylations of imidazo[1,2-a]pyridine to prepare imidazo[1,2-a]pyridine derivatives (Scheme 1). Moreover, the reaction has proceeded by using molecular oxygen as terminal oxidant, which avoided the environmentally hazardous by-products obtained with other oxidants.¹⁴

Scheme 1 Alkenylations of imidazo[1,2-a]pyridines.

The initial screening studies have been carried out using 1a and 2a as model substrate to identify and optimize many different combinations of potential catalysts, oxidants, additives, and solvents in order to improve the yields of the reaction. The results are summarized in Table 1. First, treatment of 1a with 2a in the presence of PdCl₂, Cu(OAc)₂ and AcOH at 120 °C in dioxane, a trace of the desired directly alkenylation product 3a was observed (entry 1). Other Pd-catalyst was also tested (entries 2–5), including Pd(O₂CCF₃)₂, Pd(CH₃CN)Cl₂, Pd(dba)₂, Pd(OAc)₂. Interestingly, the use of Pd(OAc)₂ afforded the corresponding products 3a in 9% GC yield, while other palladium sources gave poor yields. On changing the oxidants we observed a significant improvement by using Ag₂CO₃ as oxidant in the reaction and the product 3a was obtained in 32% GC yield (entry 6). Other silver salts, such as AgOAc or AgOTf, were also employed and the desired product was obtained in 21%, 20% yields respectively (Table 1, entries 7 and 8). Other oxidants, such as BQ, DDQ, tBuOOBz, O₂ and air were also tested (entries 9–13). The results showed that O₂ was a choice for this transformation. To our delight, the good yield was obtained, when the reaction was carried out by using Ag₂CO₃ (5 mol%) and O₂ (with oxygen ballon) as co-oxidant (entry 14) in the presence of Pd(OAc)₂. These results encouraged us to adjust additives to improve the yield (entries 15–18). We were pleased to find that the yield of 3a could be observed in 81% by using AcOH and Ac₂O as additives (entry 16). Effects of solvents and temperatures were also investigated in the following tests (entries 19–22). Among them, dioxane was demonstrated to be the best choice. Nonetheless, the yield could not be improved with the increasing reaction time to 30 h (entry 23). But decreasing the time to 12 h did affect the reaction efficiency and the low yields of 3a were obtained (entry 24).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Oxidant	Additive	Solvent	t (h)	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), catalyst (5% mol), oxidant (1.2 mmol), additive (0.5 mmol), solvent (3.0 mL).b GC yields.c 5 mol% Ag2CO3, O2 (500 mL).
1	PdCl2	Cu(OAc)2	AcOH	Dioxane	24	trace
2	Pd(O2CCF3)2	Cu(OAc)2	AcOH	Dioxane	24	5
3	Pd(CH3CN)Cl2	Cu(OAc)2	AcOH	Dioxane	24	trace
4	Pd(dba)2	Cu(OAc)2	AcOH	Dioxane	24	trace
5	Pd(OAc)2	Cu(OAc)2	AcOH	Dioxane	24	9
6	Pd(OAc)2	AgOAc	AcOH	Dioxane	24	32
7	Pd(OAc)2	Ag2CO3	AcOH	Dioxane	24	21
8	Pd(OAc)2	AgOTf	AcOH	Dioxane	24	20
9	Pd(OAc)2	BQ	AcOH	Dioxane	24	NR
10	Pd(OAc)2	DDQ	AcOH	Dioxane	24	NR
11	Pd(OAc)2	tBuOOBz	AcOH	Dioxane	24	NR
12	Pd(OAc)2	O2 (1 atm)	AcOH	Dioxane	24	27
13	Pd(OAc)2	Air (1 atm)	AcOH	Dioxane	24	5<
14^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH	Dioxane	24	69
15^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	PhCO2H	Dioxane	24	12
16^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	Dioxane	24	81
17^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	Py	Dioxane	24	40
18^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	K2CO3	Dioxane	24	12
19^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	Toluene	24	46
20^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	DMA	24	60
21^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	DMSO	24	13
22^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	DMF	24	19
23^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	Dioxane	30	77
24^c	Pd(OAc)2	O2 (1 atm)/Ag2CO3	AcOH/Ac2O	Dioxane	12	62

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With the optimized conditions in hand, we next investigated the scope of this novel highly regioselective alkenylation of imidazo[1,2-a]pyridines with styrene for synthesis of α-products. And the results are described in Table 2. A variety of imidazo[1,2-a]pyridines with electrondonating methyl groups at the 2-, 6-, 7-, and 8-positions were smoothly alkenylated at the 3-position with styrene in good yields (Table 2). Thus, we turned our attention to examine the scope of vinylarenes. Various substituted styrene was reacted well with 1 and led to the desired α-products 4a–4r in good yields. The presence of electron-withdrawing groups, such as F and Cl, were tolerated in the reaction and afforded the desired products smoothly.

Table 2 Alkenylations of imidazo[1,2-a]pyridines with styrenes^a

a Isolated yields.

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Subsequently, a variety of acrylates were examined. The desired α-product was not formed, while only β-products obtained under the optimized conditions. The results are described in Table 3. A variety of acrylates were examined. It was observed that alteration of an alkoxy part of acrylate did not change the reaction efficiency, and a similar level of product yields was obtained in the alkenylation of butyl, methyl, ethyl, and cyclohexyl acrylate. The scope of various types of imidazo[1,2-a]pyridine substrates was also extensively surveyed. The imidazo[1,2-a]pyridine and its derivatives with electrondonating methyl groups at the 2-, 6-, 7-, and 8-positions were smoothly alkenylated at the 3-position with acrylate in good yields. The substrate ethyl imidazo[1,2-a]pyridine-2-carboxylate with electronwithdrawing CO₂Et group at 2-positions also performed very well and afforded the desired product 4j in good yield. Notably, high regioselectivity was observed, when the reactions were carried out by using 2,3-dihydro-imidazo[1,2-a]pyridines with acrylate. All the results indicated that this process is highly regioselective for C-3 alkenylation.

Table 3 Alkenylations of imidazo[1,2-a]pyridines with acrylates^a

a Isolated yields.

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On the basis of the previous report and our results at this stage, we have proposed two plausible pathways for the two oxidative coupling reactions in Scheme 2. Path I:^2,15 palladation at C-3 of imidazo[1,2-a]pyridine (electrophilic substitution) was thought to occur intermediate A with the aid of oxidant. Active intermediate A then inserts into the methyl acrylate to give intermediate B, which rapidly decomposes through β-elimination to generate the desired product and Pd catalyst (regular Heck-reaction product); Path II:^1b,3l,16 palladium(II) salts tend to react with styrene to give the intermediate C, which then can undergo an intermolecular nucleophilic attack of 1a (usually at the more substituted vinylic carbon) to generate intermediate D. The corresponding product is formed via β-hydride elimination from intermediate D and releases the Pd catalyst.

Scheme 2 Proposed mechanism.

In summary, we have developed an efficient method for the selective intermolecular alkenylation of substituted imidazo[1,2-a]pyridines with diverse acrylate, acrylonitrile, and styrenes through a palladium-catalyzed C–H functionalization reaction. It represents a novel, regio- and stereoselective oxidative alkenylation process. This transformation using molecular oxygen to avoid excessive silver levels also results in a clean and rather waste-free process.

Acknowledgements

This research was financially supported by National Natural Science Foundation of China (21302023) and the Project of Department of Education of Guangdong Province (2013kjcx0111).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra09669j

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