Catalyst-free Friedel–Crafts hydroxyalkylation of imidazo[1,2-α]pyridines with ethyl trifluoropyruvate

Abstract

A catalyst free Friedel–Crafts (F–C) hydroxyalkylation of imidazo[1,2-α]pyridines with ethyl trifluoropyruvate is herein described using isopropyl ether as a solvent. Electron-donating and electron-withdrawing functional groups at various aromatic positions were well tolerated under our optimized conditions. The method enabled the generation of desired products in moderate to excellent yields under mild conditions, which makes this transformation an attractive, environmentally benign alternative for the synthesis of the target compounds.

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Imidazo[1,2-α]pyridine and its derivatives have attracted much attention recently owing to their biological activities¹ such as antiviral,² anti-inflammatory,³ anti-tuberculosis,⁴ antiulcer,⁵ and antibacterial⁶ properties. Remarkable developments have been made on the synthesis of imidazo[1,2-α]pyridine derivatives,⁷ making a wide range of drugs, including alpidem, olprinone, minodronic acid, zolimidine, necopidem, saripidem and zolpidem, more commercially available (Fig. 1).

Fig. 1 Examples of drugs containing the imidazo[1,2-α]pyridine system.

Fluorinated molecules have the ability to modulate biological functions.⁸ The introduction of trifluoromethyl group into drug molecules can bring alteration of their metabolic stability, and bioavailability.⁹ To the best of our knowledge, only a few natural compounds contain fluorine atoms. Despite fluorine atom containing natural products have been reported, compounds with trifluoromethyl group (CF₃) were less investigated. In this regard, state-of-the-art researches have been dedicated to the development of efficient synthesis of CF₃ containing drugs.¹⁰ Using trifluoropyruvates as building block is an appealing route for the trifluoromethylation because no prefunctionalization is required.¹¹ For examples, Mikami and co-workers reported a catalytic [2 + 2] cycloaddition of alkyne and trifluoropyruvate for the synthesis of stable oxetenes.¹² Li et al. showed a general and efficient method for the direct alkynylation of trifluoropyruvate and trifluoroacetophenone, which is simple and provides diverse CF₃-substituted tertiary propargyl alcohols in high yields.¹³ F–C alkylation of the aromatic and heterocyclic compounds is one of the most important C–C bond-formation reactions.¹⁴ However, the use of Lewis and Brønsted acids generates a large amounts of environmentally toxic waste. To overcome this limitation, catalyst-free F–C hydroxyalkylation reaction has emerged as an alternative strategy with atom economy and environmental benignity. Török and coworkers firstly reported the catalyst-free hydroxyalkylation of indoles with ethyl trifluoropyruvate.¹⁵ Following previous work, the Shibata group introduced environmentally benign solvent Solkane@365mfc as a medium for the F–C reaction.¹⁶ Despite the success of previous work, the development of catalyst-free F–C hydroxyalkylation reaction with improved efficiency is still a long-standing scientific challenge. Herein, we firstly report the high efficiency of catalyst-free F–C hydroxyalkylation of imidazo[1,2-α]pyridines with ethyl trifluoropyruvate in isopropyl ether.

In order to screen the optimized conditions, the F–C hydroxyalkyltion of 2-phenylimidazo[1,2-α]pyridine (1a) with ethyl trifluoropyruvate (2a) was selected as the model reaction under standard condition (Table 1). The desired product 3aa was isolated in 27% yield at room temperature in dichloromethane (DCM) under Ar for 24 h, and the ratio of 1a/2a is 1.0/2.0 (Table 1, entry 1). Further optimization showed that 3aa could be obtained in moderate to excellent yields when the solvents 1,2-dichloroethane (DCE), diethyl ether (Et₂O), toluene and isopropyl ether were examined instead (Table 1, entries 2–5), which highlights the significant influence of solvent on the reaction. When the loading of 2a decreased to 1.5 equiv. and 1.2 equiv., the yields of 3aa were reduced to 87% and 73%, respectively (Table 1, entries 6–7). To access the potential for practical applications, we proceeded the reaction under air condition. To our delightful surprise, the product 3aa was isolated in 94% yield (Table 1, entry 8). It is also noteworthy that 3aa could be obtained in high yields with shorter reaction time. For example, conversions of 99%, 98% and 84% were observed after 10 h, 8 h and 6 h reaction time (Table 1, entries 10–12). Under the optimized conditions, we were able to synthesize 3aa in gram-scale in 98% yield. The product 3aa was further confirmed by X-ray diffraction (XRD) (Fig. 2).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: imidazo[1,2-α]pyridines (0.10 mmol), Ethyl trifluoropyruvate (0.20 mmol), room temperature (about 15 °C), Ar atmosphere.b Isolated yields.c Ethyl trifluoropyruvate (0.15 mmol).d Ethyl trifluoropyruvate (0.12 mmol).e Under air.
1	DCM (2 mL)	24	27
2	DCE (2 mL)	24	62
3	Et2O (2 mL)	24	84
4	Toluene (2 mL)	24	98
5	Isopropyl ether (2 mL)	24	99
6^c	Isopropyl ether (2 mL)	24	87
7^d	Isopropyl ether (2 mL)	24	73
8^e	Isopropyl ether (2 mL)	24	94
9	Isopropyl ether (1 mL)	24	99
10	Isopropyl ether (1 mL)	10	99
11	Isopropyl ether (1 mL)	8	98
12	Isopropyl ether (1 mL)	6	84

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Fig. 2 Crystal structure of 3aa.

To expand the scope of the methodology, the F–C hydroxyalkylation was investigated with different functional groups installed onto the imidazo[1,2-α]pyridine aromatics under our optimized conditions (Scheme 1). The preliminary results demonstrated that the reaction has a high degree of functional group tolerance. Imidazo[1,2-α]pyridine bearing electron-donating groups (Me, OMe) at the pyridine ring could react smoothly at room temperature, and afforded the products 3ba and 3bb in excellent yields. It is also remarkable that the presence of electron-withdrawing groups (F, Cl, Br, I) at the pyridine ring could give products 3ca–3cd in 91–99% yields at 60 °C after 24 h. It is not surprising that stronger electron-withdrawing groups (CF₃, COOMe) could tremendously suppress the reaction activity and lead to low yields of 3bc (43%), 3ce (52%) and 3cf (53%). These results are consistent with the electronic effects of functional groups, which can either increase or decrease the electron density within the double bond and affect the reaction yields. In addition, for the 2-heteroaromatic imidazo[1,2-α]pyridines, the transformation could proceed successfully under mild conditions to obtain 3da, 3db and 3ea in high yields.

Scheme 1 Substrate scopes of catalyst-free F–C hydroxyalkylation of imidazo[1,2-α]pyridines with ethyl trifluoropyruvate in isopropyl ether. ^aReaction conditions: imidazo[1,2-α]pyridines (0.10 mmol), ethyl trifluoropyruvate (0.20 mmol), room temperature (about 15 °C), 10 h, Ar atmosphere. Isolated yields. ^bCarried out at 60 °C for 24 h. ^cCarried out at room temperature (about 15 °C) for 24 h. ^dCarried out at 60 °C for 48 h.

Different substituents on the phenyl ring of 2-phenylimidazo[1,2-α]pyridine were also synthesized and their reactivity were examined. Halides, ester, trifluoromethyl substituents were well tolerated under optimized conditions. From the isolated yields of 3fa, 3ga–3gg, 3ha–3he and 3ia–3id, generally speaking, electronic effect plays the similar role in influencing reaction efficiency as discussed previously. Furthermore, substrates bearing electron-donating groups (Me, OMe) at the meta, and para positions of the phenyl ring afforded the desired product easily, while substrates at the ortho site needed higher temperature and longer time to reach the same yield level (3ia and 3ib).

In summary, we have developed an efficient method for the synthesis of 3,3,3-trifluoro-2-hydroxy-2-(2-phenylimidazo[1,2-α]pyridin-3-yl)-propionic acid ethyl ester with a high degree of functional group tolerance. The mild reaction conditions (no additive and catalyst-free) and broad substrate scopes make this proposed method an appealing strategy to synthesize CF₃ containing bioactivity drugs.

Acknowledgements

The authors thank the National Natural Science Foundation of China for financial support (No. 21102135, 21171149, 21272217 and J1210060).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1410234. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra15678e

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