The green synthesis of N-hydroxyethyl-substituted 1,2,3,4-tetrahydroquinolines with acidic ionic liquid as catalyst

Abstract N-Hydroxyethyl-substituted 1,2,3,4-tetrahydroquinolines were synthesized by the reaction of 2-(phenylamino)ethanol with unsaturated ketone catalyzed by acidic ionic liquid N-methyl-2-pyrrolidonium dihydrogen phosphate [NMPH]H2PO4, obviating the need for toxic and expensive catalysts. The acidic ionic liquid not only showed superior performance over H3PO4 but also was stable and could be reused at least five times with a slight loss of activity. It provided a straightforward and efficient protocol for the synthesis of 1,2,3,4-tetrahydroquinoline derivatives.

In addition to the classical method, Khan et al. found that 1,2,3,4-tetrahydroquinoline derivatives could also be synthesized by the Povarov reaction using [Fe 2 (SO 4 )] 3 · xH 2 O as a catalyst [6]. Li et al. developed a domino reaction of aromatic amines, cyclic enol ethers and hemiacetals catalyzed by InCl 3 for the synthesis of 1,2,3,4-tetrahydroquinoline derivatives [7]. However, these metal-based catalysts own their drawbacks such as toxicity, corrosiveness and expensive cost. Recently, Chen and Li reported that the 1,2,3,4-tetrahydroquinoline derivatives could be prepared using acidic cation-exchange resin as a catalyst [8], and Wang and coworkers found that 2-methyl-4anilino-1,2,3,4-tetrahydroquinoline derivatives could be synthesized by the tandem cyclization between anilines and N-vinyl amides with radical cation salt as a catalyst [9]. However, all the products obtained by the methods were a mixture of cisand trans-isomers. Therefore, it is very necessary to develop effective and economical methodology for the synthesis of 1,2,3,4-tetrahydroquinoline derivatives.
Ionic liquids have emerged as green catalysts and reaction media in recent years [10][11][12][13]. They have been applied in many reactions such as the synthesis of methyl caprylate [14], extraction of Luteolin from Peanut Shells [15] and three-component cyclic condensation of aromatic aldehydes, malononitrile and dimedone [16]. To the best of our knowledge, relevant reports about the synthesis of 1,2,3,4-tetrahydroquinoline derivatives with ionic liquids have been demonstrated by several examples. Zhou [18]. However, the synthesis of 1,2,3,4-tetrahydroquinoline derivatives catalyzed by ionic liquid still is an intriguing challenge. Herein, we, for the first time, present a straightforward and efficient protocol for the synthesis of novel 1,2,3,4-tetrahydroquinoline derivatives using acidic ionic liquid as a catalyst.
2 Materials and methods 2.1 General 1 H and 13 C NMR spectra were recorded in CDCl 3 with a Bruker AVANCE DMX 500 spectrometer at 100 and 400 MHz, respectively. Chemical shifts are reported in ppm (δ), relative to tetramethylsilane (TMS) as the internal standard. IR spectra were measured with a Nicolet Nexus FTIR 670 spectrophotometer. All reactions were carried out with efficient stirring in a round bottom flask at 37°C, unless otherwise stated, and monitored by TLC. MVK was distilled before use, and other chemicals were obtained from commercial suppliers and were used without further purification. The acidic ionic liquid [NMPH]H 2 PO 4 was prepared using an earlier reported procedure [19].

Typical procedure for the synthesis of 2-(phenylamino)ethanol
To a mixture of aniline (0.1 mol, 9.3 g) and 2-chloroethanol (0.05 mol, 4 g), Et 3 N (15 mL) was added. Then, the mixture was heated to reflux and stirred for 8 h.
After the completion of reaction, the mixture was neutralized with the saturated NaHCO 3 solution, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Then, the solvent was evaporated, and the product was isolated by column chromatography. A yellow oil; 1  3 Results and discussion

Effects of ionic liquids
Initial studies were carried out using the reaction of 2-(phenylamino)ethanol with methyl vinyl ketone (MVK) as a model reaction.   Table 2, entry 10). The good result could be due to the extraction ability of CH 2 Cl 2 for the product. A control experiment was designed to demonstrate that the reaction was an acidic ionic liquid-catalyzed process. In the absence of the acidic ionic liquid, the reaction of 2-(phenylamino)ethanol with MVK could not produce the 1,2,3,4-tetrahydroquinoline derivative even in CH 2 Cl 2 ( Table 2, entry 11). Moreover, the reaction with H 3 PO 4 as a catalyst was also carried out, but the yield was significantly lower even under the same reaction conditions ( Table 1, entry 12).

Effects of time
The effect of the reaction time was presented in Table 3. The yield increased as time prolonged, and the best result was obtained when the reaction was carried out for 12 h. Longer reaction time could not increase the yield.
2-(2-Nitrophenylamino)ethanol was examined under the same reaction conditions, but the corresponding 1,2,3,4-tetrahydroquinoline derivatives could not be obtained ( Table 4, entries 5 and 6), and it could be due to the steric effect of the substituent group. Aniline and N-ethylbenzenamine were also examined under the same reaction conditions, but the corresponding 1,2,3,4-tetrahydroquinoline derivatives could not be obtained ( Table 4,

Reuse of the ionic liquid
In order to test the reuseability of [NMPH]H 2 PO 4 , the reaction of 2-(phenylamino) ethanol with MVK was repeated five times under the same reactions, and the results were presented in Table 5. The results showed that the acidic ionic liquid [NMPH]H 2 PO 4 was stable and could be reused at least 5 times with a slight loss of activity. Graph: use this for the first paragraph in a section, or to continue after an extract.

Conclusions
Novel N-hydroxyethyl-substituted 1,2,3,4-tetrahydroquinolines were synthesized with the acidic ionic liquid as a catalyst for the first time. The acidic ionic liquid showed superior performance over H 3 PO 4 under the same condition, and the acidic ionic liquid could be reused for at least five times with the consistent activity. The developed protocol provided a simple and efficient alternative for the synthesis of tetrahydroquinoline derivatives.