Skip to content
BY 4.0 license Open Access Published by De Gruyter October 26, 2020

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

  • Hui Guo EMAIL logo , Haonan Li , Xiaoyue Cao , Zuoyao Wang , Qian Zhang and Guobao Zhang

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.

1 Introduction

1,2,3,4-Tetrahydroquinoline derivatives have attracted continuous attention due to their important physiological and biological properties [1,2]. A great deal of protocols for the preparation of 1,2,3,4-tetrahydroquinoline derivatives have been developed. Diels–Alder reaction catalyzed by Lewis acids (e.g., Yb(OTf)3) is the most useful protocol for the synthesis of 1,2,3,4-tetrahydroquinoline derivatives [3,4,5]. 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 [Fe2(SO4)]3·xH2O as a catalyst [6]. Li et al. developed a domino reaction of aromatic amines, cyclic enol ethers and hemiacetals catalyzed by InCl3 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-4-anilino-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 cis- and 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 et al. reported the regioselective reduction of quinolines in ionic liquid [BMIM]PF6 with Ru/N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine as a catalyst [17]. Li et al. found that quinolines could also be regioselectively reduced in ionic liquid [Rmim][p-CH3C6H4SO3] using [RuCl2(TPPTS)2] as a catalyst [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

1H and 13C NMR spectra were recorded in CDCl3 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]H2PO4 was prepared using an earlier reported procedure [19].

2.2 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), Et3N (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 NaHCO3 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; 1H NMR (400 MHz, CDCl3): δ = 3.27 (t, J = 4 Hz, 2H), 3.79 (t, J = 4 Hz, 2H), 6.63–6.76 (m, 3H), 7.16–7.20 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 46.1, 61.0, 113.3, 117.9, 129.3, 148.0.

2.3 Typical procedure for the synthesis of N-hydroxyethyl substituted 1,2,3,4-tetrahydroquinolines

To a mixture of 2-(phenylamino)ethanol (0.5 mmol, 68 mg) in [NMPH]H2PO4 (0.5 mmol), MVK (0.5 mmol, 35 mg) and CH2Cl2 (1 mL) were added. After addition, the mixture reacted for 12 h at 37°C. The reaction was monitored by TLC [solvent system–PE:EA (1:1)]. After the completion of reaction, the reaction mixture was extracted with CH2Cl2 for several times. The solvent was evaporated, and the product was isolated by column chromatography. Yellow oil; IR (neat): 3384, 2956, 2929, 2868, 1602, 1503, 1338, 1287, 1047 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.29 (d, J = 7.2 Hz, 3H), 1.69–1.72 (m, 1H), 2.00–2.02 (m, 1H), 2.87–2.94 (m, 1H), 3.36–3.45 (m, 2H), 3.46–3.48 (m, 2H), 3.83 (t, J = 5.6 Hz, 2H), 6.63–6.70 (m, 2H), 7.06 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 22.5, 29.6, 30.8, 46.9, 54.1, 59.7, 111.3, 116.4, 126.9, 127.9, 128.2, 145.0; HRMS: calculated for C12H17NO (M+) 191.131, found 191.131.

3 Results and discussion

3.1 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 1 presents the effect of different ionic liquids on the reaction. In a first set of experiments, ionic liquids of the general [cation][BF4] and [BMIM]PF6 were tested as catalysts and a reaction medium (Table 1, entries 1–3). The results showed that the 1,2,3,4-tetrahydroquinoline derivative could not be obtained in these ionic liquids. To obtain 1,2,3,4-tetrahydroquinoline derivative, some acidic ionic liquids were used to catalyze the reaction (Table 1, entries 4–7). Although the acidic ionic liquids could promote the reaction and produce the corresponding 1,2,3,4-tetrahydroquinoline derivative, the best yield was only 30% when ionic liquid [NMPH]H2PO4 was used as a catalyst (Table 1, entry 7).

Table 1

The effect of solvent on the reaction

EntryIonic liquidYieldb (%)
1[BMIM]BF40a
2[BMIM]PF60a
3[OMIM]BF40a
4[HMIM]HSO412a
5[BMIM]HSO418a
6[NMPH]HSO419a
7[NMPH]H2PO430a
  1. a

    Reaction conditions: 0.5 mmol MVK, 0.5 mmol 2-(phenylamino)ethanol, 0.5 mmol ionic liquid, 37°C, 24 h.

  2. b

    Yield determined by HPLC.

Although better result could be obtained in ionic liquid [NMPH]H2PO4, the result still could not meet our needs. To obtain higher yield, the reaction of 2-(phenylamino)ethanol with MVK was carried out in the ionic liquid/solvent two phase system. It was found that the 1,2,3,4-tetrahydroquinoline derivative could not be produced in [NMPH]H2PO4/DMSO and [NMPH]H2PO4/DMF (Table 2, entries 1 and 2), and the reactions were less efficient in [NMPH]H2PO4/THF and other ionic liquid/solvent systems (Table 2, entries 3–8). To our delight, a promising result (89% yield) was achieved when the [NMPH]H2PO4/CH2Cl2 system was employed (Table 2, entry 10). The good result could be due to the extraction ability of CH2Cl2 for the product.

Table 2

The effect of ionic liquid/solvent two phase system on the reaction

EntryIonic liquid/solvent two-phase systemYieldb (%)
1[NMPH]H2PO4/DMSO0a
2[NMPH]H2PO4/DMF0a
3[NMPH]H2PO4/THF19a
4[NMPH]H2PO4/CH3CN27a
5[NMPH]H2PO4/Et2O25a
6[NMPH]H2PO4/acetone31a
7[NMPH]H2PO4/1,4-dioxane43a
8[NMPH]H2PO4/toluene35a
9[NMPH]H2PO4/CHCl372a
10[NMPH]H2PO4/CH2Cl289a
11CH2Cl20c
12H3PO4/CH2Cl240d
  1. a

    Reaction conditions: 0.5 mmol MVK, 0.5 mmol 2-(phenylamino)ethanol, 1 mL solvent, 0.5 mmol ionic liquid [NMPH]H2PO4, 37°C, 24 h.

  2. b

    Yield determined by HPLC.

  3. c

    Reaction conditions: 0.5 mmol MVK, 0.5 mmol 2-(phenylamino)ethanol, 1 mL solvent, 37°C, 24 h.

  4. d

    Reaction conditions: 0.5 mmol MVK, 0.5 mmol 2-(phenylamino)ethanol, 1 mL solvent, 0.5 mmol H3PO4, 37°C, 24 h.

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 CH2Cl2 (Table 2, entry 11). Moreover, the reaction with H3PO4 as a catalyst was also carried out, but the yield was significantly lower even under the same reaction conditions (Table 1, entry 12).

3.2 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.

Table 3

The effect of time on the reactionsa

EntryTime (h)Yieldb (%)
1115
2329
3551
4878
51289
62489
  1. a

    Reaction conditions: 0.5 mmol MVK, 0.5 mmol 2-(phenylamino)ethanol, 1 mL CH2Cl2, 1 mmol ionic liquid [NMPH]H2PO4, 37°C.

  2. b

    Yield determined by HPLC.

3.3 Effects of different substrates

With the optimal reaction conditions in hands, we then examined the scope and the limitation of this strategy for other structurally diverse substrates, and the results were summarized in Table 3. The reaction of 2-(phenylamino)ethanol with MVK produced 1-(2-hydroxyl-ethyl)-4-methyl-1,2,3,4-tetrahydroquinoline with high yield (Table 4, entry 1). A series of substituted 2-(phenylamino)ethanols could also react with MVK to produce the corresponding 1,2,3,4-tetrahydroquinoline derivatives (Table 4, entries 2 and 3), albeit in lower yield. 2-(3-Chlorophenylamino)ethanol reacted with sterically hindered unsaturated ketone, such as pent-1-en-3-one, and produced the 1-(2-hydroxyl-ethyl)-7-chloro-4-ethyl-1,2,3,4-tetrahydroquinoline with lower yield (Table 4, entry 4).

Table 4

The synthesis of 1,2,3,4-tetrahydroquinoline derivatives with acidic ionic liquid as catalysta

EntrySubstrate 1Substrate 2ProductYieldb (%)
1
3a89
2
3b85
3
3c80
4
3d65
5
3e78
6
3f73
7
3g85
8
3h78
  1. a

    Reaction conditions: 0.5 mmol substrate 1, 0.5 mmol substrate 2, 0.5 mmol acidic ionic liquid [NMPH]H2PO4, 1 mL CH2Cl2, 37°C, 12 h.

  2. b

    Yield determined by HPLC.

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, entries 7 and 8). The results showed that the existence of hydroxyl in the 2-(phenylamino)ethanol moiety could have an important effect on the synthesis of 1,2,3,4-tetrahydroquinoline derivatives.

3.4 Reuse of the ionic liquid

In order to test the reuseability of [NMPH]H2PO4, 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]H2PO4 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.

Table 5

The recycling of [NMPH]H2PO4a

RunYieldb
189
289
389
487
587
  1. a

    Reaction conditions: 0.5 mmol MVK, 0.5 mmol 2-(phenylamino)ethanol, 1 mmol ionic liquid [NMPH]H2PO4, 1 mL CH2Cl2, 37°C, 12 h.

  2. b

    Yield determined by HPLC.

4 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 H3PO4 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.

Acknowledgements

This work was financially supported by the Excellent Youth Training Programme Foundation of Henan Academy of Sciences (200402002).

References

[1] Guo H, Zhuang YW, Wang Y, Cao J, Guo XZ, Zhang GB. Advances in synthesis and application of 1,2,3,4-tetrahydroquinoline derivatives. Chem Ind Eng Pro. 2012;10:2288–94Search in Google Scholar

[2] Muthukrishnan I, Sridharan V, Menéndez JC. Progress in the chemistry of tetrahydroquinolines. Chem Rev. 2019;8:5057–191.10.1021/acs.chemrev.8b00567Search in Google Scholar

[3] Savitha G, Perumal PT. An efficient one-pot synthesis of tetrahydroquinoline derivatives via an aza Diels–Alder reaction mediated by CAN in an aqueous medium and oxidation to heteroaryl quinolines. Tetrahedron Lett. 2006;47:3589–93.10.1016/j.tetlet.2006.03.046Search in Google Scholar

[4] Batey RA, Powell DA, Acton A. Unprecedented sequential oxidative dimerization and cycloaddition of 1,3-diketones to fulvenes. A facile synthesis of the cyclopenta[b]chromenes. Tetrahedron Lett. 2001;42:935–8.10.1016/S0040-4039(00)02139-0Search in Google Scholar

[5] Fadel F, Titouani SL, Soufiaoui M. Synthèse de nouveaux dérivés tétrahydroquinoléines et quinoléines via la réaction d’aza-Diels–Alder suivie d’aromatisation. Tetrahedron Lett. 2004;45:5905–8.10.1016/j.tetlet.2004.05.127Search in Google Scholar

[6] Khan AT, Kumar DD, Khan MM. Ferric sulfate [Fe2(SO4)3·xH2O]: An efficient heterogeneous catalyst for the synthesis of tetrahydroquinoline derivatives using Povarov reaction. Tetrahedron Lett. 2011;52:4539–42.10.1016/j.tetlet.2011.06.080Search in Google Scholar

[7] Li ZG, Zhang JH, Li CJ. InCl3-catalyzed reaction of aromatic amines with cyclic hemiacetals in water: facile synthesis 1,2,3,4-tetrahydroquinoline derivatives. Tetrahedron Lett. 2003;44:153–6.10.1016/S0040-4039(02)02450-4Search in Google Scholar

[8] Chen L, Li CJ. Domino reaction of anilines with 3,4-dihydro-2H-pyran catalyzed by cation-exchange resin in water: an efficient synthesis of 1,2,3,4-tetrahydroquinoline derivatives. Green Chem. 2003;5:627–9.10.1039/b304431aSearch in Google Scholar

[9] Jia XD, Ren Y, Huo CD, Wang WJ, Chen XN, Xu XL, et al. Radical cation salt induced tandem cyclization between anilines and N-vinyl amides: synthesis of 2-methyl-4-anilino-1,2,3,4-tetrahydroquinoline derivatives. Tetrahedron Lett. 2010;51:6779–82.10.1016/j.tetlet.2010.10.106Search in Google Scholar

[10] Ahmed EH, Qi YL, Lai BB, Vaccaro L, Li MH, Gu YL. A sulfone‐containing imidazolium‐based brønsted acid ionic liquid catalyst enables replacing dipolar aprotic solvents with butyl acetate. Adv Synth Catal. 2019;361:3342–50.10.1002/adsc.201900246Search in Google Scholar

[11] Konstantza T. Long-term preservation of α-amylase activity in highly concentrated aqueous solutions of imidazolium ionic liquid. Green Process Synth. 2017;7:106–13.Search in Google Scholar

[12] Li MH, Wu FT, Gu YL. Brönsted acidic ionic liquid catalyzed synthesis of benzo[a]carbazole from renewable acetol and 2-phenylindoles in a biphasic system. Chin J Catal. 2019;8:1135–40.10.1016/S1872-2067(19)63370-XSearch in Google Scholar

[13] Ahmed EH, Qi YL, Yue ME, Fan WF. Novel non-toxic and non-hazardous solvent systems for the chemistry of indoles: Use of a sulfone-containing brønsted acid ionic liquid catalyst in butyl acetate. ChemCatChem. 2019;11:4403–10.10.1002/cctc.201900784Search in Google Scholar

[14] Chen KK, Du H, Zhang JW, Zhang XF, Kuang YY, Han XX. A sustainable process for enzymatic saccharification of ionic liquid-pretreated cellulosic materials. Green Process Synth. 2014;3:353–63.Search in Google Scholar

[15] Pan LS, Zhao XY, Zeng S, Xiang FY, Zhao GG, Li YF. Extraction of luteolin from peanut shells by a hydrophilic ionic liquid-based microwave-assisted method. Chem Sel. 2019;4:13589–95.10.1002/slct.201903358Search in Google Scholar

[16] Deng WX, Liu LJ, Peng YQ. Choline taurinate: a new biocompatible aminofunctionalized ionic liquid as basic catalyst and extraction solvent. Green Process Synth. 2014;7:191–7.10.1515/gps-2017-0009Search in Google Scholar

[17] Zhou HF, Li ZW, Wang ZJ, Wang TL, Xu LJ, He YM, et al. Angew Chem Int Ed. 2008;47:8464–67.10.1002/anie.200802237Search in Google Scholar PubMed

[18] Li Q, Zhang RM, Zhou LM, Fu HY, Chen H, Li XJ. Chin J Catal. 2009;3:242–6.Search in Google Scholar

[19] Guo H, Li X, Wang JL, Jin XH, Lin XF. Tetrahedron. 2010;66:8300–3.10.1016/j.tet.2010.08.017Search in Google Scholar

Received: 2020-06-02
Revised: 2020-08-09
Accepted: 2020-08-23
Published Online: 2020-10-26

© 2020 Hui Guo et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Downloaded on 29.3.2024 from https://www.degruyter.com/document/doi/10.1515/gps-2020-0056/html
Scroll to top button