HETEROCYCLES

Note | Regular issue | Vol. 78, No. 2, 2009, pp. 487-493
Received, 7th August, 2008, Accepted, 14th October, 2008, Published online, 16th October, 2008.
DOI: 10.3987/COM-08-11516

■ An Efficient Protocol for the Friediänder Synthesis of Quinolines Using the Lewis Acidic Ionic Liquid Choline Chloride·2ZNCL₂

Huey-Min Wang,* Rei-Sheu Hou, Hui-Ting Cheng, and Ling-Ching Chen*

Graduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.

Abstract

Lewis acidic ionic liquid choline chlorideÅE2ZnCl₂ is shown to be for the first time an excellent solvent and efficient catalyst for the synthesis of quinolines via Friedländer annulation under mild conditions.

Quinoline derivatives have been well known not only in medicinal chemistry, because of their wide occurrence in natural products1 and2 drugs, but also in polymer chemistry, electronics and optoelectronics for their excellent mechanical properties.3 Versatile methods for the synthesis of the quinoline ring system have been developed.4
Friedländer annulation is one of the most simple and straightforward approaches for the synthesis of quinoline derivatives. Friedländer synthesis can be catalysed by strong acids or bases, and may take place without a catalyst at higher temperature. Brønsted acids like hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and phosphoric acid were widely used as catalysts. However, many of these methods require harsh reaction condition and lead to several side reactions. Recently, Lewis acids such as ZnCl2, SnCl2, Bi(OTf)3, Sc(OTf)3, silver phosphotungstate, sodium fluoride, and AuCl3 have been reported to be effective for the synthesis of quinolines.5 However, many of these procedures suffered from harsh reaction conditions, low yields, difficulties in work up, and the use of stoichiometric and/or relatively expensive reagents. Since quinoline derivatives are increasingly useful and important in pharmaceuticals and industry, the development of simple, eco-benign, low cost protocol is still desirable.
Room temperature ionic liquids (RTILs) have gained popularity such as “green” alternative to conventional solvents, due to several interesting properties6 like negligible vapor pressure and wide liquid range. Recently, the alkylimidazolium-aluminium chloride mixtures have been studied extensively for use in acid catalysed reactions, particularly in Friedel-Crafts reactions7 However, for practical utilization, these imidazolium-based ionic liquids still suffer from the relatively expensive cost. In the case of chloroaluminate ionic liquid, their poor stability to moisture can lead to undesired side reactions. More recently, a series of inexpensive and moisture-stable Lewis acidic ionic liquids have been prepared from choline chloride and ZnCl2,8 and used in Diels–Alder9 and Fischer indole10 reactions. In this paper, we report the use of choline chloride・2ZnCl2 as solvent and catalyst for the synthesis of quinolines via Friedländer annulation under mild conditions.

Treatment of o-aminoaryl ketones (1) with dicarbonyl compounds or ketones (2) in ionic liquid choline chloride・2ZnCl2 at 80℃ for 1 h caused cyclodehydration to give quinolines (3) in good to excellent yields (Scheme 1). The results are given in Table 1. o-Aminobenzophenone (1a) react with acetylacetone and ethyl acetoactate to give the corresponding quinolines (3a, 3b) in 88 % and 90 % yield, respectively. Cyclic ketone such as cyclopentanone (2e) also underwent smooth condensation with o-aminoaryl ketones (1) to afford the respective tricyclic quinolines (3e, 3j) in 89 % and 93 % yields (Scheme 2).

In conclusion, we describe a mild and efficient route for the synthesis of quinolines and polycylic quinolines utilizing choline chloride・2ZnCl2 as solvent and catalyst via Friedländer annulation under mild conditions. This ionic liquid is cheap, moisture-stable and easy to prepare compared to imidazolium based ionic liquids.

ACKNOWLEDGEMENT
We gratefully acknowledge the National Council Science of Republic of China for financial support of this work.

EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a Shimadzu IR-27 G spectrophotometer. 1H NMR and 13C NMR spectra were recorded on a Varian Unity Plus 400 MHz. Chemical shifts (δ) were measured in ppm with respect to TMS. MS were obtained on a JEOL JMS D-300 instrument.

General procedure for the preparation quinoline (3)
A mixture of o-aminoaryl kone (1 mmol) and ketone (2 mmol) in choline chloride∙2ZnCl2 (0.5 mL) ionic liquid was stirred for 1 h at 80 ℃. The reaction mixture was extracted with EtOAc. The remaining ionic liquid was reused after drying in vacuum. The extract was dried (MgSO4) and concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column with hexane-EtOAc (3 : 1) to give quinoline (3).

1-(2-Methyl-4-phenylquinolin-3-yl)ethanone (3a)
Mp 114-115 ℃ (Lit.,11 111-112℃). IR (KBr) : 3062, 2907, 1696 cm-1; 1H NMR (CDCl3) δ : 1.95 (s, 3H), 2.66 (s, 3H), 7.30-7.32 (m, 2H), 7.30-7.39 (m, 1H), 7.44-7.48 (m, 3H), 7.57 (dd, J = 0.8, 8.4 Hz, 1H), 7.63-7.68 (m, 1H), 8.03 (d, J = 8.4Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 23.7, 31.7, 124.8, 125.9, 126.3, 128.5, 128.6, 128.8, 129.8, 129.9, 134.6, 135.0, 143.7, 147.3, 153.3, 205.5; EI-MS m/z : 261 (M+), 246, 218, 176.

2-Methyl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (3b)
Mp 99-100°C. (Lit.,11 mp 99-100°C). IR (KBr) ν : 3060, 2927, 1710 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 0.91 ( t, J = 7.3 Hz, 3H), 2.76 ( s, 3H), 4.00-4.10 ( m, 2H), 7.31-7.46 ( m, 6H), 7.54 ( d, J = 8.4 Hz, 1H), 7.67 ( t, J = 8.4 Hz, 1H), 8.04 ( d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 13.4, 23.6, 61.1, 124.9, 126.2, 128.0, 128.3, 128.6, 129.2, 130.1, 135.5, 146.1, 147.5, 154.4, 168.2; EI-MS m/z : 291 (M+), 246, 245, 218.

3,3-Dimethyl-9-phenyl-3,4-dihydro-2H-acridin-1-one (3c)
Mp 191°C. (Lit.,11 mp 195°C). IR (KBr) ν : 3065, 2868, 1682 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 1.15 ( s, 6H), 2.55 ( s, 2H), 3.26 ( s, 2H), 7.16-7.19 ( m, 2H), 7.36-7.39 ( m, 1H), 7.44-7.51 ( m, 4H), 7.71-7.75 ( m, 1H), 8.06 ( d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 28,2, 32.1, 48.2, 54.0, 122.5, 126.3, 127.2, 127.3, 127.9, 128.0, 128.1, 128.3, 131.5, 137.4, 148.8, 150.8, 160.9, 197.7; EI-MS m/z: 301 (M+), 300, 272, 245, 217, 189.
5,6-Dihydro-7-phenylbenzo[c]acridine (3d)
Mp 143-145°C. (Lit.,12 mp 148-149°C). IR (KBr) ν : 3057, 2924, 1574, 14484, 696 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 2.86-2.89 (m, 4H), 7.11-7.72 (m, 11H), 8.20 (d, J = 8.4Hz, 1H), 8.63 (dd, J = 1.2, 7.6Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 26.4, 28.2, 125.9, 126.0, 126.3, 127.2, 127.4, 127.8, 128.0, 128.4, 128.5, 128.9, 129.5, 129.6, 130.2, 135.0, 136.9, 137.5, 139.2, 147.1, 153.0; EI-MS m/z: 307 (M+), 306, 305, 230, 152.

2,3-Dihydro-9-phenyl-1H-cyclopenta[b]quinoline (3e)
Mp 1313-132°C. (Lit.,13 mp 130°C). IR (KBr) ν : 3058, 2923, 1569, 1485, 831 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 2.15-2.19 (m, 2H), 2.91 (t, J = 7.2Hz, 2H), 3.24 (t, J = 7.6Hz, 2H), 7.35-7.41 (m, 3H), 7.47-7.54 (m, 3H), 7.60-7.64 (m, 2H), 8.06-8.08 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ : 23.5, 30.3, 35.1, 125.4, 125.6, 126.2, 128.2, 128.4, 129.2, 133.6, 136.7, 142.6, 147.9, 167.4; EI-MS m/z: 245 (M+), 244, 217, 168.

1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)ethanone (3f)
Mp 155-156°C (Lit.,11 mp 154°C). IR (KBr) ν : 3049, 2925, 1699 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 1.97 (s, 3H), 2.65 (s, 3H), 7.29-7.31 (m, 2H), 7.48-7.54 (m, 4H), 7.59-7.62 (m, 1H), 7.97 (d, J = 9.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 23.7, 31.7, 124.8, 125.7, 128.8, 129.1, 129.8, 130.4, 130.8, 132.3, 134.3, 135.4, 142.9, 145.7, 153.8, 205.1; EI-MS m/z: 297 (M++2), 295 (M+), 280, 217, 176.

6-Chloro-2-methyl-4-phenylquinoline-3-carboxylic acid ethyl ester (3g)
Mp 102-105°C. (Lit.,11 mp 108°C). IR (KBr) ν : 3075,2926, 1715 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 0.85 (t, J=7.2 Hz, 3H), 2.69 (s, 3H), 3.98 (q, J = 7.2 Hz, 2H), 7.25-7.45 (m, 6H), 7.51 (dd, J = 2.4, 8.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 13.3, 23.4, 61.1, 124.8, 125.5, 128.1, 128.3, 128.4, 129.0, 130.2, 130.7, 132.0, 134.7, 145.0, 145.7, 154.6, 167.7; EI-MS m/z: 327 (M++2), 325 (M+), 280, 217, 216.

7-Chloro-3,3-dimethyl-9-phenyl-3,4-dihydro-2H-acridin-1-one (3h)
Mp 209-211°C. (Lit.,11 mp 209-211°C). IR (KBr) ν : 3071, 2946, 1693 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 1.15(s, 6H), 2.57(s, 2H), 3.25(s, 2H), 7.14-7.17(m, 2H), 7.28(d, J = 2.4 Hz, 1H), 7.42-7.55 (m, 3H), 7.69 (dd, J = 2.4, 9.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 28.3, 32.2, 48.2, 54.1, 123.2, 126.7, 127.8, 127.9, 128.2, 128.3, 130.1, 132.4, 132.5, 136.7, 147.3, 150.1, 161.4, 197.6; EI-MS m/z: 337 (M++2), 335 (M+), 334, 306, 279, 216 189.

9-Chloro-5,6-dihydro-7-phenylbenzo[c]acridine (3i)
Mp 134-136°C. (Lit.,14 mp 130°C). IR (KBr) ν : 3052, 2935, 1600, 1479, 698 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 2.81-2.90 ( m, 4H), 7.24-7.59 ( m, 10H), 8.11 ( d, J = 8.8 Hz, 1H), 8.59 ( dd, J = 1.2, 7.6 Hz,1H); 13C NMR (CDCl3, 100 MHz) δ : 26.5, 28.1, 124.8, 126.3, 127.3, 127.7, 127.9, 128.2, 128.7, 129.0, 128.3, 129.4, 129.8, 131.1, 131.6, 134.7, 136.1, 139.2, 144.5, 145.5, 153.3; EI-MS m/z: 343 (M++2), 341 (M+), 304, 152.

7-Chloro-2,3-dihydro-9-phenyl-1H-cyclopenta[b]quinoline (3j)
Mp 103-104°C. (Lit.,14 mp 105°C). IR (KBr) ν : 3038, 2923, 1601, 1483, 828 cm-1; 1H NMR (CDCl3, 400 MHz) δ : 2.17 ( m, 2H), 2.89 ( t, J = 7.6 Hz, 2H), 3.22 ( t, J = 7.6 Hz, 2H), 7.32-7.35 ( m, 2H), 7.46-7.58 ( m, 5H), 7.99 ( d, J = 8.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ : 23.4, 30.3, 35.1, 124.5, 127.0, 128.2, 128.7, 128.9, 129.1, 130.3, 131.2, 1134.6, 136.0, 141.8, 146.3, 167.8; EI-MS m/z: 281 (M++2), 279 (M+), 246, 244.

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