Gd(OTf)3-[Bmim][PF6]: A novel and recyclable catalytic system for the synthesis of quinolines

Article abstract of DOI:10.1002/jccs.200900128

A mild and efficient route for the synthesis of quinolines and polycyclic quinolines utilizing Gadolinium triflate (Gd(OTf)₃) as a novel catalyst via Friedlaender annulation in ionic liquid 1-n-butyl-3- methylimidazolium hexafluorophosphate [Bm

Full text of DOI:10.1002/jccs.200900128

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Journal of the Chinese Chemical Society, 2009, 56, 867-872
867
Communication
Gd(OTf)3–[Bmim][PF6]: A Novel and Recyclable Catalytic System for the
Synthesis of Quinolines
Jian-Long Wua (
), Rei-Sheu Houb* (
), Huey-Min Wangb (
),
Iou-Jiun Kangc (
) and Ling-Ching Chend* (
)
aKangshan Hospital of Kaohsing County, Kangshan 820, Taiwan, R.O.C.
bChung Hwa College of Medical Technology, Tainan 717, Taiwan, R.O.C.
cDivision of Biotechnology and Pharmaceutical Research, National Health Research Institutes,
Miaoli County 350, Taiwan, R.O.C.
dGraduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
A mild and efficient route for the synthesis of quinolines and polycyclic quinolines utilizing Gadolin-
ium triflate (Gd(OTf)3) as a novel catalyst via Friedländer annulation in ionic liquid 1-n-butyl-3-methyl-
imidazolium hexafluorophosphate [Bmim][PF6] under mild conditions was described.
Keywords: Quinoline; Friedländer synthesis; Gd(OTf)3; Ionic liquid.
INTRODUCTION
Quinoline derivatives have been well known not only
oline derivatives are increasingly useful and important in
pharmaceuticals and industry, the development of simple,
efficient and eco-benign protocol is still desirable.
in medicinal chemistry, because of their wide occurrence in
natural products1 and drugs,2 but also in polymer chemis-
try, electronics and optoelectronics for their excellent me-
chanical properties.3 Versatile methods for the synthesis of
the quinoline ring system have been developed.4
Room temperature ionic liquids (RTIL) are liquids
that are composed entirely of ions. In fact, ionic liquids can
now be produced which remain liquid at room tempera-
ture and below (even as low as -90 °C) and appear to be
undemanding and inexpensive to manufacture.8 Ionic liq-
uids offer an attractive alterative to conventional organic
liquids for clean synthesis, as they are easy to recycle,
lack flammability, and possess effectively no vapour pres-
sure. Compared with classical molecular solvents, the
ionic liquids are environmentally benign reaction media.9
To date some of the important reactions have been carried
out and investigated in ionic liquids, for example, Friedel-
Crafts reaction,10 alkoxycarbonylation,11 hydrogenation,12
Diels-Alder reaction,13 Wittig reaction,14 Heck reaction,15
Trost-Tsuji coupling,16 Ring-closing metathesis (RCM),17
Suzuki cross-coupling,18 Fischer indole synthesis,19 1,3-
dipolar cycloaddition reaction,20 Beckmann rearrange-
ment,21 Knoevenagel and Robinson annulation reactions,22
etc.
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 high 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 sev-
eral side reactions. Recently, Lewis acids such as ZnCl2,
SnCl2, Bi(OTf)3, Sc(OTf)3, silver phosphotungstate, so-
dium fluoride, AuCl3, and iodine5 or TEBAC6 and ionic
liquid-catalyzed7 have been reported to be effective for the
synthesis of quinolines. However, many of these proce-
dures suffered from harsh reaction conditions, low yields,
difficulties in work up, and the use of stoichiometric and/or
relatively expensive reagents. Furthermore, the synthesis
of quinolines in general have been carried out in polar sol-
vents such as acetonitrile, THF, DMF and DMSO leading
to complex isolation and recovery procedures. Since quin-
Recently, there has been growing considerable inter-
est in the use of lanthanide triflates in organic synthesis.
The reagent Gd(OTf)3 is an inexpensive, non-toxic and
moisture-stable Lewis acid.23 In this paper, we report the

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868 J. Chin. Chem. Soc., Vol. 56, No. 5, 2009
Wu et al.
use of Gd(OTf)3 as catalyst for the synthesis of quinolines
via Friedländer annulation in ionic liquid 1-n-butyl-3-meth-
ylimidazolium hexafluorophosphate ([Bmim][PF6]) under
mild conditions.
quire high temperature or drastic conditions to produce
quinoline derivatives. Furthermore, the condensation of o-
aminobenzophenone with ethyl acetoacetate in the pres-
ence of concd H2SO4 afforded the quinoline product in only
65% yield (entry 1).
RESULTS AND DISCUSSION
In conclusion, we have demonstrated a simple and ef-
ficient procedure for the synthesis of quinolines, including
polycyclic quinolines, using Gd(OTf)3–[Bmim][PF6] sys-
tem as a reusable catalyst. The significant features of this
method include operational simplicity, improved reaction
rates, high yields of products and avoidance of the use of
hazardous acids or bases.
Treatment of o-aminobenzophenone (1a) and ethyl
acetoacetate (2a) with Gd(OTf)3 as catalyst in ionic liquid
[Bmim][PF6] at 60 °C for 15 min caused cyclodehydration
to give ethyl 2-methyl-4-phenylquinoline-3-carboxylate
(3a) in 93% yield (Scheme I). When the reaction is con-
ducted in a conventional solvent, such as acetonitrile, the
preparation of 3a needs refluxing for 3 h.
EXPERIMENTAL SECTION
Scheme I
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 (d) 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-aminobenzophenone (1 mmol), ke-
tone (1.3 mmol) and Gd(OTf)3 (0.2 mmol) in [Bmim][PF6]
(2 mL) ionic liquid was stirred at 60 °C for 15 min to com-
plete the reaction. Subsequently, the reaction mixture was
extracted with EtOAc. 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). The remaining
Gd(OTf)3-[Bmim][PF6] system was dried at 80 °C under
reduced pressure and reused in subsequent runs.
This method is equally effective for both cyclic and
acyclic ketones. Cyclic ketones and various 1,3-diketones
such as acetyl acetone and 5,5-dimethylcyclohexanedione
reacted efficiently with o-aminobenzophenones to give the
corresponding substituted quinolines. The results are given
in Table 1. Interestingly, bicyclic ketone such as a-tetra-
lone (2f) also underwent smooth condensation with o-ami-
nobenzophenones to afford the respective polycyclic quin-
olines (3f, 3l) with good yields (Fig. 1).
The products were characterized by 1H, 13C NMR, IR
and mass spectroscopic data. This method is clean and free
from side reactions such as self-condensation of ketones
which are normally observed under basic conditions. Un-
like reported methods, the present protocol does not re-
Ethyl 2-methyl-4-phenylquinoline-3-carboxylate (3a)
Mp 99-100 °C. (Lit.24, mp 99-100 °C). IR (KBr) n:
3060, 2927, 1710 cm-1; 1H NMR (CDCl3, 400 MHz) d: 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)
d: 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.
1-(2-Methyl-4-phenylquinolin-3-yl)ethanone (3b)
Mp 114-115 °C. (Lit.24, 111-112 °C). IR (KBr) n:
3062, 2907, 1696 cm-1; 1H NMR (CDCl3) d: 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,
Fig. 1.

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Gadolinium Triflate Catalyzed Synthesis of Quinolines
J. Chin. Chem. Soc., Vol. 56, No. 5, 2009 869
Table 1. Gd(OTf)3 catalyzed Friedländer synthesis of quinolines in [Bmim][PF6]
Entry
2-Aminoketone 1
Ketone 2
Quinoline 3
Yield (%)
93
1a
2a
3a
1
2
3
4
1a
1a
1a
2b
2c
2d
3b
3c
3d
89
87
86
5
6
1a
1a
2e
2f
3e
3f
85
84
7
1b
2a
2b
2c
2d
2e
3g
3h
3i
90
87
86
84
83
8
1b
1b
1b
1b
9
10
11
3j
3k
1b
2f
3l
12
85

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870 J. Chin. Chem. Soc., Vol. 56, No. 5, 2009
Wu et al.
1H), 8.03 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d: 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.
3075, 2926, 1715 cm-1; 1H NMR (CDCl3, 400 MHz) d: 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) d: 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.
3,3-Dimethyl-9-phenyl-3,4-dihydro-2H-acridin-1-one
(3c)
Mp 191 °C. (Lit.24, mp 195 °C). IR (KBr) n: 3065,
2868, 1682 cm-1; 1H NMR (CDCl3, 400 MHz) d: 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) d: 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.
1-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)ethanone
(3h)
Mp 155-156 °C. (Lit.24, mp 154 °C). IR (KBr) n:
3049, 2925, 1699 cm-1; 1H NMR (CDCl3, 400 MHz) d: 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) d: 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.
2,3-Dihydro-9-phenyl-1H-cyclopenta[b]quinoline (3d)
Mp 131-132 °C. (Lit.25, mp 130 °C). IR (KBr) n:
3058, 2923, 1569, 1485, 831 cm-1; 1H NMR (CDCl3, 400
MHz) d: 2.15-2.19 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H), 3.24 (t,
J = 7.6 Hz, 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) d: 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.
7-Chloro-3,3-dimethyl-9-phenyl-3,4-dihydro-2H-
acridin-1-one (3i)
Mp 209-211 °C. (Lit.24, mp 209-211 °C). IR (KBr) n:
3071, 2946, 1693 cm-1; 1H NMR (CDCl3, 400 MHz) d: 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) d: 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-Pheyl-1,2,3,4-tetrahydroacridine (3e)
Mp 137 °C. (Lit.25, mp 138 °C). IR (KBr) n: 3061,
1
2940, 2860, 1570, 1485, 1440, 1220, 765, 705 cm-1; H
NMR (CDCl3, 400 MHz) d: 1.75-1.81 (m, 2H), 1.93-1.99
(m, 2H), 2.59 (t, J = 6.8 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H),
7.20-7.35 (m, 4H), 7.46-7.55 (m, 3H), 7.63-7.65 (m, 1H),
8.17 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d:
22.4, 22.7, 27.8, 33.3, 125.8, 125.8, 126.6, 127.1, 127.9,
128.6, 128.8, 129.0, 136.5, 144.6, 147.9, 158.5; EI-MS
m/z: 259 (M+), 244, 230, 217, 202, 189, 121.
7-Chloro-2,3-dihydro-9-phenyl-1H-cyclopenta[b]quino-
line (3j)
Mp 103-104 °C. (Lit.27, mp 105 °C). IR (KBr) n:
3038, 2923, 1601, 1483, 828 cm-1; 1H NMR (CDCl3, 400
MHz) d: 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) d: 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.
5,6-Dihydro-7-phenylbenzo[c]acridine (3f)
Mp 143-145 °C. (Lit.26, mp 148-149 °C). IR (KBr) n:
3057, 2924, 1574, 14484, 696 cm-1; 1H NMR (CDCl3, 400
MHz) d: 2.86-2.89 (m, 4H), 7.11-7.72 (m, 11H), 8.20 (d, J
= 8.4 Hz, 1H), 8.63 (dd, J = 1.2, 7.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d: 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.
7-Chloro-9-phenyl-1,2,3,4-tetrahydroacridine (3k)
Mp 163 °C. (Lit.27, mp 163 °C). IR (KBr) n: 3060,
2944, 1604, 1572, 1481, 1215, 703 cm-1; 1H NMR (CDCl3,
400 MHz) d: 1.78-1.82 (m, 2H), 1.94-1.98 (m, 2H), 2.61 (t,
J = 6.4 Hz, 2H), 3.29 (t, J = 6.4 Hz, 2H), 7.22-7.35 (m,
4H),7.46-7.65 (m, 3H), 7.94 (d, J = 8.8 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d: 22.8, 28.0, 34.1, 124.4, 127.3, 128.0,
Ethyl 6-Chloro-2-methyl-4-phenylquinoline-3-carbox-
ylate (3g)
Mp 102-105 °C. (Lit.24, mp 108 °C). IR (KBr) n: