An efficient protocol for the Friedlaender quinoline synthesis using the Lewis acidic ionic liquid choline chloride · 2ZnCl2

Article abstract of DOI:10.3987/COM-08-11516

Lewis acidic ionic liquid choline chloride · 2ZnCl₂ is shown to be for the first time an excellent solvent and efficient catalyst for the synthesis of quinolines via Friedlaender annulation under mild conditions.

Full text of DOI:10.3987/COM-08-11516

HETEROCYCLES, Vol. 78, No. 2, 2009
487
HETEROCYCLES, Vol. 78, No. 2, 2009, pp. 487 - 493. © The Japan Institute of Heterocyclic Chemistry
Received, 7th August, 2008, Accepted, 14th October, 2008, Published online, 16th October, 2008.
DOI: 10.3987/COM-08-11516
AN EFFICIENT PROTOCOL FOR THE FRIEDLÄNDER QUINOLINE
SYNTHESIS USING THE LEWIS ACIDIC IONIC LIQUID CHOLINE
CHLORIDE・2ZnCl
2
a
a
b
Huey-Min Wang, * Rei-Sheu Hou, Hui-Ting Cheng, and Ling-Ching
b
Chen *
a
Chung Hwa University of Medical Technology, Tainan 717, Taiwan, R.O.C.
b
Graduate Institute of Pharmaceutical Sciences, College of Pharmacy, Kaohsiung
Medical University, Kaohsiung 807, Taiwan, R.O.C.
Abstract - Lewis acidic ionic liquid choline chloride・2ZnCl is shown to be for
2
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
1
2
occurrence in natural products and drugs, but also in polymer chemistry, electronics and
3
optoelectronics for their excellent mechanical properties. Versatile methods for the synthesis of the
4
quinoline ring system have been developed.
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 ZnCl
2
, SnCl
2
, Bi(OTf)
3
, Sc(OTf)
3
3
, silver phosphotungstate, sodium fluoride, and AuCl have been
5
reported to be effective for the synthesis of quinolines. 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
6
conventional solvents, due to several interesting properties like negligible vapor pressure and wide

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HETEROCYCLES, Vol. 78, No. 2, 2009
liquid range. Recently, the alkylimidazolium-aluminium chloride mixtures have been studied extensively
7
for use in acid catalysed reactions, particularly in Friedel-Crafts reactions 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
8
9
10
2
from choline chloride and ZnCl , and used in Diels–Alder and Fischer indole reactions. In this paper,
we report the use of choline chloride・2ZnCl
2
as solvent and catalyst for the synthesis of quinolines via
Friedländer annulation under mild conditions.
Ph
Ph
R2
O
O
choline chloride 2ZnCl2
R
+
R
R2
8
0°C
R1
NH2
N
R1
1
2
3
Scheme 1
Treatment of o-aminoaryl ketones (1) with dicarbonyl compounds or ketones (2) in ionic liquid choline
chloride・2ZnCl at 80℃ for 1 h caused cyclodehydration to give quinolines (3) in good to excellent
2
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).
Ph
O
Ph
O
choline chloride 2ZnCl2
R
+
R
80°C
NH2
N
1
2e
(3e, 3j)
Scheme 2
In conclusion, we describe a mild and efficient route for the synthesis of quinolines and polycylic
quinolines utilizing choline chloride・2ZnCl as solvent and catalyst via Friedländer annulation under
2
mild conditions. This ionic liquid is cheap, moisture-stable and easy to prepare compared to imidazolium
based ionic liquids.

HETEROCYCLES, Vol. 78, No. 2, 2009
489
Table 1. Choline Chloride・2ZnCl
2
Catalyzed Friedländer Synthesis of Quinolines.
Entry
Substrate 1
Ketone 2
Quinoline 3
Yield/%
88
Ph
O
Ph
O
O
O
1
N
NH2
2a
1
a
3
a
Ph
O
O
O
OEt
2
3
9
8
0
7
1
a
a
OEt
N
Me
2
b
3
b
c
Ph
O
1
O
O
N
2
c
3
Ph
O
4
5
8
8
2
9
1
1
a
a
N
2
d
3
d
e
O
Ph
N
2
2
e
3
Ph
O
Ph
Cl
Cl
Cl
Cl
Cl
O
85
6
7
8
9
a
N
NH2
1
b
3
3
3
f
Ph
O
O
OEt
9
2
1
1
b
b
2b
2c
N
g
h
Ph
89
N
Ph
8
4
1
b
b
2d
2e
N
3
3
i
Ph
N
Cl
1
0
93
1
j

490
HETEROCYCLES, Vol. 78, No. 2, 2009
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
1
13
spectrophotometer. H NMR and C 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·2ZnCl
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 (MgSO ) and concentrated under
2
(0.5 mL)
4
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)
1
1
-1 1
Mp 114-115 ℃ (Lit., 111-112℃). IR (KBr) ν : 3062, 2907, 1696 cm ; H NMR (CDCl
3
) δ : 1.95 (s,
3
1
1
2
H), 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,
1
3
H), 7.63-7.68 (m, 1H), 8.03 (d, J = 8.4Hz, 1H); C NMR (CDCl3, 100 MHz) δ : 23.7, 31.7, 124.8,
25.9, 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 :
+
61 (M ), 246, 218, 176.
2
-Methyl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (3b)
1
1
-1 1
Mp 99-100°C. (Lit., mp 99-100°C). IR (KBr) ν : 3060, 2927, 1710 cm ; H 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,
1
3
1
1
2
H), 7.67 ( t, J = 8.4 Hz, 1H), 8.04 ( d, J = 8.4 Hz, 1H); C NMR (CDCl3, 100 MHz) δ : 13.4, 23.6, 61.1,
+
24.9, 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 ),
46, 245, 218.
3
,3-Dimethyl-9-phenyl-3,4-dihydro-2H-acridin-1-one (3c)
1
1
-1 1
Mp 191°C. (Lit., mp 195°C). IR (KBr) ν : 3065, 2868, 1682 cm ; H 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),
1
3
7
1
.71-7.75 ( m, 1H), 8.06 ( d, J = 8.4 Hz, 1H); C NMR (CDCl3, 100 MHz) δ : 28,2, 32.1, 48.2, 54.0,
22.5, 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.

HETEROCYCLES, Vol. 78, No. 2, 2009
491
5
,6-Dihydro-7-phenylbenzo[c]acridine (3d)
1
2
-1
1
Mp 143-145°C. (Lit., mp 148-149°C). IR (KBr) ν : 3057, 2924, 1574, 14484, 696 cm ; H 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,
1
3
7
1
3
.6Hz, 1H); C NMR (CDCl3, 100 MHz) δ : 26.4, 28.2, 125.9, 126.0, 126.3, 127.2, 127.4, 127.8, 128.0,
+
28.4, 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 ),
06, 305, 230, 152.
2
,3-Dihydro-9-phenyl-1H-cyclopenta[b]quinoline (3e)
1
3
-1 1
Mp 1313-132°C. (Lit., mp 130°C). IR (KBr) ν : 3058, 2923, 1569, 1485, 831 cm ; H NMR (CDCl3,
4
7
3
2
00 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),
1
3
.47-7.54 (m, 3H), 7.60-7.64 (m, 2H), 8.06-8.08 (m, 1H); C NMR (CDCl3, 100 MHz) δ : 23.5, 30.3,
+
5.1, 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 ),
44, 217, 168.
1
-(6-Chloro-2-methyl-4-phenylquinolin-3-yl)ethanone (3f)
1
1
-1 1
Mp 155-156°C (Lit., mp 154°C). IR (KBr) ν : 3049, 2925, 1699 cm ; H NMR (CDCl 400 MHz) δ :
3
,
1
1
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,
1
3
H); C 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,
+
+
34.3, 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)
1
1
-1 1
Mp 102-105°C. (Lit., mp 108°C). IR (KBr) ν : 3075,2926, 1715 cm ; H NMR (CDCl3, 400 MHz) δ :
.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
0
1
3
Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H); C NMR (CDCl3, 100 MHz) δ : 13.3, 23.4, 61.1, 124.8, 125.5, 128.1,
+
1
28.3, 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)
1
1
-1 1
Mp 209-211°C. (Lit., mp 209-211°C). IR (KBr) ν : 3071, 2946, 1693 cm ; H 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),
1
3
7
5
.69 (dd, J = 2.4, 9.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H); C NMR (CDCl 100 MHz) δ : 28.3, 32.2, 48.2,
3
,
4.1, 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)
1
4
-1 1
Mp 134-136°C. (Lit., mp 130°C). IR (KBr) ν : 3052, 2935, 1600, 1479, 698 cm ; H NMR (CDCl3,
00 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
4
1
3
Hz,1H); C NMR (CDCl3, 100 MHz) δ : 26.5, 28.1, 124.8, 126.3, 127.3, 127.7, 127.9, 128.2, 128.7,
29.0, 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
1

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HETEROCYCLES, Vol. 78, No. 2, 2009
+
+
(
M +2), 341 (M ), 304, 152.
7
-Chloro-2,3-dihydro-9-phenyl-1H-cyclopenta[b]quinoline (3j)
1
4
-1 1
Mp 103-104°C. (Lit., mp 105°C). IR (KBr) ν : 3038, 2923, 1601, 1483, 828 cm ; H NMR (CDCl3,
4
7
1
00 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),
1
3
.46-7.58 ( m, 5H), 7.99 ( d, J = 8.8 Hz, 1H); C NMR (CDCl3, 100 MHz) δ : 23.4, 30.3, 35.1, 124.5,
27.0, 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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