A novel preparation of 4-phenylquinoline derivatives in ionic liquids

Article abstract of DOI:10.1002/jccs.200400194

A novel preparation of 4-phenylquinoline derivatives through acid-catalyzed Friedlaender reaction in ionic liquid ([bmim][BF₄]) is described. The preparative procedure presented in this paper is operationally simple and environmentally benign.

Full text of DOI:10.1002/jccs.200400194

Journal of the Chinese Chemical Society, 2004, 51, 1339-1342
1339
A Novel Preparation of 4-Phenylquinoline Derivatives in Ionic Liquids
Xinying Zhang (
Jianji Wang* (
School of Chemical and Environmental Sciences, The Key Laboratory of Environmental Pollution Control
), Xuesen Fan (
),
) and Yanzhen Li (
)
Technology of Henan Province, Henan Normal University, Xinxiang, Henan 453007, P. R. China
A novel preparation of 4-phenylquinoline derivatives through acid-catalyzed Friedländer reaction in
ionic liquid ([bmim][BF4]) is described. The preparative procedure presented in this paper is operationally
simple and environmentally benign. The reaction media and the catalyst used can be recovered and reused for
at least four times without loss in the catalytic activity.
Keywords: Friedländer reaction; Ionic liquid; Quinoline derivatives.
INTRODUCTION
The synthesis of quinoline and its derivatives has been
terest as alternative environmentally benign reaction media.
These solvents are non-volatile, recyclable, non-explosive,
thermally stable, and easy to handle. They have been applied
in various non-catalytic and catalytic reactions,7 as well as
extraction procedures.8 In addition, catalysts with a polar or
ionic character can be immobilized in these ionic media, thus
permitting a practical method of recycling of the catalyst to-
gether with the solvent by simple extraction of products from
the ionic reaction media.9 In line with our research pro-
gramme in using ionic liquid as novel reaction media in or-
ganic reactions,10 herein we wish to report a novel and effi-
cient procedure for the preparation of 4-arylquinolines cata-
lyzed by sulfuric acid in ionic liquid (shown in Scheme I).
of considerable interest to organic and medicinal chemistry
for many years since a large number of natural products1 and
drugs2 contain this heterocyclic nucleus. For instance, a quin-
oline subunit is present in a new class of peptidoleukotriene
LTD4 antagonists developed as antiasthmatic therapeutics,3
in a series of potent 5-lipoxigenase inhibitors and also in
some new anti-inflamatory derivatives.4 Due to their impor-
tance, many methods have already been developed for the
synthesis of quinolines. However, most of these methods are
not fully satisfactory with regard to yield, reaction condi-
tions, generality and operational simplicity. Thus, a simple,
general, and efficient procedure is still in demand for the syn-
thesis of this important heterocycle.
Scheme I
As one of the most frequently used pathways to quino-
line derivatives, the Friedländer synthesis is an acid or base
catalyzed condensation followed by a cyclodehydration be-
tween an aromatic 2-aminoaldehyde or ketone with the car-
bonyl compounds containing a reactive a-methlene group.5
For instance, it has been reported that drops of concentrated
sulfuric acid or 6 N hydrochloric acid can be used as efficient
catalysts in the Friedländer condensation procedure.6 With
this method, various structurally varied substrates can give
the corresponding quinoline products in moderate to high
yields. Unfortunately, this method involves the utilization of
excessive glacial acetic acid as solvent or necessitates a metal
bath to maintain the reaction temperature at as high as 200 °C,
thus making this method unsuitable for an up-scaling pro-
cess.
Ph
Ph
N
R2
R1
X
R2
R1
X
O
Ionic liquid
H SO (cat), 800C
+
O
2
4
NH2
3
1
2
RESULTS AND DISCUSSION
The effectiveness of ionic liquid as solvent for the
Friedländer reaction was examined in the preparation of poly-
substituted quinoline derivatives (3, Scheme I) from 2-ami-
nobenzophenones (1, Scheme I) and ketones containing a re-
active a-methlene group (2, Scheme I). We set out to examine
the reaction in one of the most widely used ionic liquids,
1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]
[BF4]), using drops of concentrated sulfuric acid as catalyst
Room temperature ionic liquids, especially those based
on 1,3-dialkylimidazolium cation is attracting increasing in-

1340 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Zhang et al.
and 2-aminobenzophenone and acetophenone as the starting
materials (entry a, Table 1). The reaction was carried out by
dissolving 0.20 g (1 mmol) of 2-aminobenzophenone in 2 mL
[bmim][BF4] and followed by addition of 0.12 g (1 mmol) of
acetophenone and 2 drops of concentrated sulfuric acid, then
stirring and heating the reaction mixture at 80 °C. The prod-
uct was obtained by simple extraction with diethyl ether of
the reaction mixture and subsequent purification through a
silica gel column as a light yellow solid. The yield of the
product was found to be higher than in the case where a con-
ventional solvent, glacial acetic acid,6 was used (entry a, Ta-
ble 1).
Table 1. Synthesis of quinoline derivatives through Friedländer
reaction in ionic liquid
Entry X
R1
R2 Reaction time Products Yield (%)a
(h)
a
b
c
d
e
f
g
h
i
H
H
H
H
Cl
C6H5
4-BrC6H4
4-NO2C6H4
CH3
H
H
H
H
H
H
H
H
H
H
5
5
4
8
5
5
5
5
4
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
77, 67b
82
86
72c
75
C6H5
Cl 4-CH3C6H4
Cl 4-ClC6H4
Cl 4-BrC6H4
Cl 4-NO2C6H4
72
78
80
88
j
Cl
CH3
3j
73c
The process was then extended to other structurally
varied substrates and the results are listed in Table 1. We can
see from this table that in a similar fashion, a wide range of
ketones containing a reactive a-methlene group underwent
smooth condensation with 2-aminobenzophenones to give
substituted quinolines with short reaction times and in rea-
sonably high yields. It is worth noting that both aliphatic and
aromatic-aliphatic ketones gave the corresponding quinoline
products in almost equally fair yields. In addition, higher
yields were obtained with 4-nitroacetophone (entries c and i,
Table 1), showing that the yields of quinolines are to some ex-
tent affected by the nature of the substituents attached to the
aromatic ring of ketones.
a Isolated yields. b Yield reported in Ref. 6. c Reaction
temperature is 40 °C.
Table 2. Reusability of [bmim][BF4] together with the catalyst
Round
Yield (%)
Ionic liquid recovered (%)
1
2
3
4
77
78
75
70
99
98
95
94
other new uses of ionic liquid in the preparation of hetero-
cyclic compounds are now in progress in our laboratory.
Our attention was then directed toward the possibility
of recycling the reaction media since recovery and reuse of
the catalyst and solvent are highly preferable for a greener
process. In this work, the catalyst could be immobilized in
[bmim][BF4] at the end of the condensation reaction. After
extraction of the product with diethyl ether, the solvent
[bmim][BF4] and the catalyst could be recovered easily by
drying at 80 °C under reduced pressure for several hours. In-
vestigations by using 2-aminobenzophenone and acetophe-
none as model substrates showed that even in the fourth
round, reuse of the ionic liquid and the catalyst recovered
from the third round still gave the corresponding product
with fairly good yields (Table 2, entry 4).
EXPERIMENTAL
Melting points were measured by a Kofler micro-melt-
ing point apparatus and were uncorrected. Infrared spectra
were recorded on a Bruker Vector 22 spectrometer in KBr
with absorption in cm-1. 1H NMR spectra were determined on
a Bruker AC 400 spectrometer as CDCl3 solutions. Chemical
shifts (d) were expressed in ppm downfield from the internal
standard tetramethylsilane and coupling constants J were
given in Hz. Mass spectra were recorded on a HP5989B mass
spectrometer. Elemental analyses were performed on an EA-
1110 instrument.
In summary, this paper describes a modification of the
classical Friedländer reaction and presents a novel and effi-
cient method for the preparation of 4-phenylquinoline deriva-
tives by using ionic liquid as solvent and sulfuric acid as cata-
lyst. The simple experimental procedure combined with the
ease of recovery and reuse of the catalyst together with the
environmentally benign reaction media is expected to con-
tribute to the development of a greener and waste free chemi-
cal process for the preparation of quinoline derivatives with
potential biological activities. Further studies to develop
Typical procedure for the preparation of 2,4-diphenyl-
quinoline
2-Aminobenzophenone (1 mmol), acetophenone (1
mmol) and 2 drops of concentrated sulfuric acid were added
to a 10 mL round-bottomed flask containing 2 mL [bmim]
[BF4]. Then the mixture was stirred at 80 °C for 5 h. After
completion, the reaction mixture was extracted with diethyl

Preparation of 4-Phenylquinoline Derivatives
J. Chin. Chem. Soc., Vol. 51, No. 6, 2004 1341
ether (3 ´ 10 mL). The combined ether extractions were con-
centrated under reduced pressure and the resulting product
was charged on silica gel column and eluted with a mixture of
ethyl acetate/n-hexane (1:8) to afford pure 2,4-diphenyl-
quinoline. The rest of the viscous ionic liquid together with
the catalyst was dried at 80 °C under reduced pressure to re-
tain its activity for subsequent use. Other quinoline products
can be obtained in a similar fashion.
Calcd for C21H14ClN: C 79.87, H 4.47, N 4.44; Found: C
79.95, H 4.43, N 4.35.
6-Chloro-2-(4-methylphenyl)-4-phenylquinoline (3f)
M.p. 132-134 °C; IR n 3048, 1600, 1580 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.20 (d, 1H, J = 8.4 Hz), 8.09 (d, 2H, J =
8.0 Hz), 7.85 (d, 1H, J = 3.5 Hz), 7.82 (s, 1H), 7.67-7.64 (m,
1H), 7.57-7.52 (m, 5H), 7.33 (d, 2H, J = 8.0 Hz), 2.43 (s, 3H);
MS m/z (%): 331 (M+ + 2, 33.5), 329 (M+, 100), 294 (23).
Anal. Calcd for C22H16ClN: C 80.11, H 4.89, N 4.25; Found:
C 80.25, H 4.78, N 4.33.
2,4-Diphenylquinoline (3a)
M.p. 110-111 °C (lit. 112-113 °C11); IR n 3045, 1615,
1590 cm-1; 1H NMR (400 MHz, CDCl3) d 8.26 (d, 1H, J = 8.4
Hz), 8.19-8.22 (m, 2H), 7.91 (dd, 1H, J1 = 8.4 Hz, J2 = 1.2
Hz), 7.83 (s, 1H), 7.72-7.76 (m, 1H), 7.47-7.59 (m, 9H); MS
m/z (%): 281 (M+, 70), 280 (M+ - 1, 100), 202 (9), 139 (8).
6-Chloro-2-(4-chlorophenyl)-4-phenylquinoline (3g)
M.p. 164-166 °C; IR n 3058, 1605, 1587 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.26 (d, 1H, J = 8.4 Hz), 8.15 (d, 2H, J =
8 Hz), 7.87 (d, 1H, J = 2.2 Hz), 7.80 (s, 1H), 7.68-7.71 (m,
1H), 7.50-7.59 (m, 7H); MS m/z (%): 353 (M+ + 4, 11.7), 351
(M+ + 2, 64.9), 349 (M+, 100), 314 (33.8). Anal. Calcd for
C21H13Cl2N: C 72.02, H 3.74, N 4.00; Found: C 72.07, H
3.71, N 4.03.
2-(4-Bromophenyl)-4-phenylquinoline (3b)
1
M.p. 128-129.5 °C; IR n 3050, 1610, 1590 cm-1; H
NMR (400 MHz, CDCl3) d 8.23 (d, 1H, J = 8.0 Hz), 8.08-8.11
(m, 2H), 7.90 (d, 1H, J = 8.0 Hz), 7.72-7.78 (m, 2H),
7.64-7.67 (m, 2H), 7.47-7.59 (m, 6H); MS m/z (%): 361 (M+
+ 2, 89), 360 (M+ + 1, 100), 359 (M+, 89), 358 (M+ - 1, 95),
278 (40), 202 (17), 139 (25). Anal. Calcd for C21H14BrN: C
70.01, H 3.92, N 3.89; Found: C 69.85, H 3.88, N 3.73.
6-Chloro-2-(4-bromophenyl)-4-phenylquinoline (3h)
M.p. 174-176 °C; IR n 3061, 1600, 1590 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.14 (d, 1H, J = 8.8 Hz), 8.07 (d, 2H, J =
8.8 Hz), 7.85 (d, 1H, J = 2.2 Hz), 7.79 (s, 1H), 7.64-7.68 (m,
3H), 7.54-7.58 (m, 5H); MS m/z (%): 397 (M+ + 4, 25.8), 395
(M+ + 2, 100), 393 (M+, 79.0), 358 (17.5). Anal. Calcd for
C21H13BrClN: C 63.90, H 3.32, N 3.55; Found: C 63.85, H
3.21, N 3.53.
2-(4-Nitrophenyl)-4-phenylquinoline (3c)
M.p. 162-163 °C; IR n 3061, 1620, 1595 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.37-8.42 (m, 4H), 8.31 (d, 1H, J = 8.0
Hz), 7.96 (d, 1H, J = 8.0 Hz), 7.87 (s, 1H), 7.80 (t, 1H, J = 8.0
Hz), 7.54-7.59 (m, 6H); MS m/z (%): 326 (M+, 100), 202 (23).
Anal. Calcd for C21H14N2O2: C 77.29, H 4.32, N 8.58; Found:
C 77.15, H 4.48, N 8.63.
6-Chloro-2-(4-nitrophenyl)-4-phenylquinoline (3i)
M.p. 218-220 °C; IR n 3038, 1610, 1525 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.34-8.38 (m, 4H), 8.20 (d, 1H, J = 8.0
Hz), 7.90 (d, 1H, J = 2.4 Hz), 7.88 (s, 1H), 7.54-7.60 (m, 5H),
7.23 (dd, 1H, J1 = 9.2 Hz, J2 = 2.4 Hz); MS m/z (%): 362 (M+ +
2, 34), 360 (M+, 100), 314 (40), 278 (32), 139 (20). Anal.
Calcd for C21H13ClN2O2: C 69.91, H 3.63, N 7.76; Found: C
69.94, H 3.68, N 7.59.
2-Methyl-4-phenylquinoline (3d)
1
M.p. 93-95 °C; IR n 3057, 2971, 1617, 1485 m-1; H
NMR (400 MHz, CDCl3) d 8.09 (d, 1H, J = 8.4 Hz), 7.85 (dd,
1H, J1 = 8.4 Hz, J2 = 0.8 Hz), 7.66-7.70 (m, 1H), 7.45-7.55
(m, 5H), 7.40-7.45 (m, 1H), 7.22 (s, 1H), 2.77 (s, 3H); MS
m/z (%): 219 (M+, 100), 218 (M+ - 1, 48), 204 (14), 176 (10).
Anal. Calcd for C16H13N: C 87.64, H 5.98, N 6.39; Found: C
87.48, H 6.12, N 6.46.
6-Chloro-2-methyl-4-phenylquinoline (3j)
1
M.p. 88-90 °C; IR n 3050, 2978, 1610, 1496 cm-1; H
NMR (400 MHz, CDCl3) d 8.02 (d, 1H, J = 9.2 Hz), 7.82 (d,
1H, J = 2.4 Hz), 7.62 (dd, 1H, J1 = 9.2 Hz, J2 = 2.4 Hz),
7.46-7.57 (m, 5H), 7.26 (s, 1H), 2.77 (s, 3H); MS m/z (%):
255 (M+ + 2, 32), 253 (M+, 100), 218 (40), 176 (11). Anal.
Calcd for C16H12ClN: C 75.74, H 4.77, N 5.52; Found: C
75.88, H 4.62, N 5.63.
6-Chloro-2,4-diphenylquinoline (3e)
M.p. 130-132 °C; IR n 3050, 1610, 1589 cm-1; 1H NMR
(400 MHz, CDCl3) d 8.11-8.15 (m, 3H), 7.82 (d, 1H, J = 2.2
Hz), 7.76 (s, 1H), 7.59-7.60 (m, 2H), 7.45-7.50 (m, 7H); MS
m/z (%): 317 (M+ + 2, 33.9), 315 (M+, 100), 280 (32.0). Anal.

1342 J. Chin. Chem. Soc., Vol. 51, No. 6, 2004
Zhang et al.
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ACKNOWLEDGEMENT
This work was financially supported by the National
Natural Science Foundation of China (under NSFC grant No.
20273019) and the Research Foundation of Henan Normal
University.
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Received January 8, 2004.
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