Friedlaender synthesis of poly-substituted quinolines in the presence of triethylammonium hydrogen sulfate [Et3NH][HSO4] as a highly efficient, and cost effective acidic ionic liquid catalyst

Article abstract of DOI:10.1002/jhet.683

A rapid and an efficient method for the preparation of a variety of substituted quinolines has been developed through the reactions of o-aminoarylketones with carbonyl compounds containing a reactive α-methylene moiety in the presence of molten [Et_3<

Full text of DOI:10.1002/jhet.683

¨
1192
Friedlander Synthesis of Poly-Substituted Quinolines in the
Vol 48
Presence of Triethylammonium Hydrogen Sulfate
[Et3NH][HSO4] as a Highly Efficient, and Cost
Effective Acidic Ionic Liquid Catalyst
Esmat Tavakolinejad Kermani,* Hojatollah Khabazzadeh,*
and Tayebeh Jazinizadeh
Department of Chemistry, Shahid Bahonar University of Kerman, 76169 Kerman, Iran
*E-mail: etavakoly@yahoo.com or hkhabazzadeh@mail.uk.ac.ir
Received March 9, 2010
DOI 10.1002/jhet.683
Published online 11 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
A rapid and an efficient method for the preparation of a variety of substituted quinolines has been
developed through the reactions of o-aminoarylketones with carbonyl compounds containing a reactive
a-methylene moiety in the presence of molten [Et3NH][HSO4] under solvent-free conditions in high yields.
J. Heterocyclic Chem., 48, 1192 (2011).
INTRODUCTION
sure and are nonexplosive and thermally stable in a wide
temperature range [4]. Furthermore, they are often immisci-
ble with organic solvents because of their polar nature and
may therefore be used in biphasic systems. Now ionic
liquids have been used as environmentally benign solvents
or catalysts for a number of chemical processes [5], such as
separations [6], reactions [7], homogeneous two phase catal-
ysis [8], and polymerizations [9]. The current emphasis on
alternate reaction media is motivated by the need for effi-
cient methods for replacing toxic or hazardous solvents and
catalysts. The use of ionic liquids as alternate reaction media
may offer a convenient solution to both the solvent emission
and the catalyst recycling problem [10].
The majority of chemical transformations are done in
solution to more efficiently control the heat flow of exo-
thermic and endothermic reactions. In addition, polar
reactions that proceed via polar or ionic intermediates or
transition states are promoted by polar solvents due to a
strong stabilization by solvation. The organic reactions
that can be performed in the solid state [1] or solvent-
free are limited. Several solvents used for reactions in the
laboratory and industry belong to the group of volatile or-
ganic compounds. Solvents like chlorinated hydrocarbons
derived from methane, ethane, and propane are volatile
and chemically relatively stable; they are harmful to the
environment. Because of their persistence, they accumu-
late in the atmosphere and contribute to ozone depletion
and to smog in urban areas [2]. To overcome this concern
of synthetic organic chemistry, new ‘‘green solvents’’
have been developed, which are slowly finding their way
into chemical laboratories and industries. The new
‘‘green’’ solvents include supercritical carbon dioxide,
ionic liquids, water, and fluorous biphasic mixtures [3].
Ionic liquids have attracted considerable interest as envi-
ronmentally friendly or ‘‘green’’ alternates to conventional
molecular organic solvents they have very low vapor pres-
Notwithstanding the unique advantages of ionic
liquids as reaction media and catalysts, currently they
have not been widely applied in industry. The reason
for this is probably related to the high cost of ionic
liquids, the difficulty in separation or recycling, the pau-
city of data with regard to their toxicity and biodegrad-
ability, and so on. Recently, some new ionic liquids
have been prepared via a simple and atomeconomic
acid–base neutralization reaction. For example, Noda
et al. [11] reported the preparation and application of
the Brønsted acid–base ionic liquids from imidazole and
bis(trifluoromethanesulfonyl) amide. Han and coworkers
C
V
2011 HeteroCorporation

¨
Friedlander Synthesis of Poly-Substituted Quinolines in the Presence of
Triethylammonium Hydrogen Sulfate [Et3NH][HSO4]
September 2011
1193
¨
Scheme 1. [Et3NH][HSO4]-Catalyzed Friedlander synthesis of quinolines.
[12] prepared new ionic liquids by neutralization of 1,
1, 3, 3- tetramethylguanidine with different acids. How-
ever, the preparation of simple ammonium ionic liquid
via acid–base neutralization from cheap amine and acid
is absence in the literature.
this reaction is usually carried out in polar and in aprotic
solvents such as acetonitrile, tetrahydrofuran (THF),
dimethyl sulfoxide (DMSO), and dimethylformamide
(DMF) leading to tedious work-up procedures. Thus, the
development of simple, convenient, and environmentally
benign methods for the synthesis of quinolines is still
required. To overcome these problems, herein, we
describe the utility of [Et3NH][HSO4] in molten state
(Scheme 1), which is a mild acidic, nonvolatile, and non-
Quinolines and their derivatives are very important bio-
logical compounds that occur widely in natural products.
Some members of this family have displayed interesting
physiological activities and found attractive applications
in medicinal chemistry, being used as antimalarial [13],
antibacterial [14], anti-inflammatory [15], antihypertensive
[16], antiplatelet agents, and as tyrosine kinase inhibiting
agents [17]. In addition, quinolines are valuable synthons
used in a variety of nanostructures and mesostructures
with enhanced electronic and photonic functions [18].
Also, quinolines have been used in the study of bioor-
ganic and bioorganometallic processes [19]. There has
been tremendous interest in developing efficient methods
for quinoline synthesis [20]. Among these methods, the
¨
corrosive ionic liquid, as an efficient Bronsted acid cata-
lyst in solvent-free conditions for the Friedlander reaction.
¨
RESULTS AND DISCUSSION
Initial study was performed by treatment of 2-amino-
5-chlorobenzophenone with ethyl acetoacetate under sol-
vent-free conditions in the presence of [Et3NH][HSO4].
Best results were obtained with molar ratio 1:1.1:2 for
2-amino-5-chlorobenzophenone, ethyl acetoacetate, and
[Et3NH][HSO4] at 100ꢀC. To demonstrate the generality
of this method, we next investigated the scope of this
reaction, and the results are summarized in Table 1.
As shown in Table 1, this method is equally effective
for both cyclic and acyclic ketones. Substituted 2-amino-
aryl ketones, such as 2-aminobenzophenone and 2-amino-
5-chlorobenzophenone reacted smoothly with methylene
ketones to produce a range of quinoline derivatives. This
reaction is very clean and free from side reactions such as
self-condensation of ketones, which is normally observed
under basic conditions. Also, simple experimental proce-
dure and easy workup is another advantage of this
method. A reasonable pathway for the reaction of 2-amino
arylketone with carbonyl compounds conducted in the
presence of [Et3NH][HSO4] is presented by Scheme 2.
¨
Friedlander annulation is still one of the most simple and
straightforward procedures for the synthesis of poly-sub-
stituted quinolines.
¨
The Friedlander quinoline synthesis involves a con-
densation reaction between an aromatic ortho-aminoaryl
ketone or aldehyde with an aldehyde or ketone contain-
ing an a-methylene group, and then a cyclodehydration.
This reaction is generally carried out by refluxing either
an aqueous or an alcoholic solution of reactants in the
presence of a base at high temperature, 150–220ꢀC, in
the absence of a catalyst. However, under basic or ther-
mal-catalysis conditions, ortho-aminobenzophenone does
not react with simple ketones, such as cyclohexanone
¨
and b-keto esters. Bronsted acid catalysts such as hydro-
chloric acid, sulfuric acid, p-toluenesulfonic acid, and
polyphosphoric acid have been widely used [21]. Also,
modified methods, using Lewis acid [22] and inorganic
salt catalysts [21], ionic liquids [23], microwave condi-
tions [24], and molecular iodine [25] have been reported
for this reaction. Many of these procedures have signifi-
cant drawbacks such as low yields of the products, long
reaction times, and harsh reaction conditions. Moreover,
EXPERIMENTAL
All chemicals were purchased from Merck chemical com-
pany and were used without further purification. All products
are known and were identified by comparison of their spectral
data and physical properties with those of the authentic
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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E. Tavakolinejad Kermani, H. Khabazzadeh, and T. Jazinizadeh
Vol 48
Table 1
ꢀ
¨
[Et3NH][HSO4]-Catalyzed Fridedlander synthesis of quinolines under solvent-free conditions at 100 C.
Entry
Y
H
Ketone 2
Product 3
Time (min)
40
Yield (%)
3a
3b
3c
3d
3e
3f
93
88
92
85
93
80
80
89
94
81
93
65
Cl
H
20
25
30
47
25
20
25
15
45
30
70
Cl
H
H
3g
3h
3i
Cl
H
Cl
H
3j
3k
3l
Cl
H
samples. Melting points were obtained in open capillary tubes
and were measured on a Gallenkamp apparatus. IR spectra
were recorded using KBr pellets on a Bruker IR spectropho-
tometer. 1H- and 13C-NMR spectra were determined on a
Bruker 500-DRX Avance instrument at 500 and 125 MHz.
General procedure for preparation of substituted
quinolines. 2-Amino aryl ketone 1 (1 mmol) was added to 1.1
mmol ketone 2 and 2.0 mmol [Et3NH][HSO4]. The reaction mix-
ture was stirred at 100ꢀC for appropriate time. After completion
of the reaction (monitored by thin layer chromatography (TLC)),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Friedlander Synthesis of Poly-Substituted Quinolines in the Presence of
Triethylammonium Hydrogen Sulfate [Et3NH][HSO4]
September 2011
1195
Scheme 2. A reasonable mechanism for the reaction of 2-amino arylketones with carbonyl compounds.
10 mL of ethanol was added. The mixture was poured into cold
water, and resulting precipitate was recrystalyzed from ethanol to
give pure product 3.
use of various substrates, which make it a useful and an
attractive strategy for the synthesis of quinoline derivatives.
Ethyl-6-chloro-2-methyl-4-phenylquinoline-3-carboxylate
1
Acknowledgments. We gratefully acknowledge the financial
support from the Research Council of Shahid Bahonar University
of Kerman.
(3b). Mp (ꢀC): 90; IR (KBr): 3078, 2977, 1720 cmꢁ1; H-NMR
(CDCl3): d (ppm) 0.98 (t, J ¼ 7.0 Hz, 3H, CH3), 2.81 (s, 3H,
CH3), 4.10 (q, J ¼ 7.0 Hz, 2H, CH2), 7.37 (m, 2H, Ar-H), 7.52
(m, 3H, Ar-H), 7.57 (s, 1H, Ar-H), 7.68 (d, J ¼ 8.8 Hz, 1H,
Ar-H), 8.05 (d, J ¼ 8.8 Hz, 1H, Ar-H). 13C-NMR (CDCl3):
d (ppm) 14.0, 24.1, 61.9, 125.7, 126.4, 128.6, 128.9, 129.2,
129.7, 130.9, 131.6, 132.8, 135.4, 146.0, 147.0, 155.4, 168.5.
1-(6-Chloro-2-methyl-4-phenylquinoline-3-yl)ethanone
(3d). Mp (ꢀC): 150; IR (KBr): 3051, 2927, 1700 cmꢁ1; 1H-NMR
(CDCl3): d (ppm) 2.02 (s, 3H, CH3), 2.71 (s, 3H, CH3), 7.36 (d, J
¼ 2.3Hz, 1H, Ar-H), 7.37 (d, J ¼ 3.5 Hz, 1H, Ar-H), 7.54–7.56
(m, 3H, Ar-H), 7.60 (d, J ¼ 2.2 Hz, 1H, Ar-H), 7.67 (dd, J ¼ 2.3
Hz, J ¼ 8.9 Hz, 1H, Ar-H), 8.04 (d, J ¼ 8.9 Hz, 1H, Ar-H). 13C-
NMR (CDCl3): d (ppm) 24.2, 32.2, 125.3, 126.3, 129.4, 129.7,
130.4, 130.9, 131.4, 132.9, 134.9, 135.9, 143.6, 146.3, 154.4,
205.6.
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In conclusion, we have reported an efficient procedure for
the synthesis of quinoline derivatives using [Et3NH][HSO4]
as nontoxic, noncorrosive, and homogeneous catalyst in
molten state. The method offers advantages such as clean
reaction, high yields of products, short reaction times, and
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E. Tavakolinejad Kermani, H. Khabazzadeh, and T. Jazinizadeh
Vol 48
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