Sulfonic acid functionalized ionic liquid in combinatorial approach, a recyclable and water tolerant-acidic catalyst for one-pot friedlander quinoline synthesis

Article abstract of DOI:10.1021/cc9001313

SO₃H-functionalized ionic liquid was successfully applied as a water tolerant-acidic catalyst for the one-pot domino approach quinoline synthesis in aqueous medium. Various types of quinolines from 2-aminoaryl ketones and β-ketoesters/ketones w

Full text of DOI:10.1021/cc9001313

J. Comb. Chem. 2010, 12, 137–140
137
Sulfonic Acid Functionalized Ionic Liquid in Combinatorial
Approach, a Recyclable and Water Tolerant-Acidic Catalyst for
One-Pot Friedlander Quinoline Synthesis|
Jafar Akbari,† Akbar Heydari,*,† Hamid Reza Kalhor,‡ and Sirus Azizian Kohan§
Chemistry Department, Tarbiat Modares UniVersity, P.O. Box 14155, 4938 Tehran, Iran, Biochemistry
Department, Tarbiat Modares UniVersity, Tehran, Iran, Molecular and Medical Pharmacology
Department and The Crump Institute, UCLA School of Medicine, Los Angeles, California 90024
ReceiVed August 23, 2009
SO3H-functionalized ionic liquid was successfully applied as a water tolerant-acidic catalyst for the one-pot
domino approach quinoline synthesis in aqueous medium. Various types of quinolines from 2-aminoaryl
ketones and ꢀ-ketoesters/ketones were prepared in 85-98% yields using the catalytic system of SO3H-
functionalized ionic liquid/H2O. The ionic liquids was synthesized in a combinatorial fashion. The quinoline
products could be conveniently separated from the reaction mixture by filtration, indicating that the whole
process was performed in water and exemplifying a green chemistry. More importantly, the catalyst could
be easily recycled for five times without loss of much activity. The catalytic system, reported here, possesses
advantages of both homogeneous and heterogeneous catalysts.
1. Introduction
Zr(NO3)4, Y(OTf)3, and CAN(Cerium(IV) Ammonium Ni-
trate) have been reported for the synthesis of quinolines.10
However, many of these procedures have significant draw-
backs including low yields, long reaction times, harsh
reaction conditions, difficulties in workup, and the use of
stoichiometric amounts of catalysts. Moreover, the main
disadvantage of almost all existing methods is that the
catalysts are destroyed in the workup and cannot be
recovered. Recently, Srinivasan et al. have reported a
stoichiomethric amount of [HBIm][BF4] promoted quinoline
synthesis.11 However, these ionic liquids are sensitive to
moisture and are unstable in water,12 and a stoichiomethric
amount of ionic liquids is required. Consequently, the
development of water stable acidic catalyst for quinoline
synthesis is quite desirable.
Quinolines are very important compounds partially because
of their pharmacological properties which include wide
applications in medicinal chemistry; notable among them are
antimalarial drugs, anti-inflammatory agents, antiasthamatic,
antibacterial, antihypertensive, and tyrosine kinase inhibiting
agents.1-3 In addition, quinolines have been used for the
preparation of nano and mesostructures with enhanced
electronic and photonic properties.4 Despite quinoline usage
in pharmaceutical and other industries, comparatively few
methods for their preparation have been reported. Although
other methods such as Skraup, Doebner von Miller, and
Combes procedures for the preparation of quinolines have
been reported,5,6 the Friedlander annulation is one of the
simplest and most straightforward methods for the synthesis
of poly substituted quinolines. This method has attracted
considerable attention from the view point of combinatorial
chemistry.7 The Friedlander synthesis is an acid or base
catalyzed condensation followed by a cyclodehydration
between 2-aminoaryl ketone and a second carbonyl com-
pound including a reactive methylene group. Generally, this
reaction is carried out by refluxing an aqueous or an alcoholic
solution of reactants in the presence of a base at high
temperature.8 Under thermal or base catalysis conditions,
O-aminobenzophenone does not react with simple ketones
such as cyclohexanone and ꢀ-keto esters.9 In addition,
modified methods employing ZnCl2, phosphoric acid,
Bi(OTf)3, silver phosphotungstate, sodium fluoride, AuCl3,
One of the main principles of green chemistry is to develop
cost-effective and environmentally benign catalytic systems
which have become one of the main themes of contemporary
synthetic chemistry.13 Ionic liquids have been considered as
eco-friendly alternatives to volatile organic media because
of their negligible vapor pressure and nonflammable nature.14
One of the most remarkable feature of ionic liquids is that
the yields can be optimized by changing the anions or the
cations. Additionally, the incorporation of functional groups
can render a particular capability to the ionic liquids,
enhancing their function, which may lead to increase
reusability and stability of ionic liquids compared with the
unfunctionalized counterparts. Moreover, specific functional
groups can also be incorporated for task-specific purposes.13
Recently, sulfonic acid functionalized ionic liquids were used
as solvent-catalyst for several organic reactions such as
esterifications, Aldol condensation, Pinacole reaction, aro-
matic nitration, Biginelli reaction, and Fisher indole synthe-
sis.15 The use of such task specific ionic liquids (TSILs) as
| Dedicated to the memory of Fereidoon Ektheraei.
* To whom correspondence should be addressed. E-mail: akbar.heydari@
gmx.de. Fax: (+98) 2182883455.
† Chemistry Department, Tarbiat Modares University.
‡ Biochemistry Department, Tarbiat Modares University.
§ UCLA School of Medicine.
10.1021/cc9001313 CCC: $40.75  2010 American Chemical Society
Published on Web 11/02/2009

138 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Scheme 1. TSIL Catalyzed Friedlander Reaction
Akbari et al.
The results, shown in Table 2 indicate no significant loss of
activity of the TSIL. The recycled catalyst was characterized
with H and 13CNMR spectroscopies to confirm that its
1
structure is the same as that of the original fresh catalyst.
3. Conclusion
In summary, we have demonstrated an efficient procedure
for the synthesis of quinolines, using sulfonic acid function-
alized ionic liquid as homogeneous and reusable catalyst.
Although the reaction was accomplished in the homogeneous
model, isolation of the desired products as well as ionic
liquids could be achieved via a simple filtration, and the TSIL
could be reused. The catalytic system possesses properties
of both homogeneous and heterogeneous catalysis. The
advantages of this functionalized ionic liquid are that it can
be readily synthesized and the TSIL can be used as an
efficient catalyst as well as easily being recycled without
any decrease in catalytic activity. Moreover, this methodol-
ogy offers significant improvements in regard to the yield
of products and emphasizes the green chemistry aspects by
avoiding toxic catalysts and solvents.
catalysts is an area of current investigations and as afore-
mentioned, these TSILs may further expand the application
of ionic liquids in chemistry. These ILs are miscible in water,
and their homogeneous system is readily separated from the
reaction product, combining advantages of both homoge-
neous and heterogeneous catalysis. In continuation of our
interest in ionic liquid mediated chemical and biochemical
transformations,16 we herein report the one pot domino
approach for the synthesis of quinoline derivatives in
Friedlander manner using TSIL as a catalyst (Scheme 1). In
this reaction, the catalyst plays a dual role; it ensures an
effective condensation and cyclization of 2-aminoaryl ketone
with second carbonyl group and it also promotes the
aromatization to the final product. The approach is shown
in Scheme 1. This would be a novel application of SO3-H
functionalized ionic liquid acting as a catalyst for the
Friedlander quinoline synthesis.
Experimental Section
Preparation of ionic liquids: The synthesis of this ionic
liquid has been carried out using a similar method reported
in the literature.14c The method involves the reaction of
neutral nucleophiles N-methyl imidazole with 1,4-butane
sultone in equimolar ratio to afford the zwitterions that are
further converted into ionic liquid by acidification with
Trifilic acid in a combinatorial approach. The ionic liquid
was formed quantitatively and in high purity as assessed by
NMR.15
General Procedure for One-Pot Synthesis of Quino-
lines. TSIL (0.018 gr, 0.1 mmol) was added to a mixture
of 2-aminoaryl ketones (2 mmol) and ꢀ-ketoester/1,3-
diketone/cyclic ketone (2 mmol) in water (1 mL) at 70
°C. The mixture was stirred until completion of the
reaction, as indicated by TLC. The ionic liquid was
separated from the reaction mixture by extraction with
water. The ionic liquid being soluble in water comes in
the water layer. The products were separated by filtration
and vacuum-dried. The product was identified using NMR
in CDCl3. The ionic liquid in the filtrate was separated
from the unreacted starting materials by extracting the
filtrate with ether. Then, the water layer containing ionic
liquid was vacuum-dried at 70 °C for 5 h to remove water,
and the ionic liquid was reused.
2. Results and Discussion
Initially, we performed the reaction of 2-aminobenzophe-
none with ethyl acetoacetate to examine the potential of the
TSIL as catalyst in water as a solvent in room temperature.
The reaction turned out to be clean and simple, giving the
Friedlander condensation products in good to excellent yields.
Subsequently, we applied the condition to a variety of 2-
aminoaryl ketones and ꢀ-ketoesters (Table 1, entries 1, 2, 3,
9, 12). In addition, various 1, 3-diketones reacted with
2-aminoaryl ketones to give the corresponding quinolines
(Table 1, entries 4, 5, 6, 10, 11, 13). In the subsequent step,
we directed our study to use simple cyclic ketones and it
became apparent that the reactions proceed slower than the
other compounds (entries 7, 8).
To investigate the effect of solvent, we examined the
possibility to run the reaction in the presence of water.
Interestingly, no product in the absence of water was
observed. Indeed, it has been previously shown that the water
content certainly has an effect on the activity of the TSIL.17
Moreover, the role of water seems to be well-known in the
Friedlander reaction.18 Although the reaction seems to occur
in the concentrated organic phase constituting the reagents,
the presence of water could assist the reaction to proceed
causing the precipitation of the product. Finally, the water
tolerant acidic catalyst could be used as homogeneous
catalyst because of its good solubility in water and at the
end of the reaction the product can be precipitated and
subsequently, the catalyst may be recycled from water. The
reusability of TSIL was assessed by conducting Friedlander
reaction of 2-aminobenzophenon and ethylacetoacetate over
five successive cycles without any pretreatment of the TSIL.
Physical and Spectral Data for Selected Products. entry
1: Mp 105-106 °C. IR (neat) 3061.6, 2981.5, 1725.9, 1564.2,
1402.3, 1231.0, 1066.1 cm-1. 1H NMR (CDCl3, 500 MHz) δ
0.97 (t, J ) 7.2 Hz, 3H), 2.82 (s, 3H), 4.10 (q, J ) 7.2 Hz,
2H), 7.37-7.42 (m, 2H), 7.45-7.54 (m, 4H), 7.62 (dd, J )
8.4, 1.0 Hz, 1H), 7.75 (td, J ) 8.3, 1.5 Hz, 1H), 8.11 (d, J )
8.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 14.1, 24.3, 61.8,
125.5, 126.8, 126.9, 127.8, 128.7, 128.9, 129.3, 129.8, 130.7,
136.1, 146.7, 148.1, 155.0, 168.9; entry 7: Mp 131-132°. IR
(neat) 3059.7, 2958.1, 1611.7, 1573.0, 1492.9, 1385.8, 1211.4,
1
1026.2 cm-1. C. H NMR (CDCl3, 500 MHz) δ: 1.64-1.66

Sulfonic Acid Functionalized Ionic Liquid
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 139
Table 1. Synthesis of Quinoline Derivatives Catalyzed by TSIL in Watera
a Conditions: (A): 5 mol % TSIL, 70 °C; (B) 5 mol % TSIL, 90 °C; (C) 5 mol % TSIL, 90 °C, 1.5 equiv of 2 was used.
Table 2. Catalyst Recycling of TSIL for Quinoline Synthesis
129.9, 134.2, 138.1, 145.9, 146.2, 165.2.134.0, 137.1, 143.0,
148.4, 167.9; entry 8: Mp 148-149 °C. IR (neat) 3059.7,
2923.2, 1580.3, 1488.2, 1398.3, 1196.3, 1028.7 cm-1. 1H NMR
(CDCl3, 500 MHz) δ: 1.78-1.86 (m, 2H), 1.94-2.04 (m, 2H),
2.63 (t, J ) 6.3 Hz, 2H), 3.23 (t, J ) 6.6 Hz, 2H), 7.24-7.35
(m, 4H), 7.49-7.66 (m, 4H), 8.05 (d, J ) 8.4 Hz, 1H). 13C
NMR (CDCl3, 125 MHz) δ: 23.3, 23.4, 28.5, 34.7, 125.8, 126.2,
127.1, 128.1, 128.8, 129.0, 129.5, 137.6, 146.7, 146.9, 159.
entry
cycle
product yield
1
2
3
4
5
6
fresh
first recycle
second recycle
third recycle
fourth recycle
fifth recycle
98
98
98
96
96
96
(m, 2H), 1.88-1.89 (m, 4H), 2.70-2.75 (m, 2H), 3.31-3.33
(m, 2H), 7.24-7.38 (m, 4H), 7.48-7.65 (m, 4H), 8.06 (d, J )
8.4 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ: 27.5, 28.9, 31.1,
32.4, 40.6, 126.0, 126.8, 127.3, 128.0, 128.6, 128.9, 129.0,
Acknowledgment. This research was supported by the
National Research Council of the Islamic Republic of Iran
as a National Research project no. 984.

140 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
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CC9001313