New pyridinium-based ionic liquid as an excellent solvent-catalyst system for the one-pot three-component synthesis of 2,3-disubstituted quinolines

Article abstract of DOI:10.1021/co400144b

The synthesis of a variety of 2,3-disubstituted quinolines has been achieved successfully via a one-pot three-component reaction of arylamines, arylaldehydes and aliphatic aldehydes in the presence of butylpyridinium tetrachloroindate(III), [bpy][InCl₄], ionic liquid as a green catalyst and solvent. Mild conditions with excellent conversions, and simple product isolation procedure are noteworthy advantages of this method. The recyclability of the ionic liquid makes this protocol environmentally benign.

Full text of DOI:10.1021/co400144b

Research Article
pubs.acs.org/acscombsci
New Pyridinium-Based Ionic Liquid as an Excellent Solvent−Catalyst
System for the One-Pot Three-Component Synthesis
of 2,3-Disubstituted Quinolines
Salma Anvar,† Iraj Mohammadpoor-Baltork,*,† Shahram Tangestaninejad,*,† Majid Moghadam,†
Valiollah Mirkhani,† Ahmad Reza Khosropour,† Amir Landarani Isfahani,† and Reza Kia‡
†Catalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
‡Chemistry Department, Sharif University of Technology, P.O. Box 11155-3516, Tehran, Iran
S
* Supporting Information
ABSTRACT: The synthesis of a variety of 2,3-disubstituted
quinolines has been achieved successfully via a one-pot three-
component reaction of arylamines, arylaldehydes and aliphatic
aldehydes in the presence of butylpyridinium tetrachloroindate-
(III), [bpy][InCl4], ionic liquid as a green catalyst and solvent.
Mild conditions with excellent conversions, and simple product
isolation procedure are noteworthy advantages of this method. The recyclability of the ionic liquid makes this protocol
environmentally benign.
KEYWORDS: aldehydes, anilines, quinolines, ionic liquid, three-component reaction
Table 1. Optimization of Reaction Parameters for the
Synthesis of 4{1,1,1}
INTRODUCTION
■
a
Ionic liquids (ILs) have recently appeared as the main subject
of many studies aiming at not only understanding the nature of
these solvents but also finding their physicochemical and photo-
chemical properties in different applications such as sensors, fuel
cells, batteries, capacitors, thermal fluids, plasticizers, lubricants,
ion gels, extractants, and solvents in analysis, synthesis, catalysis,
and separation.1−6 Other new applications of the ILs are their use
as energetic compounds as well as in pharmaceutical industry.
ILs can be considered as more than just alternative “green”
solvents. They differ from molecular solvents by their unique
ionic character, as well as their “structure and organization”, which
can lead to specific effects, making them tunable and multi-
purpose materials.7−10 In addition, the combinatorial synthesis of
some fine chemicals, such as sulfonamides and carboxamides,11
3-arylideneaminoquinazolin-4(1H)-one derivatives,12 spirooxin-
doles,13 and fused pyridine derivatives14 in the presence of
ionic liquids, provides a greener means for the preparation of
these compounds.
Multicomponent reactions (MCRs) provide an opportunity
for the coupling of three or more simple and flexible building
blocks in a one-pot operation, producing complex structures
by simultaneous formation of two or more bonds, according
to the domino principle.15 Environmentally friendly operation
via reducing the number of synthetic steps, the energy con-
sumption, and the waste production are among the advantages
of MCRs. Additionally, during the past decade, industrial and
academic researchers have transformed this beneficial technol-
ogy into one of the most efficient and economic approaches
for combinatorial and parallel synthesis, as evidenced by the
increase in the literature focusing on this research field.16−22
b
entry
catalyst (mmol)
T (°C)
time (min)
yield (%)
1
no catalyst
70
70
70
70
70
70
70
70
70
70
70
70
90
50
120
30
30
30
30
30
30
30
30
30
30
30
30
30
0
70
91
80
80
70
65
75
75
96
96
88
96
70
2
[bpy]Cl (1)
3
[bpy][FeCl4] (1)
[bpy][ZnCl3] (1)
[bmim]OTf (1)
[bmim]Cl (1)
4
5
6
7
[bmim]Br (1)
8
[bmim]NO3 (1)
[bmim]BF4 (1)
[bpy][InCl4] (1)
[bpy][InCl4] (1.1)
[bpy][InCl4] (0.8)
[bpy][InCl4] (1)
[bpy][InCl4] (1)
9
10
11
12
13
14
a
4-Bromoaniline (1 mmol), 2,4-dichlorobenzaldehyde (1 mmol), and
b
heptanal (1 mmol). Isolated yield.
Among nitrogen-containing heterocycles, quinolines have
received special attention because of their abundance in a variety
Received: March 16, 2013
Revised: February 9, 2014
Published: February 12, 2014
© 2014 American Chemical Society
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a
Table 2. One-Pot Three-Component Synthesis of 2,3-Disubstituted Quinolines 4 Catalyzed by [bpy][InCl4]
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Table 2. continued
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Table 2. continued
a
b
c
Arylamine (1 mmol), arylaldehyde (1 mmol), aliphatic aldehyde (1 mmol), IL (1 mmol), 70 °C. Isolated yield. Reaction was carried out in the
presence of iodine.
of naturally occurring products and medicinally active com-
pounds.23 A great number of quinoline based compounds exhibit
a broad range of physiological and biological properties such as
antituberculosis,24 antimalarial,25 antiasthmatic,26 antidiabetic,27
and antibacterial28 activities. Because of the importance of dif-
ferent quinoline derivatives, various procedures have been
developed for the synthesis of this heterocyclic compound.29−32
In continuation of our interest in the development of useful
synthetic methodologies for the preparation of fine chemicals;33
herein, we report a convenient and efficient one-pot three-
component protocol for the synthesis of 2,3-disubstituted
quinolines starting directly from arylamines, arylaldehydes and
aliphatic aldehydes in the presence of [bpy][InCl4] ionic liquid
as the catalyst and solvent. The preparation of quinolines from
the reaction of 2-aminoaryl ketones with β-ketoesters/ketones,
by three-component reaction of aldehydes, alkynes, and amines,
or from the reaction of 2-aminoaryl ketones with phenyl-
acetylenes has been previously reported in the presence of
ionic liquids,34 but to the best of our knowledge, this is the first
report on the synthesis of quinolines via a one-pot three-
component reaction of arylamines, arylaldehydes and aliphatic
aldehydes in the presence of [bpy][InCl4] ionic liquid.
The substrate scope of [bpy][InCl4]-catalyzed system was
then examined under the optimized reaction condition. As
shown in Table 2, a wide variety of arylaldehydes containing
electron-withdrawing and electron-donating groups at the para
or meta position were reacted with anilines containing para
or meta electron-withdrawing substituents and aliphatic aldehydes
(Figure 1) to afford the corresponding 2,3-disubstituted quino-
lines in excellent yields. It is noteworthy that the ortho-substituted
aldehydes 2-bromobenzaldehyde and 2-methoxybenzaldehyde,
and the ortho-substituted anilines 2-chloroaniline and
2-bromoaniline were efficiently converted into the desired
2,3-disubstituted quinolines under the same reaction conditions.
The heterocyclic aldehydes thiophene-2-carbaldehyde and furfural
took part in the reaction smoothly affording the expected
products in excellent yields. The results show that [bpy][InCl4] is
an efficient catalyst for the preparation of a large spectrum of
2,3-disubstituted quinolines in good yields (Table 2). It was
also found that anilines with electron-donating groups ((4-MeO,
4-Me) did not take part in the reaction to give the corresponding
quinolines.
It is important to note that some of these reactions were also
carried out in the presence of iodine as a catalyst32 (Table 2,
entries 1, 3, 5 and 12). Under these conditions, the desired
quinolines were obtained in only 40−49% yields. These results
clearly show that the present IL catalyst is more efficient and
convenient for the synthesis of quinolines.
To prepare the quinolines with alkyl substituents at 2- and
3-positions, the reaction of 4-bromoaniline (1 mmol) with
heptanal (2 mmol) or butanal (2 mmol) was examined in the
presence of [bpy][InCl4] (1 mmol). As shown in Scheme 1, the
desired quinolines were not obtained under these conditions.
Consequently, the present method could be used only for the
synthesis of quinolines containing aryl and alkyl substituents at
2- and 3-positions, respectively, in excellent yields.
RESULTS AND DISCUSSION
■
First, the model reaction of 4-bromoaniline, 2,4-dichlorobenzal-
dehyde, and heptanal was performed in the presence of different
ILs (Table 1). It was observed that all of the investigated ILs
were capable of catalyzing the synthesis of desired quinoline
4{1,1,1}. However, the yield of the corresponding quinoline was
higher in the presence of [bpy][InCl4] (Table 1, entry 10).
Then, different reaction conditions such as the amount of IL,
temperature, and reaction time were checked (Table 1). The
results revealed that the best yield of the desired quinoline was
obtained by carrying out the reaction with 1:1:1:1 molar ratios
of 4-bromoaniline, 2,4-dichlorobenzaldehyde, heptanal and
[bpy][InCl4] at 70 °C for 30 min (Table 1, entry 10).
The recovery and reusability of the catalyst, which is very
important for industrial purposes and is highly recommended
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Figure 1. Diversity of reagents.
a
Scheme 1. Reaction of Arylamine with Aliphatic Aldehydes
Table 3. Recycling of the IL in the Synthesis of 4{1,1,1}
b
run
yield (%)
1
2
3
4
5
6
96
95
95
93
90
90
a
4-Bromoaniline (1 mmol), 2,4-dichlorobenzaldehyde(1 mmol),
b
heptanal (1 mmol), 70 °C, and 30 min. Isolated yield.
organic transformations.35−37 Accordingly, a plausible mecha-
nism for this IL catalyzed three-component synthesis of
2,3-disubstituted quinolines is proposed in Scheme 2. First,
the [bpy][InCl4] IL catalyzes the keto−enol tautomerization of
aliphatic aldehyde and also activates the imine to give 5 and 6,
respectively. The in situ formed enol attacks the activated imine
to give 7, which upon intramolecular Friedel−Crafts reaction
and subsequent dehydration in the presence of IL produces
dihydroquinoline 8 and releases the catalyst (IL) for the next
catalytic cycle. Finally, aromatization of dihydroquinoline 8 under
air atmosphere affords the desired product 4. As we mentioned,
anilines with electron-donating groups did not take part in the
reaction to give the corresponding quinolines. It seems that
for green processes, was also explored in the model reaction.
To test the reusability of the catalyst, after completion of
the reaction, the mixture was diluted with 5 mL of water and
5 mL of EtOAc and shaken vigorously. The organic layer was
separated from the IL. The aqueous layer was evaporated and
the ionic liquid was dried at 60−70 °C under vacuum and then
reused. The results showed that the [bpy][InCl4] catalyst could
be used at least six times without any significant loss in the yield
of the product (Table 3).
It is evident from the literature that ILs containing
chloroindate(III) exhibit Lewis acid properties in various
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Scheme 2. Proposed Mechanism for [bpy][InCl4] Catalyzed Three-Component Synthesis of 2,3-Disubstituted Quinolones 4
EXPERIMENTAL PROCEDURES
■
General Information. Melting points were determined
using a Stuart Scientific SMP2 apparatus without correction.
FT-IR spectra were obtained as KBr pellets using a Jasco 6300
instrument in the range of 400−4000 cm−1. H and 13C NMR
1
(500 and 125 MHz) spectra were recorded on a Bruker-AC 500
spectrometer in CDCl3 solution. Mass spectra were recorded
on a Platform II spectrometer from Micromass; EI mode at
70 eV. Elemental analysis was carried out on a LECO, CHNS-
932 instrument.
Preparation of [bpy][InCl4]. A mixture of pyridine
(0.096 g, 1.2 mmol) and 1-chlorobutane (0.105 g, 1.1 mmol)
was stirred under reflux conditions for 72 h in dark. The reac-
tion mixture was cooled and the resulting solid was recrystall-
ized from MeCN/EtOAc (1:1), filtered under vacuum and
Figure 2. X-ray Crystallography structure of compound 4{1,7,2}. The
methyl segment shows disorder and the minor fragment is shown as
open line.
washed with EtOAc. The excess solvent was then removed
under vacuum at 70 °C. The IL was prepared by stirring [bpy]
Cl (0.171 g, 1 mmol,) with InCl3 (0.219 g, 1 mmol) at room
temperature for 10 min. mp: 68−70 °C. IR (KBr): νmax = 3130,
3085, 2963, 2935, 2877, 1633, 1487, 1466, 1178, 769,
electron-donating substituent increases the electron density on
the nitrogen in aniline, so, an acid−base complex is rapidly
formed between amino group and the catalyst, which prevents
further reaction leading to the desired quinoline.
1
681 cm−1. H NMR (500 MHz, CDCl3): δ = 0.76 (t, J =
7.2 Hz, 3H), 1.16−1.22 (m, 2H), 1.80−1.86 (m, 2H), 4.45 (t,
J = 7.6 Hz, 2H), 7.89 (t, J = 7.2 Hz, 2H), 8.37 (t, J = 7.6 Hz,
1H), 7.68 (d, J = 5.6 Hz, 2H). 13C NMR (125 MHz, CDCl3):
δ = 12.57, 18.63, 32.49, 61.66, 128.09, 144.12, 145.37. Anal.
Calcd for C9H14Cl4InN: C, 27.52; H, 3.59; N, 3.57. Found: C,
27.60; H, 3.54; N, 3.65.
Typical Procedure for the Synthesis of 6-Bromo-2-
(2,4-dichlorophenyl)-3-pentylquinoline 4{1,1,1}. To a
mixture of 4-bromoaniline (0.172 g, 1 mmol), 2,4-dichloroben-
zaldehyde (0.174 g, 1 mmol), and hexanal (0.114 g, 1 mmol),
was added [bpy][InCl4] (0.390 g, 1 mmol). The reaction mixture
was stirred at 70 °C for 30 min. The progress of the reaction
was monitored by TLC (eluent = n-hexane/EtOAc = 9/1). After
completion of the reaction, the mixture was diluted with water
(5 mL) and EtOAc (5 mL) and shaken vigorously. The organic
layer was separated from the IL. The IL was dried at 60−70 °C
under vacuum to remove water and reused. The organic layer
was dried over Na2SO4 and evaporated. The crude product was
purified by recrystallization from EtOH to obtain the pure
1
The structures of the products were characterized by IR, H
and 13C NMR spectroscopy, mass spectrometry and elemental
analysis. The structure of the product 4{1,7,2} was additionally
confirmed by X-ray crystal structure analysis (Figure 2, CCDC-
851671).
CONCLUSION
■
We have developed a novel and facile protocol for the synthesis
of 2,3-disubstituted quinolines through a one-pot three-
component reaction of arylamines, arylaldehydes, and aliphatic
aldehydes using [bpy][InCl4] as a green catalyst and solvent.
The waste-free process combined with recovery and reusability
of the catalyst make this method economic and benign for the
synthesis of quinolines. In addition, excellent yields, short reaction
times, mild conditions, avoiding hazardous organic solvents,
and simple experimental procedure are other advantages of the
present method.
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product 4{1,1,1}. mp: 133−134 °C. IR (KBr): νma1x = 2923, 2854,
1593, 1468, 1376, 1344, 1099, 817, 644 cm−1. H NMR (500
MHz, CDCl3): δ = 0.75 (t, J = 6.8 Hz, 3H), 1.14−1.16 (m, 4H),
1.47−1.46 (m, 2H), 2.44−2.60 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H),
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133.65, 134.44, 134.96, 135.70, 137.72, 144.72, 158.00. MS: m/z
= 423.17 ([M]+, 94.20), 422.04 (62.80), 388.04 (64.73), 330.94
(65.70), 250.00 (77.78), 113.87 (91.79), 77.89 (5.28), 55.92
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ASSOCIATED CONTENT
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1H and 13C NMR spectra for all products and crystallographic
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AUTHOR INFORMATION
Corresponding Authors
*Fax: +98(311)6689732. Phone: +98(311)7932705. E-mail:
imbaltork@sci.ui.ac.ir
■
*Fax: +98(311)6689732. Phone: +98(311)7932705. E-mail:
stanges@sci.ui.ac.ir.
Funding
The authors are grateful to the Center of Excellence of
Chemistry and Research Council of the University of Isfahan
for financial support of this work.
Notes
The authors declare no competing financial interest.
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