An efficient and rapid approach to quinolines via Friedlaender synthesis catalyzed by silica gel supported sodium hydrogen sulfate under solvent-free conditions

Article abstract of DOI:10.1007/s00706-007-0678-2

A simple and efficient method for the synthesis of quinolines and polycyclic quinolines using silica gel supported sodium hydrogen sulfate as reusable eco-friendly catalyst via Friedlaender annulation under solvent-free conditions is described. Springer-V

Full text of DOI:10.1007/s00706-007-0678-2

Monatshefte f u¨ r Chemie 138, 659–661 (2007)
DOI 10.1007/s00706-007-0678-2
Printed in The Netherlands
An Efficient and Rapid Approach to Quinolines via Friedl a¨ nder Synthesis
Catalyzed by Silica Gel Supported Sodium Hydrogen Sulfate
Under Solvent-Free Conditions
Minoo Dabiri, Seyyedeh Cobra Azimi, and Ayoob Bazgirꢀ
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Received February 14, 2007; accepted March 8, 2007; published online May 11, 2007
#
Springer-Verlag 2007
Summary. A simple and efficient method for the synthesis
of quinolines and polycyclic quinolines using silica gel sup-
ported sodium hydrogen sulfate as reusable eco-friendly cat-
alyst via Friedl a¨ nder annulation under solvent-free conditions
is described.
ple ketones, such as cyclohexanone and ꢀ-keto esters
7]. Subsequent work showed that acid catalysts are
[
more effective than base catalysts for the Friedl a¨ nder
annulation. Acid catalysts such as hydrochloric acid,
sulfuric acid, p-toluenesulfonic acid, and polyphos-
phoric acid have been widely employed for this
conversion [6a, 8]. In addition, modified methods
Keywords. Friedl a¨ nder; Solvent-free; Silica gel supported
sodium hydrogen sulfate; Quinoline; Reusable catalyst.
employing phosphoric acid, diphosgene, AuCl , NaF,
3
Introduction
ZnCl , microwave, and ionic liquids have been re-
2
ported for the synthesis of quinolines [8, 9]. Recently,
Y(OTf ) has been employed for this conversion [10].
Quinolines and their derivatives have recently received
great attention because of their wide range of therapeu-
tic and biological properties [1]. They have emerged
as antimalarial, antiasthmatic, anti-inflamatory, an-
tibacterial, antihypertensive, and tyrosine kinase
PDGF-RTK inhibiting agents [2, 3]. Moreover, poly-
quinolines are found to undergo hierarchical self-
assembly into a variety of nano- and meso-structures
with enhanced electronic and photonic functions [4].
The simple and straightforward method for the
synthesis of polysubstituted quinolines was reported
by Friedl a¨ nder in 1882 [5]. Friedl a¨ nder reactions are
generally carried out either by refluxing an aqueous
or alcoholic solution of reactants in the presence of
base or by heating a mixture of the reactants at high
3
However, most of these methods have significant
drawbacks such as low yields of the products, pro-
longed reaction times, harsh reaction conditions, and
the use of hazardous and often expensive catalysts.
Moreover, this reaction is usually carried out in polar
solvents such as acetonitrile, THF, DMF, and DMSO
leading to tedious work-up procedures. The main dis-
advantage of most of the existing methods is that the
catalysts are destroyed in the work-up procedure and
cannot be recovered or re-used.
Therefore, to avoid these limitations, the discovery
of a new and efficient catalyst with high catalytic
activity, short reaction time, recyclability, and simple
work-up for the preparation of quinoline derivatives
under neutral and practical conditions is of prime in-
terest. Due to the acidic properties of silica gel sup-
ported sodium hydrogen sulfate (NaHSO –SiO ) in
ꢁ
temperatures ranging from 150 to 220 C in the absence
of catalyst [6]. Under thermal or base catalysts con-
ditions, o-aminobenzophenone fails to react with sim-
4
2
recent years, NaHSO –SiO has been used as an
4
2
ꢀ Corresponding author. E-mail: a_bazgir@sbu.ac.ir
efficient heterogeneous catalyst for many organic

6
60
M. Dabiri et al.
transformations [11], because of its low cost, ease
of preparation [11b], catalyst recycling, and ease of
handling. Since the reaction is heterogeneous in nat-
ure, the catalyst can conveniently be separated by sim-
ple filtration. However, there are no reports on the use
of NaHSO –SiO for the synthesis of quinolines via
acetylacetone (2a, 1 mmol) to afford the product 3a
ꢁ
under solvent-free conditions at 100 C (Scheme 1).
The best result was obtained with 0.2 g of catalyst.
Higher amounts of catalyst did not improve the re-
sult to any greater extent.
Then, various cyclic 1,3-diketones, such as
1,3-cyclohexanedione, 5,5-dimethylcyclohexanedione
(dimedone), and acyclic 1,3-diketones including
acetylacetone and ethyl or methyl acetoacetate reacted
with 2-aminobenzophenone or 2-amino-5-chloro-ben-
zophenone (1b) in the presence of the optimized quan-
tity of NaHSO –SiO under solvent-free conditions at
4
2
Friedl a¨ nder annulation. The use of NaHSO –SiO as
4
2
a recyclable catalyst makes the process convenient,
economic, and environmentally benign.
In continuation of our interest on the application of
heterogeneous catalysts, especially NaHSO –SiO ,
4
2
for development of useful synthesis methodology
12], we wish to report a simple, convenient, and
4
2
ꢁ
[
100 C. In all cases corresponding substituted quin-
olines were obtained in excellent yields for reaction
times of 1–1.5 h (Table 1).
high-yielding method for the synthesis of polysubsti-
tuted quinolines via Friedl a¨ nder annulation using sil-
ica gel supported sodium hydrogen sulfate as reusable
eco-friendly catalyst under solvent-free conditions.
Interestingly, cyclic ketones such as cyclopenta-
none, cyclohexanone, and cycloheptanone reacted
with 2-aminoarylketones to afford the respective
tricyclic quinolines in excellent yields for 1–1.5 h
Results and Discussion
(
Table 1). In general, the reaction is very clean, rap-
We started to study this condensation reaction by
examining the amount of catalysts for the reaction
involving 2-aminobenzophenone (1a, 1 mmol) with
id, efficient, and free from side reactions, such as
self-condensation of ketones which is normally ob-
served under basic conditions.
Scheme 1
Table 1. NaHSO –SiO catalyzed synthesis of quinoline derivatives
2
4
a
Yield =%
Entry
Compound 1
Compound 2
Quinoline 3
Time=h
Ref.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
acetylacetone (2a)
ethyl acetoacetate (2b)
methyl acetoacetate (2c)
cyclopentanone (2d)
cyclohexanone (2e)
cycloheptanone (2f)
dimedone (2g)
1,3-cyclohexanedione (2h)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
1
1
1
1
87
92 (91, 90, 91)
[9e]
[9e]
This work
[9e]
[9e]
b
94
90
91
86
95
85
82
84
92
85
83
94
96
88
1
1.5
1.5
1
1
1
1
1
1
[9e]
[13]
[13]
[9e]
[9e]
[14]
[9e]
[9e]
2a
2b
2c
2d
2e
2f
1
1
1
1
1
1
1
1.5
1.5
1
[9e]
[13]
[13]
2g
2h
a
b
Isolated yields. Isolated yields after recycling of catalyst

Quinolines via Friedl a¨ nder Synthesis
661
(
1
1
CDCl ): ꢂ ¼ 23.34, 52.40, 125.34, 126.02, 128.20, 128.57,
In these experiments the product was isolated by
filtration and the catalyst could be reloaded with
fresh reagents for further runs. Thus, recyclization
of catalyst is possible without significant loss of ac-
tivity (Table 1, entry 2). Finally, it should be men-
tioned that when reactions were carried out in the
absence of catalyst for long period of time (4–5 h)
3
29.01, 129.08, 129.92, 131.69, 132.83, 134.70, 145.24,
46.42, 154.94, 168.27 ppm.
Acknowledgements
We gratefully acknowledge the financial support from the
Research Council of Shahid Beheshti University.
ꢁ
and in solvent free condition at 100 C the yields of
products were low (<30%).
References
In conclusion, we have developed a simple, effi-
cient, and green methodology for the synthesis of
quinolines using NaHSO –SiO under solvent-free
conditions. The simple experimental procedure, sol-
vent-free reaction conditions, good yields, and utili-
zation of an inexpensive and reusable catalyst are the
advantages of the present method.
[
[
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1
3
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1
was heated at 100 C. The reaction was monitored by TLC.
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ꢁ
4
2
5
: 2251
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884; (b) Arcadi A, Chiarini M, Giuseppe SD, Marinelli
After completion, the reaction mixture was washed with
1
3
0cm EtOAc and filtered to recover the catalyst. Evapora-
7
tion of the solvent followed by purification by column chro-
matography (silica gel, EtOAc:n-hexane, 1:8) afforded the
corresponding pure quinoline derivative.
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Methyl-2-methyl-4-phenylquinoline-3-carboxylate
(
White powder (0.26 g, 94%), mp 147–149 C; IR (KBr):
3c, C H NO )
18 15 2
[
[
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ꢁ
ꢂ1
ꢁ
(
(
ꢀ¼ 3030, 2958, 1704, 1615 cm ; MS: m=z (%) ¼ 277
þ
1
M , 100), 246 (89), 218 (76); H NMR (CDCl ): ꢂ ¼ 2.84
3 3
3
1
3
C
s, CH ), 3.58 (s, OCH ), 7.27–8.22 (m, H–Ar) ppm;
NMR (CDCl ): ꢂ ¼ 23.25, 52.30, 125.19, 126.61, 126.87,
3
1
1
27.43, 128.10, 128.36, 128.71, 129.15, 130.93, 135.35,
46.64, 147.46, 154.57, 168.54 ppm.
[
12] (a) Dabiri M, Arvin-Nezhad H, Khavasi HR, Bazgie A
(
(
2007) Tetrahedron 63: 1770; (b) Shaabani A, Bazgir A
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Methyl-6-chloro-2-methyl-4-phenylquinoline-3-carboxylate
3k, C H ClNO )
Dabiri M, Bazgir A (2006) Dye and Pigments 71: 68;
(d) Bazgir A (2006) J Chem Res (s): 1
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[14] Muscia GC, Bollini M, Carnevale JP, Bruno AM, Asis
SE (2006) Tetrahedron Lett 47: 8811
(
White powder (0.29 g, 92%), mp 131–133 C; IR (KBr):
1
8
14
2
ꢁ
ꢂ1
þ
ꢁ
ꢀ¼ 3027, 2964, 1701, 1617cm ; MS: m=z (%) ¼ 311 (M ,
1
100), 281 (181), 252 (40); H NMR (CDCl ): ꢂ ¼ 2.81 (s,
CH ), 3.59 (s, OCH ), 7.26–8.13 (m, H–Ar) ppm; C NMR
3
1
3
3
3