Chitosan-SO3H: An efficient, biodegradable, and recyclable solid acid for the synthesis of quinoline derivatives via Friedl?nder annulation

Article abstract of DOI:10.1016/j.tetlet.2013.07.165

Chitosan-SO₃H is found to catalyze the Friedl?nder condensation/annulation reaction of 2-aminoaryl ketones with α-methyleneketones to produce the corresponding quinoline derivatives in high yields in short reaction times. The use of recyclable

Full text of DOI:10.1016/j.tetlet.2013.07.165

Accepted Manuscript
Chitosan-SO H: an efficient, biodegradable and recyclable solid acid for the
3
synthesis of quinoline derivatives via Friedländer annulation
B.V. Subba Reddy, A. Venkateswarlu, G. Niranjan Reddy, Y.V. Rami Reddy
PII:
S0040-4039(13)01392-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.165
TETL 43401
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 May 2013
26 July 2013
31 July 2013
Please cite this article as: Subba Reddy, B.V., Venkateswarlu, A., Niranjan Reddy, G., Rami Reddy, Y.V., Chitosan-
SO H: an efficient, biodegradable and recyclable solid acid for the synthesis of quinoline derivatives via
3
Friedländer annulation, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.165
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Graphical Abstract
Chitosan-SO3H: an efficient, biodegradable and
recyclable solid acid for the synthesis of quinoline
derivatives via Friedländer annulation
Leave this area blank for abstract info.
B. V. Subba Reddy,* A. Venkateswarlu, G. Niranjan Reddy, Y. V. Rami Reddy

Tetrahedron Letters
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Tetrahedron Letters
journal homepage: www.elsevier.com
Chitosan-SO3H: an efficient, biodegradable and recyclable solid acid for the synthesis of
quinoline derivatives via Friedländer annulation
B.V. Subba Reddy,*a A.Venkateswarlu, a,b G. Niranjan Reddy,a Y. V. Rami Reddyb
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India. E-
mail:basireddy@iict.res.in; Fax:91-40-27160512. bDepartment of Chemistry, Sri Venkateswra University, Tirupati, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
Chitosan-SO3H is found to catalyze the Friedlander condensation/annulation reaction of 2-
aminoaryl ketones with -methyleneketones to produce the corresponding quinoline
derivatives in high yields in short reaction times. The use of recyclable and biodegradable
chitosan-SO3H makes this method quite simple, more convenient and economically viable
compared to acid catalyzed methods reported in the literature.
2009 Elsevier Ltd. All rights reserved.
Keywords:
o-Aminoaryl ketones,
Biodegradable solid acid,
Friedländer annulation,
Quinoline synthesis
Quinoline derivatives are important class of nitrogen-
containing heterocycles with a wide range of medicinal
properties such as antimalarial, antiasthmatic,
antihypertensive, antibacterial, anti-inflammatory and
tyrosine kinase inhibitors.1-5 In addition to medicinal
properties, quinolines are known to undergo hierarchical
self-assembly into a variety of nanostructures and
mesostructures with improved electronic and photonic
functions.6 In particular, aminoquinolines are found to
inhibit acetylcholinesterase7 and butyrylcholinesterase
family of enzymes.8 Furthermore, quinoline nucleus is
frequently found in several natural products (Figure 1).9
Figure1. Examples of biologically active quinoline
derivatives
Due to their importance as substructures in a wide range
of synthetic and natural products, several efforts have
been devoted to the development of novel protocols for
the preparation of quinoline derivatives.10 The
Friedländer condensation is one of the simplest and
direct methods for the synthesis of substituted
quinolines,11 which was generally carried out by
refluxing the reactants either in aqueous or alcoholic
solution in the presence of a base at 150–220 ˚C.11a
However, 2-aminobenzophenone fails to undergo
coupling with simple ketones such as cyclohexanone
and β-ketoesters under basic or thermal conditions.12
Subsequently, acid catalysts were proved to be more
effective than base catalysts for the Friedländer
annulation. Brønsted acids13-16 such as hydrochloric
acid, sulfuric acid, p-toluenesulfonic acid, phosphoric

2
Tetrahedron Letters
acid, dodecylphosphonic acid, PEG-supported sulfonic
acid, sulfonic acid-functionalized ionic liquids and o-
benzenedisulfonimide as well as Lewis acids17-23 have
been reported for this transformation. Despite the
importance of these reported protocols, many of these
procedures often suffer from strong acidic conditions,24a-
c
unsatisfactory yields,24a,d high temperature,24a long
Scheme 2. Annulation of 2-aminoaryl ketones with
cyclic ketones
reaction times24d and the use of expensive reagents.17a,19
Therefore, new catalytic systems are being continuously
explored in search of improved efficiencies and cost
effectiveness.
In recent years, sulfonic acid functionalized
heterogeneous catalysts have emerged as user-friendly
catalysts due to their significant advantages over the
homogeneous catalytic systems such as recyclability,
enhanced selectivity, ease of product separation,
operational simplicity and minimal waste disposal.25,26
Following our interest on the catalytic application of
solid acid catalysts,27 we herein report a novel and
efficient catalyst, chitosan-SO3H for the synthesis of
highly substituted quinolines. Initially, we attempted the
condensation of 2-aminobenzophenone (1) with ethyl
acetoacetate (2) in the presence of chitosan-SO3H. The
reaction proceeds smoothly in refluxing ethanol
affording the corresponding ethyl 2-methyl-4-phenyl-
quinoline-3-carboxylate, 3a in 90% yield in a short
reaction time (entry a, Table 1, Scheme 1).
Scheme 1. Condensation of 2-aminobenzophenone with
ethyl acetoacetate
To realize the efficiency and scope of chitosan-SO3H
catalyzed synthesis of quinolines, 2-aminoarylketones
were treated with various carbonyl compounds
including β-ketoesters, cyclic ketones and acyclic 1,3-
diketones under optimized reaction conditions. Notably,
various -ketoesters including methyl and/or ethyl
acetoacetate, ethyl α-chloroacetoacetate and ethyl
benzoacetate participated well in this annulation
reaction (entries b-d, g and h, Table 1). Futhermore, 1,3-
diketones such as acetylacetone and acetyl propanone
were also effective for this transformation (entries i, j
and m-o Table 1).
In addition, the cyclic ketones such as cyclohexanone
and cyclopentanone (entries e, f, k and l, Table 1) also
underwent smooth annulation with 2-aminoarylketones
under the influence of chitosan-SO3H to furnish the
corresponding tricyclic quinoline derivatives (Scheme
2).

Tetrahedron Letters
3
the yield of product 3a was 90%, while the recovered
catalyst gave the yield of 88, 86 and 83% over three
cycles respectively.28,29
The catalyst was also applied for the synthesis of
sterically hindered quinolines by the condensation of
1,3-diphenyl-1,3-propandione
with
5-nitro-2-
In summary, we have demonstrated the Friedländer
annulation using a highly acidic chitosan-SO3H catalyst
as a recyclable and biodegradable catalyst for the
synthesis of substituted quinolines. This method not
only offers substantial improvements in the reaction
rates and yields, but also avoids the use of strong acid
catalysts.
aminobenzophenone (entry n, Table 1). The catalyst
was also effective for the synthesis of quinolines from
substituted 2-aminoarylketones such as 5-chloro- and 5-
nitro-2-aminobenzophenone (entries c, d, n and o, Table
1). In all the cases, the corresponding quinolines were
obtained in good to excellent yields in short reaction
times (Table 1). Next, we tested the efficiency of
chitosan-SO3H in the synthesis of 4-aminoquinoline by
acetoacetate. To our surprise, the desired 4-
aminoquinoline 5 was obtained in 85% yield (Scheme
3).
Acknowledgements
AV thanks CSIR, New Delhi for the award of a
fellowship. B.V.S. thanks CSIR, New Delhi as part of
XII five year plan program under title ORIGIN (CSC-
0108).
References and Notes
Scheme 3. Condensation of anthranilonitrile with ethyl
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the desired product 3a in higher yield than other acid
catalysts (entry h, Table 2).
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4
Tetrahedron Letters
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brown solution, and then 75 mL of 2.5 N sodium hydroxide
was added. The resulting sodium salt of sulfated chitosan was
then precipitated with 500 mL of ethanol. The precipitate was
again dissolved in 200 mL of water and then subjected to
dialysis in a seamless tubing'' for three days against distilled
water. After concentration of the solution under reduced
pressure to 100 mL, a solution of sat. sodium chloride (10
mL) was added and the resulting mixture was then
precipitated as its sodium salt with 150 mL of ethanol; yield
3.0 g [α]D -23 (c 1.5, water). See ref: (a) Wolfrom, M. L.;
Shen Han, T. M. J. Am. Chem. Soc. 1959, 81, 1764. (b)
Hayashi, J. US 5229504A. The number of active acid sites
(H+) of the chitosan-SO3H was determined by acid-base
titration and it was found to be 0.50 m equiv/g. This amount
corresponds to about 0.91% of the sulfur content,
demonstrating that most of the sulfur species are present in
the form of sulfonic acid groups. The degree of sulfonation
was determined to be 1.17 and 1.39 respectively after 1 h and
20 h by elemental analysis.
General procedure: A mixture of 2-aminoarylketone (1.0
mmol), -methyleneketone (1.0 mmol) and chitosan-SO3H
(obtained from Aldrich) (100 mg) in ethanol (5 mL) was
stirred at 50 ºC for the specified time (see Table 1). After
completion, as monitored by TLC, the catalyst was separated
by filtration and the residue was washed with ethanol (5 mL).
The combined organic layers were concentrated under
reduced pressure and the crude product was purified by silica
gel column chromatography using ethyl acetate–n-hexane
(1:9) as eluent to afford the pure quinoline derivative. The
products 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3k, 3j, 3m are
known in literature.30
14.
15.
16.
17.
18.
19.
20.
29.
21.
22.
23.
24.
Spectral data for the new products:
(4-Methyl-2-phenylquinolin-3-yl)(phenyl)methanone (3i):
1H NMR (CDCl3, 500 MHz): δ 2.63 (s, 3H), 6.66-6.61 (m,
3H), 7.31-7.22 (m, 5H), 7.62 (d, J = 8.3 Hz, 1H), 7.70 (dd, J
= 6.8, 1.5 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.3
Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 75
MHz): δ 200.6, 156.0, 150.2, 137.4, 134.3, 133.5, 131.9,
130.3, 129.3, 128.6,128.5, 128.1, 127.1, 123.9, 118.1, 117.4,
27.8. IR (KBr): υmax 3423, 2918, 2853, 1678, 1560, 1383,
1211, 1123, 788, 707 ESI-MS: m/z 324(M+H)
25.
6-Nitro-2,4-diphenylquinolin-3-yl)(phenyl)methanone
1
(3n): H NMR (300 MHz, CDCl3): δ 7.23-7.16 (m, 2H),
7.39-7.26 (m, 7H), 7.50 (d, J = 7.8 Hz, 3H), 7.68-7.62 (m,
3H), 8.39 (d, J = 8.0 Hz, 1H), 8.52 (dd, J = 8.0, 2.3 Hz,,
1H), 8.58 (d, J = 2.3 Hz, 1H); 13C NMR (75 MHz, CDCl3):
δ 123.3, 124.9, 128.1, 129.0, 129.1, 129.3, 131.5, 133.3,
137.6, 138.9, 148.8, 149.0, 159.7, 170.8, 195.9; IR (KBr):
υmax 3425, 2918, 2853, 1688, 1560, 1420, 1211, 1023, 858,
607; ESI-MS: m/z: 440 (M+Na).
26.
27.
Ethyl
2-ethyl-6-nitro-4-phenylquinoline-3-carboxylate
(3o): 1H NMR (300 MHz, CDCl3): δ 0.98 (t, J = 7.0 Hz, 3H),
2.84 (s, 3H), 2.84 (q, J = 7.0 Hz, 2H), 7.35-7.40 (m, 2H),
7.53-7.58 (m, 3H), 8.21 (d, J = 9.0 Hz, 1H), 8.49 (dd, J = 9.0,
2.4 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 13.6, 24.0, 61.7, 123.4, 123.7, 128.7, 129.2, 129.3,
134.1, 145.6, 148.0, 149.6, 158.7, 167.4.; IR (KBr): υmax
3423, 2918, 2853, 1678, 1560, 1383, 1211, 1123, 788, 707;
ESI-MS: m/z: 359 (M+Na).
28.
Preparation of chitosan-SO3H: A freshly distilled, pyridine
(60 mL) was placed in a three-necked flask at 0 ˚C. To this
cold solution, 10 mL of chlorosulfonic acid was added slowly
through a dropping funnel over a period of 30-40 min. To this
mixture, 40 mL of a suspension of chitosan (3.5 g) in
pyridine was added and the whole mixture was heated on a
boiling water-bath for 1 h. After cooling to room temperature,

Tetrahedron Letters
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