Water mediated synthesis of substituted quinolines - A new green approach to the Friedlaender annulation

Article abstract of DOI:10.1002/jhet.5570430537

A new green approach to the Friedlaender Quinoline synthesis is described for the preparation of polysubstituted quinolines from o-amino aryl ketones and carbonyl compounds containing active methylene group mediated by water and catalysed by KHSO₄

Full text of DOI:10.1002/jhet.5570430537

Sep-Oct 2006
1379
Water Mediated Synthesis of Substituted Quinolines –
A New Green Approach to the Friedländer Annulation
Nagarajan Panneer Selvam, Chandramathi Saravanan, D. Muralidharan
and Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai-20, INDIA.
Fax: +91-44-24911589; Tel: +91-44-24913289; Email: ptperumal@gmail.com
Received November 25, 2005
R2
R2
N
R3
R4
R3
KHSO4
O
R1
+
O
R1
water:ethanol(8:2)
Reflux, 3-8hr
NH2
R4
A new green approach to the Friedländer Quinoline synthesis is described for the preparation of
polysubstituted quinolines from o-amino aryl ketones and carbonyl compounds containing active
methylene group mediated by water and catalysed by KHSO in good yields.
4
J. Heterocyclic Chem., 43, 1379 (2006).
Introduction.
applications of quinolines in the biological and other
studies necessitate the development of convenient, eco-
benign synthetic routes.
The presence of the Quinoline scaffold in the frame
work of the various pharmacologically active compounds
with antimalarial, anti-inflammatory, antiasthmatic,
antibacterial, antihypertensive and tyrosin kinase PDGF-
RTK inhibiting properties [1-3] has enthused researchers to
study their other potential biological activities. In addition,
benzo [5,6] pyrrolizino[1,2-b]quinoline system is shown to
display potent in vitro cytotoxic activity against the MCF7
cell [4]. Recently quinolines are also shown to be potential
agent for the treatment of the erectile dysfunction as they
exhibit more potent and selective PDE5 inhibitor activity
The growing awareness of the pressing need for greener
and more sustainable technologies has focused attention on
the use of atom efficient catalytic methodologies for the
manufacture of fine chemicals and pharmaceuticals.
Another aspect, which is receiving increasing attention, is
the use of alternative reaction media that circumvent the
problems associated with many of the traditional volatile
organic solvents. The state of the art, use of alternative
reaction media for green, sustainable organic synthesis is
reviewed [11]. Liquid-liquid biphasic catalysis provides an
alternative to the more traditional solid heterogeneous
catalysts. Considering the toxicity of solvents, nowadays
neat or solvent free reactions are preferred. However when a
reaction medium is unavoidable, the best solvent to opt for
is water. Catalysis in aqueous biphasic systems is an
industrially attractive methodology, which has found broad
applications.
[
5]. Furthermore Quinoline scaffolds are used for the
preparation of nano and mesostructures with enhanced
electronic and photonic properties [6].
Despite numerous methods reported such as Skraup,
Doebner, Von Miller and Combes [7,8] the Friedländer
annulation is the most simple and effective method for the
synthesis of polysubstituted quinolines. Friedländer
method is acid or base catalyzed annulation of o-amino
aryl ketones with carbonyl compound containing a
reactive ꢀ-methylene group.
Friedländer reactions are generally carried out in
alcoholic medium, in the presence of a base or by heating
a mixture of the reactants at high temperature [9].
Literature reports show that acid catalysts are more
effective than base catalysts for the Friedländer annulation
Recently, there has been considerable interest in the
KHSO mediated organic synthesis [12] as it is water
4
soluble as well as cost effective; moreover it is easy to
handle and its separation from the reaction mixture is also
easier.
Herein, we wish to report a simple, convenient and
greener as well as water mediated synthesis of
polysubstituted quinolines by using potassium bisulphate
at reflux temperature.
[
10]. Numerous Bronsted acid catalysts that are reported
require high temperature and prolonged reaction time and
moreover lead to the formation of various by-products.
The Lewis acids are effective to the Friedländer
condensation, but the usage of Lewis acid like
AlCl .3H O, ZnCl and AuCl .3H 0 limits the green
Accordingly, treatment of o-amino substituted aromatic
ketones with carbonyl compounds in the presence of
potassium bisulphate in water:ethanol (8:2) at reflux
temperature resulted in the formation of various 2,3,4-
trisubstituted quinolines (Scheme 1) in good yields
without the need for purification.
3
2
2
3
2
approach in the large scale application. Variety of

1
380
N. P. Selvam, C. Saravanan, D. Muralidharan and P. T. Perumal
Vol 43
Scheme 1
We extended our protocol to various ꢀ-ketoesters such
as ethyl acetoacetate, isopropyl acetoacetate and
dicarbonyl compounds like acetyl acetone and 5,5-
dimethylcyclohexandione (dimedone) with o-amino
acetophenone, 5-chloro-2-aminobenzophenone and o-
amino benzophenone at reflux temperature to afford the
corresponding substituted quinolines. Interestingly cyclic
O
O
CH3
CH3
KHSO4
+
Water:Ethanol (8:2)
Reflux, 3h
NH2
N
Table 1
Quinolinea
o
c
Entry 2-aminoketone Ketone
Mp( C)
Time (h) Yield (%)
O
O
O
O
3
8
85
69
1
2
3
138(140-142)b
148(151-152)b
NH
2
N
O
O
Cl
Cl
Cl
NH
O
2
O
O
N
O
Cl
O
O
04(108)b
1
8
79
94
NH
O
2
N
O
O
1
87(190-192)b
4
4
NH
O
2
O
N
O
1
14(118-120)b
5
6
71
5
6
N
NH
O
2
O
O
110(113-114)b
90
NH
O
2
O
O
N
O
O
O
O
O
O
90d
7
8
9
64
4
8
5
NH
2
N
O
75(78-79)b
94
94
61
NH
O
2
N
O
NH
O
2
O
N
N
N
O
O
Cl
Cl
Cl
10
8(105)b
9
8
4
72
NH
O
2
Cl
11
72(175)b
1
93
NH
2
a
1
13
b
All the products were characterized by IR, H NMR, C NMR and Mass Spectra. Melting points reported are uncorrected. Literature values [14]
c
d
are indicated in parenthesis. Isolated yields. Products were extracted in ethylacetate.

Sep-Oct 2006
Water Mediated Synthesis of Substituted Quinolines
1381
ketones such cyclohexanone, cyclopentanone, cyclo-
heptanone and cyclooctanone reacted with 2-amino aryl
ketones to afford the respective tricyclic quinolines. This
class of cyclic ketones give usually unsatisfactory yields
at room temperature or even higher temperature by using
Bronsted acid [13]. However the reaction is fairly clean,
rapid and efficient under the condition reported by us. The
results are summarized in Table 1.
2-Methyl-4-phenyl-quinoline-3-carboxylic acid isopropyl ester
(
7).
This compound was obtained as yellow colour solid, mp 64
°C; IR (KBr): 3012, 2914, 2800, 1807, 1710, 1569, 1471, 1230,
-1 1
828, 750 cm ; H NMR (500 MHz, CDCl
3
): ꢀ = 0.96(d, 6H, J =
6
7
7
8
1
.1Hz), 2.77(s, 3H), 4.95(heptet, 1H, J = 6.1Hz), 7.34(m, 2H),
.38(t, 1H, J = 7.65Hz), 7.44 (d, 2H, J = 1.5Hz), 7.46(m, 1H),
.53(d, 1H, J = 8.4Hz), 7.61(t, 1H, J = 7.65Hz), 8.05 (d, 1H, J =
13
.4Hz); C NMR (125 MHz, CDCl
3
): ꢀ = 21.33, 23.77, 69.12,
In conclusion, we have developed an expedient,
potassium bisulphate catalyzed, water mediated synthesis
of polysubstituted quinolines. Even though Lewis acids
and other Bronsted acids are known to catalyze this
reaction, this protocol offers several advantages including:
25.30, 126.46, 126.52, 127.81, 128.30, 128.52, 128.88, 129.56,
130.25, 135.74, 146.01, 147.69,154.58, 167.99; MS: m/z 306
+
(M ).
Anal. Calcd. For
20 2
C H19NO : C, 78.66;H, 6.27;N, 4..39.
Found: C, 78.65; H, 6.28; N, 4.38.
(
a) cleaner reactions, (b) higher yields of the products
3,3,9-Trimethyl-3,4-dihydro-2H-acridin-1-one (9).
without employing any purification methods like column
chromatography or recrystallisation (c) simple experi-
This compound was obtained as light brown colour solid, mp
9
4 °C; IR (KBr): 2949, 2800, 1694, 1614, 1350, 884, 830,
-1 1
mental procedure and
(d) use of aqueous-ethanol
761cm ; H NMR (500 MHz, CDCl ): ꢀ = 1.12(s, 6H), 2.65(s,
3
medium, which makes it an useful and attractive process
for the synthesis of polysubstituted quinolines.
2H), 3.06(s, 3H), 3.16(s, 2H), 7.55 (t, 1H, J = 7.65Hz), 7.74(t,
1
H, J =7.65Hz), 7.97(d, 1H, J = 8.4Hz), 8.20(d, 1H, J= 9.15Hz);
1
3
C NMR (125 MHz, CDCl
54.85, 124.29, 125.69, 126.65, 127.77, 128.71, 131.81, 147.85,
3
) : ꢀ = 16.13, 28.31, 32.19, 48.18,
Acknowledgement.
+
1
50.36, 161.09, 203.77; MS: m/z 240 (M ).
Anal. Calcd. For C16 : C, 80.30; H, 7.16; N, 5.85.
Found: C, 80.31; H, 7.15; N, 5.84.
One of the authors N.P.S. expresses his gratitude to
CSIR, New Delhi, India for financial support.
H17NO
2
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1
13
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1
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1
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N. P. Selvam, C. Saravanan, D. Muralidharan and P. T. Perumal
Vol 43
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