An improved quinoline synthesis in the presence of nickel chloride

Article abstract of DOI:10.3987/COM-07-11202

NiCl₂·6H₂O has been used as an efficient catalyst for the synthesis of quinolines by the reaction of 2-aminoaryl ketones and (α-methyleneketones under the solvent-free conditions. The clean, mild acidity conditions and quantitative y

Full text of DOI:10.3987/COM-07-11202

HETEROCYCLES, Vol. 75, No. 2, 2008
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HETEROCYCLES, Vol 75, No. 2, 2008, pp. 397 - 401. © The Japan Institute of Heterocyclic Chemistry
Received, 13th August, 2007, Accepted, 29th October, 2007, Published online, 30th October, 2007. COM-07-11202
AN IMPROVED QUINOLINE SYNTHESIS IN THE PRESENCE OF
NICKEL CHLORIDE
Minoo Dabiri,* Mostafa Baghbanzadeh, and Elham Arzroomchilar
aDepartment of Chemistry, Faculty of Science, Shahid Beheshti University, Postal
Code 1983963113, Evin, Tehran, Iran
E-mail: m-dabiri@sbu.ac.ir
Abstract – NiCl2·6H2O has been used as an efficient catalyst for the synthesis of
quinolines by the reaction of 2-aminoaryl ketones and α-methyleneketones under
the solvent-free conditions. The clean, mild acidity conditions and quantitative
yields of products are attractive features of this reaction which build a suitable
method for sensitive substrates, particularly in drug synthesis.
INTRODUCTION
The quinoline nucleus occurs in several natural compounds (Cinchona alkaloids) and pharmacologically
active substances displaying a broad range of biological activity.1 The biological activity of quinoline
compounds has been found to possess antiasthmatic,2 antibacterial,3 anti-inflammatory4 and
antihypertensive properties.5 In addition to the medicinal applications, quinolines have been employed in
the study of bioorganic and bioorganometallic processes.6 The Friedländer reaction is a well-known
method for preparing quinolines and polypyridyl bridging ligands,7 it is still considered as one of the most
useful methods for preparing quinolines and related bicyclic azaaromatic compounds. Classically, the
process consists of an acid or base catalyzed condensation followed by a cyclodehydration between a
2-aminoaryl ketone and a carbonyl compound possessing a reactive α-methylene group. The Friedländer
reaction is 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 temperature ranging from 150 to 220 ºC in the
absence of catalysts.8 Under thermal or base catalysis conditions, o-aminobenzophenone fails to react
with simple ketones such as cyclohexanone and β-keto esters.9 Subsequent work showed that acid
catalysts are more effective than base catalysts for the Friedländer annulation. Protic acids10 as well as
Lewis acids11 are known to promote these reactions. However, most of the methods have significant
drawbacks such as low yields of the products, harsh reaction conditions, difficulties in workup, and use of
stoichiometric quantities of reagents. Since quinoline derivatives are increasingly useful and important in

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HETEROCYCLES, Vol. 75, No. 2, 2008
drugs and pharmaceuticals, the development of a simple, efficient, and environmentally benign protocol
is still desirable.
Recently, NiCl2·6H2O was shown to be an effective promoter for the Biginelli three-component
condensation reaction.12 It has also been reported as a mild useful and inexpensive Lewis acid catalyst for
the
synthesis
of
α-aminonitriles,13a
formal
hydrochromination
of
alkynes,13b
and
2,4,5-triarylimidazoles.13c
RESULTS AND DISCUSSION
In continuation of our interest in synthesis of heterocyclic compounds using heterogeneous catalyst and
Lewis acids,14 here in we report a new catalytic method for the synthesis of poly substituted quinolines in
the presence of NiCl2·6H2O.
At first we studied the efficacy of our catalyst in a model reaction between 2-aminoenzophenone, and
ethyl acetoacetate under solvent-free conditions at 80 ºC. It was found that the best results were obtained
using 5 mol% of catalyst. Intrigued by the results obtained, substituted quinolines were prepared from
different 2-aminoaryl ketones and various α-methyleneketones (Scheme 1).
Ph
Ph
X
R2
R1
O
X
NiCl2.2H2O (5 mol%)
solvent-free, 80 oC
O
R2
+
R1
N
NH2
X = H, Cl
4h
Scheme 1
2-Aminoaryl ketones included 2-aminobenzophenone derivatives while the α-methyleneketones included
cycloalkanones, 1,3-diketones (cyclic and acyclic) and β-keto esters (Table 1). The quinolines were
formed in high yields (88-95%) within 4 h. The method showed the compatibility with different
functional groups such as alkyl, acyl, halogen and alkoxycarbonyl. The catalyst, NiCl2·6H2O is
commercially available, inexpensive and nonhazardous. To illustrate the need of catalyst, NiCl2.6H2O, for
this reaction, experiments were conducted in which the reaction of 2-aminoenzophenone, and ethyl
acetoacetate was studied in the absence of catalyst. The reaction was not completed even after 24 h.
In conclusion, the present work describes an efficient new methodology for the synthesis of a class of
poly substituted quinolines by one-pot reaction of 2-aminoaryl ketones and various α-methyleneketones.
The cheapness and availability of the reagents, easy and clean work-up procedure and good yields make
the method attractive for the synthesis of various quinolines.

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399
EXPERIMENTAL
Melting points were measured on an Electrothermal 9200 apparatus. IR spectra were recorded on FT-IR
102MB BOMEM apparatus. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer
1
operating at an ionization potential of 70 eV. H and 13C NMR spectra were recorded on a BRUKER
DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz.
General Procedure
A mixture of 2-aminoaryl ketone (1.0 mmol), α-methyleneketone (1.1 mmol) and NiCl2·6H2O (0.05
mmol) was heated under solvent-free conditions with stirring at 80ºC for 4 h. After completion of the
reaction as indicated by TLC (eluent: n-hexane/EtOAc: 2/1) the reaction mixture was washed with H2O
×
(2 10 mL), and filtered. Finally the crude solid product was recrystallized from EtOH.
Table 1: Synthesis of quinolines in the presence of NiCl2.2H2O under solvent-free conditions at 80˚C in 4 h.
2-Aminoaryl
ketone
Mp (˚C)
Entry
CH-acid
Product
Yield (%)a
Found
Reportedb
Ph
Ph
O
O
O
110-11110f
O
1
2
3
4
5
90
91
94
90
89
111-112
100-101
156-157
130-132
190-192
N
NH2
Ph
O
Ph
O
O
O
99-10010f
155-15610f
130-13110f
190-19110f
OEt
OEt
N
NH2
Ph
O
Ph
O
O
NH2
N
Ph
Ph
O
NH2
N
Ph
O
Ph
O
O
O
N
NH2
Ph
N
O
Ph
O
O
O
O
O
6
7
8
9
92
89
88
92
155-156
185-186
106-107
208-209
156-15710f
185-1869
107-1099
209-21010f
NH2
Ph
Ph
O
Cl
Cl
Cl
O
NH2
Ph
N
Ph
O
Cl
O
NH2
Ph
N
Ph
N
O
O
O
Cl
Cl
O
NH2

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HETEROCYCLES, Vol. 75, No. 2, 2008
Ph
Ph
O
Cl
Cl
Cl
165-16610f
152-1539
O
10
11
95
91
164-165
150-151
NH2
Ph
N
Ph
O
O
O
Cl
O
NH2
N
a Isolated yield.
b The products were characterized by comparison of their spectroscopic and physical data with authentic
samples synthesized by the procedures given in the references.
ACKNOWLEDGEMENTS
Financial support by the Research Council of Shahid Beheshti University is gratefully acknowledged.
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