Oxalic acid: An efficient and cost-effective organic catalyst for the Friedlaender quinoline synthesis under solvent-free conditions

Article abstract of DOI:10.1007/s00706-007-0712-4

Oxalic acid is used as an efficient catalyst in the condensation of 2-aminoaryl ketones with carbonyl compounds leading to the formation of quinolines in excellent yields under solvent-free conditions. This methodology offers significant improvements for

Full text of DOI:10.1007/s00706-007-0712-4

Monatshefte f u¨ r Chemie 138, 1249–1252 (2007)
DOI 10.1007/s00706-007-0712-4
Printed in The Netherlands
Oxalic Acid: An Efficient and Cost-Effective Organic Catalyst
for the Friedl a¨ nder Quinoline Synthesis under Solvent-Free Conditions
ꢀ
Minoo Dabiri , Mostafa Baghbanzadeh, and Maryam S. Nikcheh
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran, Iran
Received May 8, 2007; accepted (revised) May 11, 2007; published online September 24, 2007
#
Springer-Verlag 2007
Summary. Oxalic acid is used as an efficient catalyst in the
condensation of 2-aminoaryl ketones with carbonyl com-
pounds leading to the formation of quinolines in excellent
yields under solvent-free conditions. This methodology offers
significant improvements for the synthesis of quinolines with
regard to the yield of products, simplicity in operation, inex-
pensive reagents, and green aspects by avoiding toxic catalysts
and solvents.
hydration between an aromatic 2-aminoaldehyde or
ketone and a carbonyl compound containing an acti-
vated ꢀ-CH acid functionality. The Friedl a¨ nder re-
action can occur under base [2c, d, 3d, 5], Brønsted
acid [3d, 5a, 6], Lewis acid [7], inorganic salt [8], or
ionic liquid-catalyzed [9] conditions. Generally, bet-
ter product yields have been achieved for the acid-
catalyzed Friedl a¨ nder reaction [5a]. Most of the
reported protocols for the synthesis of quinolines
suffered from the use of harmful organic solvents,
high reaction temperatures, prolonged reaction times,
low product yields, and complicated work-up proce-
dures. Thus, the development of simple, convenient,
and environmentally friendly approaches for the syn-
thesis of quinolines is still demanding.
Keywords. Heterocycle; Friedl a¨ nder synthesis; Quinoline;
Solvent-free.
Introduction
Quinolines and their derivatives are very important
compounds because of their wide occurrence in nat-
ural products [1] and biologically active compounds
[
2]. A large variety of quinolines have displayed
As part of a continuing effort in our laboratory
toward the development of new methods for the ex-
peditious synthesis of biologically relevant hetero-
cyclic compounds [10], we became interested in the
possibility of developing an efficient method to con-
struct the quinoline scaffold.
interesting physiological activities and found attrac-
tive applications as pharmaceuticals and agrochem-
icals, as well as being general synthesis building
blocks [1b]. Many synthesis methods such as Skraup,
Doebner–von Miller, Friedl a¨ nder, and Combes re-
actions have been developed for the preparation of
quinolines [3], but due to their great importance, the
development of novel synthesis approaches remains
an active research area [4]. Amongst various meth-
odologies reported for the preparation of quinolines,
Friedl a¨ nder annulation is one of the simplest and
most straightforward protocols. Friedl a¨ nder synthe-
sis involves a condensation followed by a cyclode-
Results and Discussion
Initial study was performed by treatment of 2-ami-
nobenzophenone with ethyl acetoacetate under sol-
vent-free conditions in the presence of a catalytic
ꢁ
amount of oxalic acid (10 mol%) at 80 C. To our
delight, we observed the formation of ethyl 2-meth-
yl-4-phenylquinoline-3-carboxylate. Complete con-
version and 91% isolated yield was obtained after
ꢀ Corresponding author. E-mail: m-dabiri@sbu.ac.ir

1
250
M. Dabiri et al.
Scheme 1
ꢁ
Table 1. Friedl a¨ nder synthesis of quinolines in the presence of oxalic acid under solvent-free condition at 80 C for 2 h
a
ꢁ
b
Entry
2-Aminoaryl ketone
CH-acid
Product
Yield=%
Mp= C
Ref.
1
90
111–112
100–101
[6g]
[6g]
2
3
91
94
156–157
130–132
190–192
155–156
185–186
[6f]
[6f]
[6f]
[6f]
[9]
4
5
6
7
90
89
92
89
8
9
88
92
106–107
208–209
[9]
[6g]
1
1
0
1
95
91
164–165
150–151
[6g]
[9]
a
Isolated yield
The products were characterized by comparison of their spectroscopic and physical data with authentic samples synthesized by
the procedures given in the references
b

An Efficient and Cost-Effective Organic Catalyst
1251
2
h. Among the conditions (EtOH, THF, H O, MeCN,
2
General Procedure for the Synthesis of Quinolines
A mixture of 1.0 mmol 2-aminoaryl ketone, 1.1 mmol ꢀ-CH
toluene, and solvent-free) screened, solvent-free was
demonstrated as the best condition. Further studies
showed that 1–5 mol% of catalyst were also efficient
in this reaction at the expense of reaction time
acid, and 0.013g oxalic acid (0.1mmol) was heated under
ꢁ
solvent-free conditions with stirring at 80 C for 2 h. After
completion of the reaction as indicated by TLC (eluent: n-
hexane=ethyl acetate ¼ 2=1) the reaction mixture was washed
3
(5 mol%: 5 h, 90% yield; 1 mol%, 1 d, 88% yield).
with 2ꢂ10cm H O, and filtered. The crude solid product
2
To demonstrate the generality of this method, we next
investigated the scope of this reaction (Scheme 1)
and the results are summarized in Table 1.
As shown in Table 1, this method is equally effec-
tive for both cyclic and acyclic ketones. Substituted
was recrystallised from ethanol.
Acknowledgement
Financial support by the Research Council of Shahid Beheshti
University is gratefully acknowledged.
2
-aminoaryl ketones, such as 2-aminobenzophenone
and 2-amino-5-chlorobenzophenone reacted smooth-
ly with methylene ketones to produce a range of
quinoline derivatives. Complete conversion and good
to excellent isolated yields were observed for all
substrates employed. This reaction is very clean and
free from side reactions such as self-condensation of
ketones, which is normally observed under basic con-
ditions. In the absence of catalyst, the reaction did
not yield any product even after long reaction times.
Interestingly, cyclic ketones, such as cyclopenta-
none, cyclohexanone, dimedone, and 1,3-cyclohexa-
dione also underwent smooth condensation with
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In conclusion, we describe an efficient route for
the synthesis of quinolines and polycyclic quinolines
utilizing oxalic acid as an organic catalyst via
Friedl a¨ nder annulation. This method not only pro-
vides an excellent complement to quinoline syn-
thesis via Friedl a¨ nder annulation, but also avoids
the use of hazardous acids or bases and harsh re-
action conditions. The advantages of this method
include good substrate generality, the use of inex-
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