Cu(I)-catalyzed three component coupling protocol for the synthesis of quinoline derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01240-6

Synthesis of 2,4-disubstituted quinolines has been achieved in a one-pot reaction from an aryl amine, an aldehyde and a terminal alkyne using CuCl (30 mol%) as a catalyst.

Full text of DOI:10.1016/S0040-4039(02)01240-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6485–6488
Cu(I)-catalyzed three component coupling protocol for the
synthesis of quinoline derivatives
H. Z. Syeda Huma,a,b Rajkumar Halder,b Swinderjeet Singh Kalra,a Jagattaran Dasb and
Javed Iqbala,b,
*
aDepartment of Chemistry, Indian Institute of Technology, Kanpur 208016, India
bDr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
Received 5 April 2002; revised 12 June 2002; accepted 24 June 2002
Abstract—Synthesis of 2,4-disubstituted quinolines has been achieved in a one-pot reaction from an aryl amine, an aldehyde and
a terminal alkyne using CuCl (30 mol%) as a catalyst. © 2002 Elsevier Science Ltd. All rights reserved.
Quinolines and their derivatives are very important in
medicinal chemistry because of their wide occurrence in
natural products1 and drugs.2 The classical method of
quinoline synthesis is Skraup’s procedure.3 Quinolines
can be prepared from aminoarenes and olefins using
transition metal complexes as catalysts.4,5 Also, quinoli-
nes can be synthesized from aminoarenes and aliphatic
aldehydes under non-acidic conditions.6 Most of these
synthetic protocols for quinolines suffer from harsh
reaction conditions, poor yields and/or the use of
expensive catalysts.
Typically, the arylamine (1.5 mmol) and an aromatic
aldehyde (1.5 mmol) were taken along with a catalytic
quantity of CuCl (30 mol%) in dry THF. The resulting
mixture was stirred at 25°C for 15 minutes. At this
stage the terminal alkyne (1 mmol) was introduced into
the reaction mixture and the temperature was raised to
60–70°C for 6–10 hours. The solvent was removed
under reduced pressure and the resulting mixture was
purified by column chromatography to afford 2,4-di-
substituted quinoline 1 in satisfactory to good yields
(Scheme 1, Table 1). Benzaldehyde and p-anisidine
reacted with 1-hexyne or 1-octyne to give the corre-
sponding disubstituted quinolines 1a and 1b, respec-
tively, in good yields (Table 1, entries 1 and 2). It is
interesting to note that propargyl alcohol and propar-
gyl acetate reacted with the aldehyde and amine to give
the corresponding disubstituted quinolines 1c–g, which
are amenable to further functionalization at the 4-posi-
tion (Table 1, entries 3–7). A careful analysis of the
reaction mixture revealed that benzylamines 3 (reduced
product of the in situ formed Schiff base) obtained
from the aldehyde and amine were present as by-
In an ongoing project in our laboratory on the synthe-
sis of functionalized quinolines, we required an efficient
route for the synthesis of these heterocycles. To the best
of our knowledge there is no simple and efficient
method for the formation of a functionalized quinoline.
Herein we report a novel, efficient and general route for
the synthesis of 2,4-disubstituted quinolines 1 (Scheme
1) in a one-pot synthesis from an aryl amine, an
aldehyde and a terminal alkyne using a cheap catalyst,
CuCl.7
R2
R3
R2
NH2
CuCl (30 mol%)
R3
R1CHO
+
+
+
N
1
R1
THF, reflux
HN
R2
HN
R1
R2
R1
R3
2
3
+
Scheme 1.
* Corresponding author. Present address: Director, Regional Research Laboratory, Trivandrum 695 019, India; e-mail: javediqbaldrf@
hotmail.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01240-6

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H. Z. Syeda Huma et al. / Tetrahedron Letters 43 (2002) 6485–6488
Table 1. Cu(I)-catalyzed synthesis of quinoline derivatives
products (ꢀ40%) along with the expected quinoline
reaction of propargyl alcohol, benzaldehyde and o-
nitro-p-methoxyaniline gave the corresponding propar-
gylamine 2d as the only product (Table 2, entry 4).
Similarly the reaction of 1-hexyne with benzaldehyde
and o-nitro-p-methoxyaniline afforded the correspond-
ing propargylamine 2e as the sole product (Table 2,
entry 5). The reaction of isobutyraldehyde, p-anisidine
and propargyl alcohol gave a mixture of the corre-
sponding quinoline 1j and the propargyl amine 2f
derivative (Table 2, entry 6). A careful analysis of the
reaction mixtures affording only the propargylamine,
revealed the absence of any benzylamine derivative 3. It
appears that the propargylamine 2 is a precursor to
quinoline 1 as we have observed that 2a is transformed
to the corresponding quinoline 1h when heated with
derivatives (Scheme 1).
We have also studied the effect of the nature of the
alkyne on the outcome of these reactions. Accordingly,
propargyl alcohol when reacted with benzaldehyde and
anisidine afforded a mixture of the corresponding quin-
oline 1h and the substituted propargyl amine 2a (Table
2, entry 1). A similar mixture of products 1i and 2b was
obtained when benzaldehyde and anisidine were reacted
with 1-methylprop-2-yn-1-ol (Table 2, entry 2). Interest-
ingly, the reaction of 1,1-dimethylprop-2-yn-1-ol with
benzaldehyde and p-anisidine gave the corresponding
propargyl amine 2c as the only product in good yield
(Table 2, entry 3). It is also interesting to note that the

H. Z. Syeda Huma et al. / Tetrahedron Letters 43 (2002) 6485–6488
6487
Table 2. Cu(I)-catalyzed synthesis of propargyl amine and quinoline derivatives
Entry Aldehyde
R1
Aniline
R2
Alkyne
R3
Quinoline
yielda
Propargyl amine
yielda
OH
OMe
MeO
-CH2OH
p-OMe
Ph
Ph
Ph
1
N
Ph
OH
HN
1h (37%)
Ph
2a (15%)
OH
OMe
MeO
-CH(CH3)OH
2
p-OMe
p-OMe
N
Ph
OH
HN
Ph
1i (35%)
2b (14%)
OMe
-C(CH3)2OH
3
4
OH
HN
Ph
2c (47%)
OMe
p-OMe
o-NO2
Ph
-CH2OH
O2N
OH
HN
Ph
2d (48%)
OMe
p-OMe
o-NO2
O2N
Hexn
n-Hex
Ph
5
HN
Ph
2e (30%)
OMe
OH
MeO
OH
-CH(CH3)2
6
HN
-CH2OH
p-OMe
N
1j (31%)
2f (9%)
a
isolated yield
CuCl under the reaction conditions described above
(Scheme 2).
OMe
OH
OH
MeO
CuCl (30 mol%)
THF, reflux
70%
Based upon these findings we propose the following
mechanism for the conversion of the three components
to a quinoline. At first, a Schiff’s base A is formed from
the aldehyde and the amine under the reaction condi-
tions. Cu-acetylide B, generated in situ then adds to
imine A to give intermediate 2 which in turn undergoes
HN
N
Ph
2a
1h
Ph
Scheme 2. Cu-catalyzed conversion of a propargylamine to a
quinoline.

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H. Z. Syeda Huma et al. / Tetrahedron Letters 43 (2002) 6485–6488
Scheme 3. Proposed mechanism for Cu(I)-catalyzed quinoline synthesis.
propargyl–allenyl isomerization to form I (Scheme 3).
Next, coordination of copper(I) to the terminal bond of
allene I would give intermediate II which will trigger an
intramolecular nucleophilic attack to produce the zwit-
terion III.8 The latter would then isomerize via a 1,2-
shift and proton transfer to A into the more stable
zwitterionic intermediate IV, and protonated A (i.e.
AH+). The intermediate IV would transform into quin-
oline 1 and benzylamine 3 by an oxidative process
(hydride transfer to B) (Scheme 3). It may be noted
here that the cyclization of compound 2 to quinoline 1
involves an oxidative process in which the Schiff’s base
may play the role of a sacrificial oxidizing agent leading
to the benzylamine derivatives 3 (40%). However the
role of oxygen in this oxidation cannot be ruled out, as
these reactions are not conducted under rigorously anaer-
obic conditions.
Research Foundation, Hyderabad for the financial sup-
port of this work.
References
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In summary, irrespective of mechanism, we have devel-
oped an efficient and general route to 2,4-disubstituted
quinolines in a one-pot synthesis from an arylamine, an
aldehyde and a terminal alkyne. This methodology
appears very attractive for a combinatorial synthesis of
quinolines for which efforts are in progress in our
laboratory.
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Acknowledgements
We thank the DST, New Delhi and Dr. Reddy’s