One-pot synthesis of substituted quinolines by iridium-catalyzed three-component coupling reaction

Article abstract of DOI:10.1246/cl.2005.106

A convenient and efficient synthesis of substituted quinolines in a simple one-pot reaction of an arylamine 1, an aromatic aldehyde or aliphatic aldehyde 2 and an aliphatic aldehyde 3 in the presence of transition metal complexes or Lewis acids was developed. Among them, the iridium catalyst [Ir(cod)Cl] ₂ catalyzed the reaction most efficiently. Copyright

Full text of DOI:10.1246/cl.2005.106

1
06
Chemistry Letters Vol.34, No.1 (2005)
One-pot Synthesis of Substituted Quinolines
by Iridium-catalyzed Three-component Coupling Reaction
Ã
Takeyuki Igarashi, Takashi Inada, Tadao Sekioka, Takayuki Nakajima, and Isao Shimizu
Department of Applied Chemistry, School of Science and Engineering, Waseda University,
Okubo 3-4-1, Shinjuku-ku, Tokyo 169-8555
(Received September 21, 2004; CL-041103)
A convenient and efficient synthesis of substituted quino-
tanal was obtained in good yield (73%) by the reaction in the ab-
sence of a benzaldehyde 2a (Table 1, Entry 6).
lines in a simple one-pot reaction of an arylamine 1, an aromatic
aldehyde or aliphatic aldehyde 2 and an aliphatic aldehyde 3 in
the presence of transition metal complexes or Lewis acids was
developed. Among them, the iridium catalyst [Ir(cod)Cl]2
catalyzed the reaction most efficiently.
NH2
CHO
O
[Ir(cod)Cl] ( 5.0 mol %)
2
+
+
H
o
DMSO, 90 C, 17 h
1
a
2a
3a
+
Ph
N
N
4
a
5a
Development of quinoline synthesis has been of considera-
ble interest in organic synthesis because of their wide occurrence
Table 1. Synthesis of quinoline 4a by iridium-catalyzed three-
component coupling reaction
1
2
in natural products and usefulness for drug design. Classical
3
methods for the synthesis of quinolines, such as the Skraup,
4
a
Equivalent
Yield/%
4a
5
6
7
Entry
Doebner-von Miller, Conrad-Limbach, Combes, Pfitzinger,
1
a
2a
3a
5a
8
and Friedl a¨ nder quinoline syntheses, require harsh reaction con-
ditions and the yields are unsatisfactory in most cases. There-
fore, a simple, general and efficient method for the preparation
of quinoline ring system is in demand and modern synthetic
methods for quinoline using a transition metal-catalyst have
been investigated.9 Dzhemilev reported that 2,3-disubstituted
1
2
3
4
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
5.0
10
1.0
0
1.0
1.0
1.0
1.0
1.0
2.5
42
51
61
58
63
0
28
22
11
9
8
73
,10
b
5
ꢀ
quinolines were synthesized with a PrCl3 catalyst at 190 C from
arylamine 1, an aromatic or aliphatic aldehyde 2 and aliphatic al-
6
a
b
Isolated yield based on aniline 1a. N-Benzylideneaniline
was used in stead of 1a and 2a.
9
dehyde 3. In our synthetic studies utilizing iridium-catalysts we
have found the three-component coupling reaction proceeds at
ꢀ
Formation of quinoline is expected to be catalyzed by vari-
ous acids.11 In this case, Lewis acids such as AlCl3, TiCl4,
HfCl4, and Yb(OTf)3 exhibit also considerable activities for
the synthesis of quinoline 4a as shown in Table 2. However,
the iridium catalyst gave the best result for the one-pot quinoline
synthesis (Table 2, Entry 2).
lower temperature 90 C (Scheme 1). We present here the results
of the iridium-catalyzed quinoline synthesis.
NH2
R3
R2
[
Ir(cod)Cl] (5.0 mol %)
2
O
2
R3
+
R CHO+
H
o
N
DMSO, 90 C, 17 h
R1
R1
1
2
3
4
Catalyst (5 mol% on metal)
1a
+
2a
+
3a
4a
Scheme 1. Iridium-catalyzed quinoline synthesis.
o
DMSO, 90 C, 17 h
In a typical experiment, a mixture of an aniline 1a and a
benzaldehyde 2a in a 1:1 ratio in DMSO was stirred in the pres-
ence of iridium catalyst (5 mol %) at room temperature for 1 h.
Table 2. Effect of catalysts on three-component coupling
reaction
Entry
Catalysts
Yield/%a
Butanal 3a was added and the resulting mixture was heated at
ꢀ
90 C for 17 h. The usual work up and chromatographic purifica-
1
2
3
4
5
6
blank
[Ir(cod)Cl]2
AlCl3
TiCl4
HfCl4
Yb(OTf)3
PrCl3/3 PPh3
N.R.
61
45
55
54
61
17
ꢀ
tion gave 4a and 5a in 42 and 28% yields (Table 1, Entry 1). Us-
ing N-benzylideneaniline as the starting material instead of an
aniline and a benzaldehyde gave a satisfactory result (4a: 63%
yield, 5a: 8%) (Table 1, Entry 5). However, mostly imines are
hygroscopic and difficult to purify by distillation or column
chromatography. Therefore three-component coupling reaction
using an aromatic amine, and two aldehydes directly without iso-
lation of imines is desirable for practical synthesis. When two
equiv. of 2a was used, the ratio of the desired quinoline 4a
was raised and 4a was obtained in 51% yield. When 5 equiva-
lents or 10 equivalents of 2a was used, the desired quinoline
b
7
a
b
Isolated yield based on aniline 1a. Reaction at 190 C
in DMF. No formation of 4a at 90 C in DMF, but 5a was
obtained in 35% yield.
9
ꢀ
Various substituted quinolines were obtained using iridium-
catalyzed three-component coupling reaction in a one pot. A
wide range of substituted anilines, aromatic aldehydes, and ali-
4a was obtained in 61 or 58% yields with small amounts of 5a
(
Table 1, Entries 3 and 4). The 1:2 adduct 5a of aniline and bu-
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.1 (2005)
107
phatic aldehydes were subjected to this procedure to synthesize
the corresponding quinolines in yields as shown in Table 3.
Functional groups such as methoxy, fluoro, carboxylic acid
and heterocycles as a pyridine and a furan are incorporated in
this synthesis.
O
O
R3
R3
R2
H
H
3
+
2
R CHO
NH2
N
- H O
R1
R1
1
2
2
L Ir
n
IrLn
5 Imine
NH2
R3
R2
O
R3
R3
[
Ir(cod)Cl] (5.0 mol %)
H
R3
O
2
2
R3
+
R CHO+
H
o
N
N
H
7
R2
DMSO, 90 C, 17 h
N
R2
- H2
N
R2
R1
R1
- H2O R1
R1
R1
H
4
1
2
3
4
6
β-Aminoaldehyde
Table 3. Synthesis of substituted quinolines by iridium-cata-
lyzed three-component coupling reaction
Scheme 2. Plausible reaction mechanism.
Productsa
arylamine, an aromatic aldehyde and an aliphatic aldehyde in
the presence of catalytic amount of iridium complex.
MeO
N
N
N
References
1
OMe
4
a 69%
4b 77%
4c 41%
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N
N
2
4
d 74%
4e 40%
4f 45%
MeO
N
N
N
3
1, 1031 (1988).
4
g 73%
4h 59%
4i 99%
3
a) H. Skraup, Chem. Ber., 13, 2086 (1880). b) R. H. F.
Mansake and M. Kulka, Org. React., 7, 59 (1953).
4
5
6
7
8
9
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F
MeO
MeO
MeO
N
N
N
4
j 83%
4k 78%
4l 61%
a) U. M. Dzhemilev, F. A. Selimov, R. A. Khusnutdinov,
A. A. Fatyknov, L. M. Khalilov, and G. A. Tolstikov,
Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 1407. b) U. M.
Dzhemilev, F. A. Selimov, and R. A. Khusnutdinov, Izv.
Akad. Nauk SSSR, Ser. Khim., 1990, 2447. A reviewer kindly
suggested PrCl3 is known to catalyze the same reaction.
Comparing the reactivity as shown in Table 2, iridium
catalyst is much more efficient for the quinoline synthesis.
0 a) C. Theeraladanon, M. Arisawa, A. Nishida, and M.
Nakagawa, Tetrahedron, 60, 10799 (2004). b) C.
Theeraladanon, M. Arisawa, A. Nishida, and M. Nakagawa,
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MeO
Ph
MeO
OMe
N
N
N
N
4
m 53%
4n 52%
4o 7%
MeO
MeO
N
MeO
O
N
N
1
4
p 75%
4q 53 %
4r 44%
MeO
F
N
N
N
OMe
CO H
2
4
s 37%
4t 45%
4u 47%
6
485 (2002). f) Y. Watanabe, Y. Tsuji, Y. Ohsugi, and J.
aThe reactions were carried out using conditions of Entry 6 in
Table 1 for 4a–4k and those of Entry 2 for 4l–4u.
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Watanabe, S. C. Shim, and T. Mitsudo, Bull. Chem. Soc.
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The mechanism for the conversion of the three components
to a quinoline is ambiguous but can be explained tentatively as in
Scheme 2. A ꢀ-amino aldehyde 6 is preformed by three-compo-
nent direct-Mannich reaction, followed by subsequent cycliza-
tion and aromatization under the catalyst of [Ir(cod)Cl]2.
11 Recently T. Akiyama reported synthesis of aryl-substituted
quinolines via Brꢀnsted acid-catalyzed [4+2] aza Diels-
Alder Reaction. T. Akiyama, S. Nakashima, K. Yokota,
and K. Fuchibe, Chem. Lett., 33, 922 (2004).
In summary, we have developed an efficient and general
route to substituted quinolines in a one-pot synthesis from an
Published on the web (Advance View) January 5, 2005; DOI 10.1246/cl.2005.106