A novel and facile method for the synthesis of 2,3-disubstituted quinolines by a three-component coupling reaction

Article abstract of DOI:10.1055/s-2007-991058

A Lewis acid effectively catalyzed the three-component coupling reaction of an aromatic amine and aldehyde with ethyl propiolate, and the 2,3-disubstituted quinoline was regioselectively obtained in a good yield (up to 83% GC yield). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991058

LETTER
2639
A Novel and Facile Method for the Synthesis of 2,3-Disubstituted Quinolines
by a Three-Component Coupling Reaction
2
,3-Disubstitu
a
ted Quinoli
t
nes by
o
a
Three-Com
s
ponent
C
h
oupling Reac
i
tion Kikuchi, Masahiro Iwai, Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551,
Japan
Fax +81(3)38171895; E-mail: fukuzawa@chem.chuo-u.ac.jp
Received 17 July 2007
as antimalarials, antibacterials, psychopharmacological
Abstract: A Lewis acid effectively catalyzed the three-component
drugs, and so on.2 Furthermore, these compounds are ver-
coupling reaction of an aromatic amine and aldehyde with ethyl
satile synthons for the preparation of molecules having
propiolate, and the 2,3-disubstituted quinoline was regioselectively
obtained in a good yield (up to 83% GC yield).
electronic and photonic characteristics.3 Because of their
importance, numerous methods have been developed for
Key words: Lewis acid, quinolines, three-component coupling
the construction of these substituted quinolines; for exam-
ple, Friedländer reaction, Skraup reaction and Combes
reaction.4 Although these methods are convenient for
obtaining the polysubstituted quinolines, the synthesis of
2-aryl-3-carboalkoxy quinoline has rarely been reported
using these and other methods;5 these methods would not
have provided enough quinoline libraries. Therefore, a
simple, expeditious and reasonable method is still
required.
reaction, regioselectively
In 2001, Balalaie et al. reported that the three-component
coupling reaction of amine, aldehyde, and ethyl propiolate
was mediated by microwave irradiation and N-substituted
1,4-dihydropyridines (Hantzsch pyridines) were obtained
in good yields.1 However, it required expensive micro-
wave apparatus and severe reaction conditions. So, we
tried to perform this reaction using catalytic amount of
Lewis acid. Then, we carried out the reaction of p-tolui-
dine (1a; 0.5 mmol), benzaldehyde (2a; 0.54 mmol), and
ethyl propiolate (3; 0.6 mmol) using Ga(OTf)3 (10 mol%)
at reflux in EtOH (5 mL) for 24 hours. Contrary to our
expectations, the 2,3-disubstituted quinoline 4aa bearing
an ester group at the 3-position was obtained as a major
product (83% yield) together with a small amount of the
1,4-dihydropyridines (<10%; Scheme 1). We are sur-
prised at and interested in this reaction, which would be a
useful method for the synthesis of substituted quinolines.
In this study, we have developed a novel and facile meth-
od for the synthesis of several 2,3-disubstituted quinolines
bearing an ester group at the 3-position using the three-
component coupling reaction of an amine, an aldehyde,
and ethyl propiolate in the presence of a catalytic amount
of Lewis acids.
We first investigated several solvents for the reaction of
1a and 2a with 3 using a catalytic amount of Ga(OTf)3 (10
mol%; Table 1). When we used other alcoholic solvents,
such as MeOH and n-PrOH, the yields of the quinoline
4aa were lower than that with EtOH (entries 2 and 3).
Toluene,6 1,2-dichloroethane and THF did not seem to be
appropriate solvents, as the yields were unsatisfactory
(entries 4–6). As a result, EtOH was revealed to be the
solvent of choice.7
NH2
CHO
CO2Et
Me
Table 1 Effect of Solvent in the Reaction of p-Toluidine (1a),
Benzaldehyde (2a) with Ethyl Propiolate (3) Using Ga(OTf)3
(10 mol%)a
1a
2a
3
Ga(OTf)3
N
Ph
(10 mol%)
Entry
Solvent
Yield (%)b
83
EtOH
Me
CO2Et
1
2
3
4
5
6
EtOH
reflux, 24 h
4aa; 83% yield
MeOH
56
Scheme 1
n-PrOH
Toluene
1,2-dichloroethane
THF
36
Substituted quinolines play important roles in medicinal
chemistry because quinoline-containing natural products
have interesting biological activities and are widely used
37
trace
trace
a Reaction conditions: Ga(OTf)3 (0.05 mmol), 1a (0.5 mmol), 2a (0.54
mmol), 3 (0.6 mmol), solvent (5 mL), reflux for 24 h.
b GC yield.
SYNLETT 2007, No. 17, pp 2639–2642
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991058; Art ID: U06707ST
© Georg Thieme Verlag Stuttgart · New York
1
6
.1
0
.
2
0
0
7

2640
S. Kikuchi et al.
LETTER
We next examined various Lewis acids in this reaction
and these results are summarized in Table 2.8 The reaction
was smoothly mediated by several Lewis acids but hardly
proceeded in the absence of Lewis acid (entry 1).
Ga(OTf)3 and Sc(OTf)3 were the most effective catalysts
that regioselectively produced the desired quinoline 4aa
in high yields without contamination of the regioisomers
(entries 2 and 3). In(OTf)3 and Yb(OTf)3 also could cata-
lyze the reaction and 4aa was obtained in moderate yields
(entries 4 and 5). The use of BF3·OEt2, AlCl3 and InBr3 as
a catalyst resulted in lower yields. The unreacted starting
compounds were recovered or 1,4-dihydropyridines were
produced (5–10%; entries 6–8). TiCl2(Oi-Pr)2 worked as
effectively as Sc(OTf)3. In this case, the yield of 4aa was
77% (entry 9).
Table 3 2,3-Disubstituted Quinoline Synthesis by the Three-Com-
ponent Coupling Reaction of Several Substrates Using Sc(OTf)3
under Optimal Conditionsa
NH2
CHO
CO2Et
R1
1a–h
R2
2a–c
3
Sc(OTf)3
N
(10 mol%)
R2
CO2Et
EtOH
R1
reflux, 24 h
4
Entry R1
R2
Product
4aa
4aa
4ba
4ca
Yield (%)b
1
2c
3d
4d
5
p-Me (1a)
p-Me (1a)
p-Et (1b)
p-i-Pr (1c)
p-MeO (1d)
H (1e)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
p-Cl (2b)
p-Cl (2b)
p-F (2c)
80
Table 2 Effect of Lewis Acid in the Reaction of p-Toluidine (1a),
Benzaldehyde (2a) with Ethyl Propiolate (3)a
83
70 (64)e
79 (75)e
33
Entry
Lewis Acid
none
Yield (%)b
1
2
3
4
5
6
7
8
9
0
83
80
69
63
55
56
36
77
4da
4ea
Ga(OTf)3
Sc(OTf)3
In(OTf)3
Yb(OTf)3
BF3·OEt2
AlCl3
6
28
7
p-Cl (1f)
o-Me (1g)
m-Me (1h)
m-Me (1h)
p-Me (1a)
H (1e)
4fa
21
8
4ga
4ha
4ha
4ab
4eb
4ec
15
9d
10c
11d
12
13
42 (40)e,f
34f
53g
InBr3
33
TiCl2(Oi-Pr)2
a Reaction conditions: Lewis acid (0.05 mmol), 1a (0.5 mmol), 2a
(0.54 mmol), 3 (0.6 mmol), EtOH (5 mL), reflux for 24 h.
b GC yield.
H (1e)
32
a Reaction conditions: Sc(OTf)3 (0.05 mmol), 1a (0.5 mmol), 2a (0.54
mmol), 3 (0.6 mmol), EtOH (5 mL), reflux for 24 h.
b GC yield.
c Ga(OTf)3 was used as a catalyst instead of Sc(OTf)3.
d Double scale.
We then carried out the reaction of several amines 1a–h,
aldehydes 2a–c with ethyl propiolate (3) using Sc(OTf)3
or Ga(OTf)3 (10 mol%) under the optimal conditions and
these results are summarized in Table 3.9 The reaction of
p-ethylaniline (1b) and p-isopropylaniline (1c) smoothly
proceeded to give the corresponding quinolines 4ba and
4ca in good yields, respectively (entries 3 and 4). We
examined the substituent effect of the para position of
aniline on the product yield, but no remarkable difference
between electron-donating and electron-withdrawing
groups was observed with respect to the yields (entries
5–7). The reaction of o-toluidine (1g) and m-toluidine
(1h) gave the quinolines 4ga and 4ha10 in low and moder-
ate yields, respectively (entries 8–10). We investigated
the reaction of p-chlorobenzaldehyde (2b) and p-fluoro-
benzaldehyde (2c) and obtained the desired quinolines in
moderate yields (entries 11–13).
e Isolated yield is given in parentheses.
f The ratio of regioisomers (5-methyl/7-methyl) was not determined.
g Isolated yield.
NH2
O
OEt
CO2Et
H
O
Me
3
1a
2d
Sc(OTf)3
N
CO2Et
CO2Et
(10 mol%)
EtOH
Me
reflux, 24 h
4ad; 34% yield
When we performed the reaction using ethyl glyoxalate
(2d) instead of aromatic aldehyde under the same condi-
tions (Scheme 2), we obtained the 2,3-dicarboethoxy
quinoline 4ad in moderate yield (34%).11
Scheme 2
Synlett 2007, No. 17, 2639–2642 © Thieme Stuttgart · New York

LETTER
2,3-Disubstituted Quinolines by a Three-Component Coupling Reaction
2641
3960. (d) Wu, J.; Xia, H.; Gao, K. Org. Biomol. Chem. 2006,
4, 126. (e) Tanaka, S.; Yasuda, M.; Baba, A. J. Org. Chem.
2006, 71, 800. (f) Wu, Y.; Liu, L.; Li, H.; Wang, D.; Chen,
Y. J. Org. Chem. 2006, 71, 6592. (g) Korivi, R. P.; Cheng,
C. J. Org. Chem. 2006, 71, 7079. (h) Sakai, N.; Annaka, K.;
Konakahara, T. J. Org. Chem. 2006, 71, 3653. (i) Asao, N.;
Iso, K.; Yudha, S. S. Org. Lett. 2006, 8, 4149. (j) Sromek,
A. W.; Rheingold, A. L.; Wink, D. J.; Gevorgyan, V. Synlett
2006, 2325. (k) Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi,
E.; Verdecchia, M. Synlett 2006, 3218. (l) Muscia, G. C.;
Bollini, M.; Carnevale, J. P.; Bruno, A. M.; Asis, S. E.
Tetrahedron Lett. 2006, 47, 8811. (m) Cho, C. S.; Ren, W.
X.; Shim, S. C. Tetrahedron Lett. 2006, 47, 6781. (n) Lin,
X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron Lett. 2006, 47,
3127. (o) Wang, G.-W.; Jia, C.-S.; Dong, Y.-W.
Ethyl 3-ethoxyacrylate (6), which could result from the
1,4-addition of ethanol to ethyl propiolate, might be in-
volved in the reaction.12 It would react with the imine to
produce quinoline.4a,13 So, we separately performed the
reaction of ethyl 3-ethoxyacrylate (6) with imine 5 [or
p-toluidine (1a) and benzaldehyde (2a)]. However, this
reaction hardly gave the quinoline under the same condi-
tions, and the starting imine 5 was recovered
(Scheme 3).14
The reaction might proceed with the Diels–Alder-type
cycloaddition of the imine with ethyl propiolate (3),
although the regioselectivity of the product can not be
explained.
Tetrahedron Lett. 2006, 47, 1059. (p) Li, A.; Ahmed, E.;
Chen, X.; Cox, M.; Crew, A. P.; Dong, H.; Jin, M.; Ma, L.;
Panicker, B.; Siu, K. W.; Steinig, A. G.; Stolz, K. M.;
Tavares, P. A. R.; Volk, B.; Weng, Q.; Werner, D.;
Mulvihill, M. J. Org. Biomol. Chem. 2007, 5, 61.
N
Ph
EtO
CO2Et
Me
5
6
(q) Arcadi, A.; Bianchi, G.; Inesi, A.; Marinelli, F.; Rossi, L.
Synlett 2007, 103.
Sc(OTf)3
N
Ph
(10 mol%)
(5) There are a few reports for the synthesis of 2-aryl-3-
carboalkoxy quinoline using Friedländer reaction. For
examples, see: (a) Patteux, C.; Levacher, V.; Dupas, G. Org.
Lett. 2003, 5, 3061. (b) Leleu, S.; Papamicaël, C.; Marsais,
F.; Dupas, G.; Levacher, V. Tetrahedron: Asymmetry 2004,
15, 3919.
×
EtOH
Me
CO2Et
reflux, 24 h
4aa
Scheme 3
(6) When this reaction was carried out at reflux in toluene, the
major product was the 1,4-dihydropyridines. The investiga-
tion regarding the synthesis of 1,4-dihydropyridines will be
reported elsewhere in due course.
In conclusion, we have developed a useful method for the
synthesis of the 2,3-disubstituted quinolines bearing an
ester group at the 3-position by the three-component cou-
pling reaction of an amine, aldehyde, and ethyl propiolate
using a catalytic amount of Sc(OTf)3. Further studies on
the reaction mechanism are now in progress.
(7) We performed this reaction using TfOH (10 mol%) at reflux
in EtOH, and obtained the quinoline 4aa in 50% yield..
(8) General Procedure: To the EtOH (5 mL) solution of 1a
(53.9 mg, 0.5 mmol), 2a (55 mL, 0.54 mmol) and Lewis acid
(0.05 mmol, 10 mol%) was added 3 (61 mL, 0.6 mmol) using
a microsyringe and then the mixture was refluxed for 24 h.
The reaction was quenched with sat. aq NaHCO3 and the
mixture was extracted with EtOAc. The combined organic
layers were dried over MgSO4. The organic layer was
filtered and concentrated under reduced pressure. The yield
of 4aa was determined by GC using biphenyl as the internal
standard. The quinoline 4aa was purified by preparative
TLC (SiO2; hexane–EtOAc, 7:1) and/or recycling
Acknowledgment
This work was financially supported by a Chuo University Joint
Research Grant.
References and Notes
(1) Balalaie, S.; Kowsari, E. Monatsh. Chem. 2001, 132, 1551.
(2) (a) Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford / New
York, 1996, 245. (b) Michael, J. P. Nat. Prod. Rep. 1997, 14,
605.
(3) (a) Aggarwal, A. K.; Jenekhe, S. A. Macromolecules 1991,
24, 6806. (b) Zhang, X.; Shetty, A. S.; Jenekhe, S. A.
Macromolecules 1999, 32, 7422. (c) Jenekhe, S. A.; Lu, L.;
Alam, M. M. Macromolecules 2001, 34, 7315. (d) Aoki, S.;
Sakurama, K.; Matsuo, N.; Yamada, Y.; Takasawa, R.;
Tanuma, S.; Shiro, M.; Takeda, K.; Kimura, E. Chem. Eur.
J. 2006, 12, 9066. (e) Qu, S.; Lin, Z.; Duan, C.; Zhang, H.;
Bai, Z. Chem. Commun. 2006, 4392. (f) Shavaleev, N. M.;
Adams, H.; Best, J.; Edge, R.; Navaratnam, S.; Weinstein, J.
A. Inorg. Chem. 2006, 45, 9410.
preparative HPLC (GPC column, CHCl3 as an eluent) and
was fully characterized.
Ethyl 6-Methyl-2-phenylquinoline-3-carboxylate (4aa):
1H NMR (300 MHz, CDCl3): d = 1.06 (t, J = 6.9 Hz, 3 H),
2.55 (s, 3 H), 4.17 (q, J = 6.9 Hz, 2 H), 7.44 (m, 3 H), 7.62
(m, 4 H), 8.07 (d, J = 9.0 Hz, 1 H), 8.55 (s, 1 H). 13C NMR
(CDCl3): d = 13.6, 21.5, 61.4, 125.4, 125.8, 126.8, 128.1,
128.3, 128.4, 129.1, 133.8, 137.2, 138.3, 140.8, 146.9,
157.2, 168.1.
(9) The reaction with imine 5, which was prepared from 1a and
2a, using Sc(OTf)3 yielded the quinoline 4aa in 60% yield.
(10) CCDC 650434 contains the supplementary crystallographic
data for compound 4ha. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033.
(11) Typical Procedure (Scheme 2): To the EtOH (7 mL)
solution of 1a (107.2 mg, 1.0 mmol), 2d (110 mL, 1.1 mmol),
which was distilled from P2O5 before use, and Sc(OTf)3
(49.2 mg, 0.10 mmol) was added 3 (122 mL, 1.2 mmol) using
a microsyringe and then the mixture was refluxed for 24 h.
(4) For recent reports on the synthesis of quinoline derivatives,
see: (a) Duvelleroy, D.; Perrio, C.; Parisel, O.; Lasne, M.-C.
Org. Biomol. Chem. 2005, 3, 3794. (b) Kouznetsov, V. V.;
Méndez, L. Y. V.; Gómez, C. M. M. Curr. Org. Chem. 2005,
9, 141. (c) Familoni, O. B.; Klaas, P. J.; Lobb, K. A.;
Pakade, V. E.; Kaye, P. T. Org. Biomol. Chem. 2006, 4,
Synlett 2007, No. 17, 2639–2642 © Thieme Stuttgart · New York

2642
S. Kikuchi et al.
LETTER
2 H), 8.09 (d, J = 5.8 Hz, 1 H), 8.67 (s, 1 H). 13C NMR
(CDCl3): d = 14.1, 21.6, 61.4, 62.2, 122.5, 127.1, 127.3,
129.4, 134.6, 138.7, 138.9, 146.6, 147.0, 165.3, 166.9.
(12) The CuOTf-catalyzed 1,4-addition of EtOH to ethyl
propiolate has been reported. See: Bertz, S. H.; Dabbagh, G.;
Cotte, P. J. Org. Chem. 1982, 47, 2216.
(13) (a) Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.;
Fujiwara, Y. Synthesis 1995, 801. (b) Kobayashi, S.;
Ishitani, H.; Nagayama, S. Synthesis 1995, 1195.
(14) In this reaction, ethyl 3,3-diethoxypropionate was obtained
predominantly.
The reaction was quenched with sat. aq NaHCO3 and the
mixture was extracted with EtOAc. The combined organic
layers were dried over MgSO4. This organic layer was
filtered and concentrated under reduced pressure. The
residue was purified by short column chromatography
(hexane–EtOAc, 6:1) and recycling preparative HPLC (GPC
column, CHCl3 as an eluent) to give the pure 4ad in 34%
yield.
Diethyl 6-Methylquinoline-2,3-dicarboxylate (4ad): 1H
NMR (300 MHz, CDCl3): d = 1.45 (m, 6 H), 2.57 (s, 3 H),
4.43 (q, J = 7.0 Hz, 2 H), 4.52 (q, J = 7.0 Hz, 2 H), 7.67 (m,
Synlett 2007, No. 17, 2639–2642 © Thieme Stuttgart · New York

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