A copper(II)-catalyzed protocol for modified Friedl?nder quinoline synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.07.067

2-Aminobenzyl alcohol reacts with an array of ketones in dioxane at 100 °C in the presence of a catalytic amount of CuCl₂ along with KOH under O₂ atmosphere to afford the corresponding quinolines in good yields. 2-Aminobenzyl alcohol is also oxidatively coupled and cyclized with various aldehydes by step-by-step procedure, an initial treatment of 2-aminobenzyl alcohol in the presence of CuCl₂ and KOH in dioxane under O₂ atmosphere and subsequent addition of aldehyde to the mixture followed by stirring under argon atmosphere, to give 3-substituted quinolines in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2006.07.067

Tetrahedron Letters 47 (2006) 6781–6785
A copper(II)-catalyzed protocol for modified
Friedl a¨ nder quinoline synthesis
a,
b
b,
*
*
Chan Sik Cho, Wen Xiu Ren and Sang Chul Shim
a
Research Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, South Korea
b
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, South Korea
Received 20 June 2006; revised 13 July 2006; accepted 14 July 2006
Available online 4 August 2006
Abstract—2-Aminobenzyl alcohol reacts with an array of ketones in dioxane at 100 °C in the presence of a catalytic amount of
CuCl along with KOH under O atmosphere to afford the corresponding quinolines in good yields. 2-Aminobenzyl alcohol is also
2
2
oxidatively coupled and cyclized with various aldehydes by step-by-step procedure, an initial treatment of 2-aminobenzyl alcohol in
the presence of CuCl and KOH in dioxane under O atmosphere and subsequent addition of aldehyde to the mixture followed by
2
2
stirring under argon atmosphere, to give 3-substituted quinolines in moderate to good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Many synthetic methods have been developed and doc-
CHO
umented for quinolines due to their intrinsic pharmaco-
base
route a
1
logical and biological activities. Besides conventionally
named routes, transition metal-catalyzed reactions for
such quinoline skeletons have also been attempted as
alternative methods because of the facility and efficiency
NH2
R
O
R
R
R
N
2
OH
NH2
[Ru], base
route b
of reaction and the wide availability of substrate. As
part of our continuing studies toward transition metal-
catalyzed cyclization reactions, we also reported on sev-
eral transition metal-catalyzed routes for quinolines via
ruthenium-catalyzed alkyl or alkanol group transfer
from alkylamines or alkanolamines to N-atom of ani-
Scheme 1.
2
b,3,4
5
catalyst and a hydrogen acceptor12 (or the use of excess
starting ketone to 2-aminobenzyl alcohol). Herein, we
describe a copper-catalyzed oxidative cyclization of 2-
aminobenzyl alcohol with ketones as well as aldehydes
lines
(amine exchange reaction or amine scrambling
reaction ) and palladium-catalyzed coupling and cycli-
zation between 2-iodoaniline and propargylic alcohols.
6
Among them, in connection with this letter, 2-amino-
benzyl alcohol was found to be oxidatively coupled
1
3
leading to quinolines.
7
and cyclized with ketones (Scheme 1, route b) and sec-
8
The results of several attempted oxidative cyclizations of
2-aminobenzyl alcohol (1) with acetophenone (2a) are
listed in Table 1. Treatment of equimolar amounts of
1 and 2a in dioxane in the presence of a catalytic amount
ondary alcohols in the presence of a ruthenium catalyst
along with a base to give quinolines.9
,10
However, this
protocol, even though superior to conventional
1
1
Friedl a¨ nder quinoline synthesis (Scheme 1, route a)
of CuCl (1 mol %) along with KOH at 100 °C for 5 h
2
in a sense of price and stability of 2-aminobenzyl alco-
hol, led us to seek for a new elegant catalyst alternative
since it also has some drawbacks requiring an expensive
afforded 2-phenylquinoline (3a) in 65% yield without
any identifiable products (run 1). In contrast to our
recent report on ruthenium-catalyzed synthesis of
7
quinolines from 1 and ketones, no direct transfer
hydrogenation product 1-phenylethanol was produced.
This result indicates that the present reaction proceeds
irrespective of transfer hydrogenation from 1 to 2a. In
the case of ruthenium-catalyzed version, 2 equiv of 2a
Keywords: Aldehydes; 2-Aminobenzyl alcohol; Copper catalyst;
Ketones; Quinolines.
*
Corresponding authors. Tel.: +82 53 950 7318; fax: +82 53 950 6594
C.S.C); e-mail: cscho@knu.ac.kr
(
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.067

6782
C. S. Cho et al. / Tetrahedron Letters 47 (2006) 6781–6785
Table 1. Cu-Catalyzed optimization of conditions for the reaction of 1 with 2a
OH
NH2
O
CuCl /O (1 atm)
KOH, dioxane
2
2
+
Ph
N
Ph
1
2a
3a
a
Run
[2a]/[1]
KOH (mmol)
Cu (mmol)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
1
1
1.2
2
1.2
1.2
1.2
1.2
1.2
1
3
3
3
3
3
3
3
3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
2
(0.01)
(0.01)
(0.01)
(0.01)
(0.01)
(0.005)
(0.05)
5
5
5
5
20
5
5
5
5
65
70
77
77
79
73
79
78
51
CuCl (0.01)
CuCl (0.01)
b
9
2
Reaction conditions: 1 (1 mmol), dioxane (5 mL), 100 °C, O
2
(1 atm).
a
Isolated yield based on 1.
b
The reaction was carried out under air.
to 1 was necessary for the effective formation of quino-
lines. This could be due to partial consumption of 2a
corresponding quinoline 3o was also formed and the
yield was lower than that when previously described
ketones such as aryl(methyl) ketones, alkyl(aryl) ketones
and alkyl(methyl) ketones were used. Cyclic ketones
such as 4-phenylcyclohexanone (2p) and 1-tetralone
(2q) were also reacted with 1 to give 3-phenyl-1,2,3,4-tet-
rahydroacridine (3q) and 5,6-dihydrobenzo[c]acridine
(3r) in 63% and 65% yields, respectively.
7
leading to 1-phenylethanol by ruthenium-catalyzed
1
2
transfer hydrogenation of 2a by 1. A slightly increased
yield of 3a was observed with an increased amount of
KOH (run 2). The molar ratio of 2a to 1 affected the
yield of 3a, higher molar ratio up to [2a]/[1] = 1.2 result-
ing in the effective formation of 3a (runs 3 and 4). The
reaction gave no significant change on the quinoline
yield for a longer reaction time (run 5). The optimiza-
We then examined a similar oxidative cyclization
1
3
tion for CuCl amount was achieved with 1 mol % based
between 1 with aldehydes. Table 3 shows several
attempted results for the reaction between 1 and octyl
aldehyde (4a). Treatment of 1 with 4a under similar cat-
alytic system used in the reaction of 1 with ketones affor-
ded 3-hexylquinoline (3r) in only 29% yield (run 1).
However, step-by-step procedure, an initial treatment
2
on 1 (runs 3, 6 and 7). The reactivity toward the forma-
tion of 3a using CuCl under the employed conditions
was revealed to be as similarly effective as that using
CuCl (run 8). However, performing the reaction under
2
air atmosphere resulted in a lower yield of 3a compared
with that under O atmosphere (run 9).
of 1 in the presence of a catalytic amount of CuCl along
2
2
with KOH in dioxane for 5 h under O atmosphere and
2
Having established the reaction conditions, various
ketones 2 were subjected to react with 1 in order to
investigate the reaction scope and several representative
results are summarized in Table 2. Various aryl(methyl)
ketones (2a–i) having electron donating and withdraw-
ing substituents on the aromatic ring were readily
coupled and cyclized with 1 to give the corresponding
quinolines (3a–i) in the range of 42–82% yields. Here
again, the conventional transfer hydrogenated aryl-
subsequent addition of 4a to the mixture followed by
stirring for 20 h resulted in an increased yield of 3r
(run 2). Performing the second reaction stage under air
gave no significant change on the product yield (run
3). On the other hand, when the atmosphere of second
reaction stage was changed from O or air to argon, a
2
considerably increased yield of 3r was obtained (run
4). However, increasing the amount of CuCl catalyst
2
to 10 mol % rather lowered the quinoline yield (run 5).
(
methyl) carbinols were not detected at all on GLC
1
2
analysis. The position and electronic nature of the
substituent on the aromatic ring of aryl(methyl) ketones
had no relevance to quinoline yield except for 4 -cyano-
Given suitable reaction conditions, various aldehydes 4
were subjected to react with 1 in order to investigate
the reaction scope and several representative results
are summarized in Table 4. From the reaction between
1 and straight aldehydes (4a–d), the 3-substituted quin-
olines (3r–u) were formed in the range of 48–67% yields.
The product yield had no relevance to the chain length
of 4a–d. In the case of valeraldehyde (4b), the second
stage reaction was carried out at a lower reaction tem-
perature to obtain an allowable yield of 3-propylquino-
line (3s). Hydrocinnamaldehyde (4e) having a phenyl
group at position 3 reacts similarly with 1 to give 3-benz-
ylquinoline (3v) in 46% yield. The reaction proceeds
likewise with isovaleraldehyde (4f) and 3-phenylbutyral-
dehyde (4g), which have substituents such as methyl and
0
acetophenone (2i). The reaction proceeds likewise with
heteroaryl(methyl) ketone 2j to give the corresponding
quinoline 3j in similar yield. 2 -Acetonaphthone (2k)
0
was also readily oxidatively coupled and cyclized with
1
to afford 2-(2-naphthyl)quinoline (3k) in 77% yield.
Similar reaction rate and yield were observed with alkyl-
aryl) ketone 2l, which has only methylene reaction site.
(
In the cases of alkyl(methyl) ketones (2m and 2n), the
corresponding quinolines were produced as a regio-
isomeric mixture, favoring cyclization at less-hindered
7
,8,11c
methyl position over a-methylene.
With dialkyl
ketone 2o having only methylene reaction site, the

C. S. Cho et al. / Tetrahedron Letters 47 (2006) 6781–6785
Table 2. Cu-Catalyzed synthesis of quinolines 3 from 1 and 2
6783
Ketones 2
Quinolines 3
Yield (%)
O
R
N
R
R = Ph (2a)
R = Ph (3a)
77
79
80
71
82
75
68
71
42
62
77
R = 4-MeC
R = 3-MeC
R = 2-MeC
6
H
H
H
4
4
4
(2b)
(2c)
(2d)
R = 4-MeC
R = 3-MeC
R = 2-MeC
6
6
6
H
H
H
4
4
4
(3b)
(3c)
(3d)
6
6
R = 4-MeOC
R = 2-MeOC
6
H
H
4
(2e)
(2f)
R = 4-MeOC
R = 2-MeOC
6
H
H
4
4
(3e)
(3f)
6
4
6
R = 4-FC
R = 3-CF
6
H
C
4
(2g)
R = 4-FC
R = 3-CF
6
4
H (3g)
C
3
6
H
4
(2h)
(2i)
3
6
H
4
(3h)
(3i)
R = 4-CNC
6
H
4
6 4
R = 4-CNC H
R = 2-Thienyl (3j)
R = 2-Naphthyl (3k)
R = 2-Thienyl (2j)
R = 2-Naphthyl (2k)
O
6
4
4
2
8
4
Ph
N
N
N
Ph
2
l
3l
O
a
Ph
Ph
2
m
3m
3n
O
b
2
n
O
3
3
4
6
6
8
3
5
4
4
N
2
o
3
o
O
Ph
N
N
3
p
Ph
2
p
O
2
q
3q
(0.01 mmol), KOH (3 mmol), dioxane (5 mL), O (1 atm), 100 °C, for 5 h.
Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), CuCl
-Benzyl-2-methylquinoline was also formed in 18% yield.
2
2
a
3
b
3-Butyl-2-methylquinoline was also formed in 23% yield.
Table 3. Cu-Catalyzed oxidative cyclization of 1 with 4a under several conditions
OH 1. CuCl , KOH
2
2
. Octyl aldehyde (4a)
NH2
N
1
3r
Time (h) and atmosphere
20 (O
Run
CuCl
2
(mmol)
Yield (%)
1
2
3
4
5
0.01
0.01
0.01
0.01
0.1
2
)
29
47
47
67
54
5 (O
5 (O
5 (O
5 (O
2
2
2
2
2
) and 20 (O )
) and 20 (Air)
) and 20 (Ar)
) and 20 (Ar)
Reaction conditions: 1 (1.5 mmol), KOH (3 mmol), dioxane (3 mL), 100 °C; 4a (1 mmol), dioxane (3 mL), 100 °C.

6784
C. S. Cho et al. / Tetrahedron Letters 47 (2006) 6781–6785
Table 4. Cu-Catalyzed synthesis of quinolines 3 from 1 and 4
Aldehydes 2
Quinolines 3
Yield (%)
R
O
R
H
N
R = Hexyl (4a)
R = Propyl (4b)
R = Pentyl (4c)
R = Decyl (4d)
R = Hexyl (3r)
R = Propyl (3s)
R = Pentyl (3t)
R = Decyl (3u)
67
48
48
50
a
O
Ph
4
6
6
Ph
H
N
4e
3v
O
a
4
H
N
4
f
3
3
3
w
O
Ph
Ph
H
46
N
N
4
g
x
Ph
O
Ph
41
H
4
h
y
Reaction conditions: 1 (1.5 mmol), CuCl
2
(0.01 mmol), KOH (3 mmol), dioxane (3 mL), O
2
(1 atm), 100 °C, for 5 h; 4 (1 mmol), dioxane (3 mL), Ar,
1
00 °C, for 20 h.
Second stage (90 °C).
a
O
Ph
CHO
OH
NH2
Ph
O
2
a
NH2
1
O2
O2
5
NH2
6
CuII
CuI
-H O
2
a
2a
2
CHO
N
OH
N
N
Ph
Ph
7
Ph
8
3a
O
H
Ph
CHO
N
Ph
4
h
5
N
Ph
H
9
3y
Scheme 2.
phenyl at position 3, and the corresponding 3-isopropyl-
quinoline (3w) and 3-(1-phenylethyl)quinoline (3x) were
also formed in 64% and 46% yields, respectively. Here
again, in the case of 4f the second step reaction was per-
formed at a lower reaction temperature because of low
boiling point of 4f. The reaction of phenylacetaldehyde
As concerns the reaction pathway, it seems to proceed
via the initial oxidation of 1 to 2-aminobenzaldehyde
(5) under CuCl /O system, which in turn triggers cross
2
2
aldol condensation with 2a to give enone 6 (Scheme
1
1d,14,15
2).
This is followed by cyclodehydration to form
quinoline 3a. An alternative route for 3a involves keti-
mine aldehyde 8 formation, which is formed by the con-
densation between 5 and 2a as well as the oxidation of
(
4h), which has a phenyl substituent at position 2, with
also proceeds to give 3-phenylquinoline (3y).
1

C. S. Cho et al. / Tetrahedron Letters 47 (2006) 6781–6785
6785
ketimine alcohol 7 initially formed from 1 and 2a, and
subsequent intramolecular aldol-type condensation of
Shim, S. C. Tetrahedron 2001, 57, 3321; (d) Cho, C. S.;
Kim, J. H.; Choi, H.-J.; Kim, T.-J.; Shim, S. C. Tetra-
hedron Lett. 2003, 44, 2975.
. For a review: Murahashi, S.-I. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2443.
. (a) Cho, C. S. J. Organomet. Chem. 2005, 690, 4094; (b)
Cho, C. S.; Lee, N. Y.; Kim, T.-J.; Shim, S. C. J.
Heterocycl. Chem. 2004, 41, 409.
. Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Chem.
Commun. 2001, 2576.
8
. The reaction with aldehyde 4h for quinoline 3y also
5
6
similarly proceeds via an aldimine 9 formation followed
by the intramolecular aldol reaction.
In summary, we have shown that 2-aminobenzyl alcohol
can be oxidatively cyclized with ketones as well as alde-
hydes in the presence of a copper catalyst and a base to
afford quinolines in good yields. We believe that the
present reaction will work as a useful procedure for
transition metal-catalyzed modified Friedl a¨ nder quinol-
ine synthesis since it proceeds not only in the presence
of a cheap copper catalyst but also in the absence of a
hydrogen acceptor.
7
8. Cho, C. S.; Kim, B. T.; Choi, H.-J.; Kim, T.-J.; Shim, S. C.
Tetrahedron 2003, 59, 7997.
9
. For similar ruthenium- and iridium-catalyzed oxidative
cyclization of 2-aminobenzyl alcohol with ketones leading
to quinolines: (a) Motokura, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Tetrahedron Lett. 2004, 45, 6029; (b)
Mart ´ı nez, R.; Brand, G. J.; Ram o´ n, D. J.; Yus, M.
Tetrahedron Lett. 2005, 46, 3683; (c) Taguchi, K.; Saka-
guchi, S.; Ishii, Y. Tetrahedron Lett. 2005, 46, 4539.
0. It has recently been found that carbonyl compounds (or
secondary alcohols) are coupled with primary alcohols in
the presence of a ruthenium catalyst and a base: (a) Cho,
C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J. Org. Chem.
Acknowledgements
1
The present work was supported by the Korea Research
Foundation Grant funded by Korea Government
2
001, 66, 9020; (b) Cho, C. S.; Kim, B. T.; Kim, T.-J.;
(
2
MOEHRD, Basic Research Promotion Fund) (KRF-
005-015-C00264). C.S.C. gratefully acknowledges a
Shim, S. C. Tetrahedron Lett. 2002, 43, 7987; (c) Cho, C.
S.; Kim, B. T.; Kim, H.-S.; Kim, T.-J.; Shim, S. C.
Organometallics 2003, 22, 3608.
Research Professor Grant of Kyungpook National
University (2005).
1
1. (a) Friedl a¨ nder, P. Chem. Ber. 1882, 15, 2572; For a
review, see: (b) Cheng, C.-C.; Yan, S.-J. Org. React. 1982,
2
8, 37; For a regioselective Friedl a¨ nder quinoline synthe-
References and notes
sis, see: (c) Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes,
D. L.; Reider, P. J. Org. Lett. 2001, 3, 1101; (d)
Muchowski, J. M.; Maddox, M. L. Can. J. Chem. 2004,
82, 461.
1
. (a) Jones, G. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New
York, 1984; Vol. 2, p 395; (b) Arcadi, A.; Chiarini, M.;
Giuseppe, S. D.; Marinelli, F. Synlett 2003, 203, and
references cited therein.
12. For recent reviews on transition metal-catalyzed transfer
hydrogenation, see: (a) Zassinovich, G.; Mestroni, G.;
Gladiali, S. Chem. Rev. 1992, 92, 1051; (b) B a¨ ckvall, J.-E.;
Chowdhury, R. L.; Karlsson, U.; Wang, G. In Perspec-
tives in Coordination Chemistry; Williams, A. F., Floriani,
C., Merbach, A. E., Eds.; VCH: New York, 1992; pp 463–
486; (c) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997,
30, 97; (d) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem.
Rev. 1998, 98, 2599; (e) Palmer, M.; Wills, M. Tetra-
hedron: Asymmetry 1999, 10, 2045.
13. For ruthenium-catalyzed oxidative cyclization of 2-amino-
benzyl alcohol with aldehydes leading to 3-substituted
quinolines Cho, C. S.; Ren, W. X.; Shim, S. C. Bull.
Korean Chem. Soc. 2005, 26, 2038.
14. Hudlick y´ , M. Oxidation in Organic Chemistry; American
Chemical Society: Washington, DC, 1990; pp 114–126.
15. We confirmed in a separate experiment that 1 was oxidized
2
3
. (a) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett.
2
001, 3, 1109, and references cited therein; (b) Cho, C. S.;
Oh, B. H.; Kim, J. S.; Kim, T.-J.; Shim, S. C. Chem.
Commun. 2000, 1885, and references cited therein.
. (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett.
1
999, 40, 1499; (b) Cho, C. S.; Oh, B. H.; Shim, S. C. J.
Heterocycl. Chem. 1999, 36, 1175; (c) Cho, C. S.; Kim, J.
S.; Oh, B. H.; Kim, T.-J.; Shim, S. C. Tetrahedron 2000,
5
6, 7747; (d) Cho, C. S.; Kim, T. K.; Kim, B. T.; Kim,
T.-J.; Shim, S. C. J. Organomet. Chem. 2002, 650, 65; (e)
Cho, C. S.; Lee, N. Y.; Kim, T.-J.; Shim, S. C.
J. Heterocycl. Chem. 2004, 41, 423.
. For our recent report on synthesis of indoles via similar
ruthenium-catalyzed alkanol group transfer from alkanol-
amines to N-atom of anilines: (a) Cho, C. S.; Lim, H. K.;
Shim, S. C.; Kim, T. J.; Choi, H.-J. Chem. Commun. 1998,
4
to 5 in 50% yield with 85% conversion of 1 under CuCl
2
/
O
2
/KOH catalytic system, however, benzyl alcohol was
9
95; (b) Cho, C. S.; Kim, J. H.; Shim, S. C. Tetrahedron
not effectively oxidized to benzaldehyde (11% yield) under
the same catalytic system.
Lett. 2000, 41, 1811; (c) Cho, C. S.; Kim, J. H.; Kim, T.-J.;