Silver-catalyzed cascade reaction of o-aminoaryl compounds with alkynes: An aniline mediated synthesis of 2-substituted quinolines

Article abstract of DOI:10.1016/j.tetlet.2010.12.102

An efficient silver-catalyzed, aniline mediated cascade hydroamination/cycloaddition of o-aminoaryl compounds including o-aminoaryl aldehydes, o-aminoaryl ketones with alkynes for the synthesis of 2- or 2,4-substituted quinolines is reported. The reactions proceed with high regioselectivity to afford mono- or disubstituted quinoline derivatives in good to high yields using AgOTf as the catalyst in the air.

Full text of DOI:10.1016/j.tetlet.2010.12.102

Tetrahedron Letters 52 (2011) 1108–1111
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silver-catalyzed cascade reaction of o-aminoaryl compounds with alkynes:
an aniline mediated synthesis of 2-substituted quinolines
⇑
Hongfeng Li, Chengyu Wang, He Huang, Xiaolei Xu, Yanzhong Li
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Institute of Medicinal Chemistry, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient silver-catalyzed, aniline mediated cascade hydroamination/cycloaddition of o-aminoaryl
compounds including o-aminoaryl aldehydes, o-aminoaryl ketones with alkynes for the synthesis of 2-
or 2,4-substituted quinolines is reported. The reactions proceed with high regioselectivity to afford
mono- or disubstituted quinoline derivatives in good to high yields using AgOTf as the catalyst in the air.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 6 October 2010
Revised 17 December 2010
Accepted 24 December 2010
Available online 7 January 2011
Keywords:
Silver catalysis
Quinolines
Cascade Reaction
Hydroamination
Quinoline skeletons are important substructures in a large
number of natural or designed products with interesting biological
activities. The quinoline ring system occurs widely in drugs with
reactions. We previously reported the Cu-catalyzed synthesis of
benzofurans by the three-component reaction of salicylaldehyde,
alkyne, and amines. We envisioned that by changing the salicyl-
1
11
activities, such as antibacterial, antiinflammatory, antifungal and
aldehyde to o-aminoaryl aldehyde, the 3-aminoindole or disubsti-
1
c,2
analgesic properties.
They are also useful synthetic building
tuted 4-aminodihydroquinoline would be formed (Scheme 1, (Eq.
3
12
blocks in organic chemistry. The classical methods for the synthe-
sis of quinolines include Skraup, Doebner-von Miller, Friedlander
and Combes reactions, etc.4 Among them, Friedlander reaction
is one of the most straightforward methods and excellent works
1)). Interestingly, only 2-substituted quinolines were obtained
(Scheme 1, (Eq. 2)). Herein, we report a regioselective synthesis
of 2 or 2,4-substituted quinolines from the reaction of o-aminoaryl
aldehyde or o-aminoarylketone, alkyne and aniline catalyzed by
simple silver salt.
–7
8
have been disclosed. The reported procedures usually involve
acid- or base-catalyzed condensation between a 2-aminoaryl ke-
tone or an aldehyde and a carbonyl compound possessing a reac-
We started our investigation with the reaction of 2-aminobenz-
aldehyde (1a), dibenzylamine (4a), and phenylacetylene (2a) using
tive
a
-methylene group. Recently, reports concerning transition
2 3 4
20 mol % CuI as the catalyst in the presence of K CO , Bu NBr in tol-
uene at 110 °C as reported previously, only the dimmerization of
phenyacetylene was detected (Table 1, entry 1). Then we carried
9
11
metal mediated synthesis of quinolines have also appeared, many
transition metals, such as rhodium,
copper, and ruthenium
9a,b
9c
8b
9d
iron, zinc, iridium,
9
e
9f,g
were used. Although these methods
out the reactions without the addition of K
2
CO
3
4
and Bu NBr. When
are effective, most of them suffer from strong acid or base condi-
tions, high reaction temperatures. Furthermore, for most of these
processes one of the reactants was limited to the carbonyl com-
the catalyst was changed to 2 mol % of NaAuCl
4
ꢀ2H O, no reaction
2
took place (Table 1, entry 2). It was interesting to note that in the
absence of a secondary amine 4a, 2-aminobenzaldehyde reacted
with phenylacetylene to give 2-phenyl quinoline 3a in 23% yield.
pound bearing a reactive
a-methylene group. Therefore, the devel-
opment of new procedures with novel substrate scope is in great
Five mole percent of NaAuCl
to 47% (Table 1, entry 4). Surprisingly, the addition of a primary
amine of aniline remarkably improved the product yield to 63%
4
ꢀ2H
2
O increased the product yield
1
0
demand. Recently, Che and coworkers reported an efficient
synthesis of 2,4-disubstituted quinolines from the reaction of
o-aminoaryl ketones with terminal alkynes using special gold
(Table 1, entry 5). Other acids, such as BF
3
2
ꢀEt O and TfOH gave
1
0a
complexes.
However, o-aminoaryl aldehydes were not applica-
no desired product. We were happy to see when the catalyst was
changed to AgOTf, the reaction was completed in 3 h, and the
desired quinoline derivative 3a was obtained in 78% isolated yield
ble in the reaction, possibly due to their readily self-condensation
(
Table 1, entry 9). Control experiments without the addition
⇑
Corresponding author. Fax: +86 021 62233969.
E-mail address: yzli@chem.ecnu.edu.cn (Y. Li).
of AgOTf or aniline resulted in no or trace amount of the desired
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.102

H. Li et al. / Tetrahedron Letters 52 (2011) 1108–1111
R3
1109
R3 R4
H
R4
R1
N
N
R1
R2
R1
O
R4 Cat. M
R3
or
HN
(eq. 1)
NH2
N
R2
R2
N
H
H
H
NH2
R2
O
Cat. Ag
R1
R1
(eq. 2)
NH2
R2
N
Cascade hydroamination/cycloaddition reactions
Scheme 1. The reaction of o-aminoaryl aldehyde, alkyne and amine.
Table 1
o-aminoaldehydes and terminal alkynes to explore the scope of
the cascade hydroamination-cyclization reactions under the opti-
mized conditions. The representative results are shown in Table 2.
The reaction was applicable to various terminal alkynes and o-ami-
noaldehydes. Alkyne 2b with an electron-donating (–p-Me) aryl
group reacted smoothly with 1a to give the quinoline 3b in 74% yield
Optimization of reaction conditions for the synthesis of 3a
O
H
Catalyst
Ph
amine, 80 oC, air
NH2
N
Ph
(
2
Table 2, entry 2), the electron-donating (–p-OMe) aryl group alkyne
c afforded 3c in 77% yield (Table 2, entry 3). While 2d with elec-
1
a
2a
3a
Entry Catalyst (mol %)
Amine (equiv)
Dibenzylamine (1.0) Toluene
O (2) Dibenzylamine (2.0) DCE
O (2)
O (5)
O (5) Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Aniline (4)
Solvent
Yielda
tron-withdrawing (–p-Cl) aryl group gave rise to the corresponding
3d in 78% yield, along with 78% of aniline recovered (Table 2, entry
4
b,c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
CuI (20)
—
—
c
NaAuCl4ꢀ2H
NaAuCl4ꢀ2H
NaAuCl4ꢀ2H
NaAuCl4ꢀ2H
2
2
2
2
). When 4-aminophenylacetylene (2e) was employed, the corre-
—
—
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
23%
47%
63%
sponding quinoline was produced in 84% yield, in which the NH
2
group was well tolerated during the reaction (Table 2, entry 5).
Moreover, aliphatic acetylenes, such as 1-hexyne (2f) and
1-octyne (2g) were also compatible under the reaction conditions,
furnishing the desired quinolines in good yields, however,
10 mol % of AgOTf and longer reaction time were required (Table
2, entries 6 and 7). It is worthy to note that when 2-pyridyl acetylene
(2h) was used, a 3-pyridyl substituted quinoline 3j was produced in
high yield (Table 2, entry 10). It indicated that the regioselectivity of
the hydroamination of 2-pyridyl acetylene is different from that of
the other alkynes. Similarly, 2i with a strong electron-withdrawing
(–p-CN) aryl group gave rise to the corresponding 3-substituted
c
BF
3
2
ꢀEt O (5)
—
—
c
TfOH (5)
AgOTf (2)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
—
51%
78%
39%
d
0
1
2
3
4
5
6
7
8
9
e
57%
Chlorobenzene 63%
Toluene
CH CN
37%
24%
61
3
1.4-Dioxane
DCE
p-Toluidine (4)
Butan-1-amine (4)
Aniline (4)
—
73
f
DCE
DCE
DCE
NR
c
14
—
quinoline 3m in 67% yield (Table 2, entry 13).
AgOTf
Trace
Substrate scope of the reaction could be extended to substituted
o-aminoarylaldehydes and o-aminoaryl ketones, the desired quin-
olines were obtained in good yields. When 5-bromo-2-aminoalde-
hyde (1b) was used, the reaction was completed cleanly with 2g to
afford 3h in 81% yield (Table 2, entry 8). 5-Methoxy-2-aminoalde-
hyde (1c) furnished 3i in 66% yield (Table 2, entry 9), in which both
-Br and -OMe are well tolerated, it offers the possibility for further
diversification of the quinoline moiety. o-Aminoaryl ketone with a
methyl group, namely 1-(2-aminophenyl)ethanone (1d) reacted
with phenylacetylene under the optimal reaction conditions to
give the desired 4-methyl substituted quinoline 3k in moderated
yield (Table 2, entry 11). Similarly, o-aminoaryl ketone bearing a
phenyl group furnished the corresponding 4-phenyl substituted
quinoline 3l in 69% yield (Table 2, entry 12). It should be noted that
when internal alkynes such as diphenylacetylene was treated with
1a under the optimized reaction conditions, no desired quinoline
was observed, only the condensation reaction between 1a and ani-
line took place.
a
Isolated yield; unless otherwise noted, all the reactions were carried out with
the ratio of 1a:2a:4b = 1:3:4.
b
1
2 3 4
equiv of K CO and 1 equiv of Bu NBr were added.
c
d
e
f
No desired product.
The ratio of 1a:2a:4b = 1:1.5:4.
The ratio of 1a:2a:4b = 1:3:2.
NR = no reaction.
product (Table 1, entries 18 and 19). Less AgOTf (2 mol %) gave only
1% yield (Table 1, entry 8). Decreasing the amount of 2a to
.5 equiv also resulted in much lower yield (Table 1, entry 10).
5
1
When p-toluidine was used, the product yield was slightly lower
than that of aniline (Table 1, entry 16). However, butan-1-amine
gave no desired product (Table 1, entry 17). Switching to other sol-
vents such as chlorobenzene, acetonitrile or 1,4-dioxane afforded
much lower yields (Table 1, entries 12–15). It was clear that the
optimized reaction condition was to use 5 mol % of AgOTf as the
catalyst with aniline as the additive under an air atmosphere using
dichloroethane as the solvent.
To view the insight of the interesting quinoline forming reac-
tion, we first carried out the reaction of 2-aminobenzaldehyde
(1a) with aniline (4b) under the optimal conditions for 3 h, then
phenylacetylene (2a) was added to the reaction mixture, no de-
sired product could be observed (Eq. 3). This result indicated that
Having established an effective catalytic system for the synthesis
of quinolines, we next examined the reaction of a variety of

1
110
H. Li et al. / Tetrahedron Letters 52 (2011) 1108–1111
Table 2
Synthesis of quinolines from the reaction of o-aminoarylaldehydes, terminal alkynes and aniline
O
R2
R1
R2
Cat. AgOTf, PhNH
DCE, 80 oC, air
2
R1
R3
NH2
R3
N
Entry
1
o-Aminoarylaldehyde
1a: R1 = R2 = H
Alkyne
Product
Yielda (%)
78
2a: R3 = Ph
3a
Ph
N
2
3
4
1a
1a
1a
2b: R3 = 4-MeC
6
H
4
3b
4-MeC H4
74
N
N
N
N
6
2c: R3 = 4-MeOC
H
77
3c
6
4
4-MeOC H4
6
2d: R3 = 4-ClC
3d
78b
6
H
4
4-ClC H4
6
5
1a
2e: R3 = 4-NH
2
C
6
H
4
3e
84
NH2
6
7
1a
1a
2f: R3 = Bu
3f
Bu
72c
75c
N
N
2g: R3 = Hex
3g
Hex
Br
8
9
1b: R1 = Br, R2 = H
2g
2a
3h
81c
66
N
Hex
MeO
1c: R1 = OMe, R2 = Me
3i
N
Ph
1
1
0
1
1a
2h: R3 = 2-Pyridyl
N
83
3
j
N
1d: R1 = H, R2 = Me
2a
2a
55d
3
k
N
Ph
Ph
Ph
1
1
2
3
1e: R1 = H, R2 = Ph
69d
67
3
l
N
N
4
-CNC H4
6
1a
2i: R3 = 4-CNC
H
6 4
3m
a
b
c
Isolated yield.
Along with 78% of aniline recovered.
0 mol % AgOTf was used and the reaction time was 6 h.
The reaction time was 36 h.
1
d
the quinoline formation through the condensation of 1a and 4b
could be ruled out.
Ph
HN
O
NH
2
Ph
H
Cat. AgOTf
H
NH2
o
o
80 C, 3h
Ph
O
1) Cat. AgOTf, 80 C, 3h
ð3Þ
No desired product
o
ð4Þ
2)
Ph, 80 C, 3h
NH2
Another possible pathway involving the three-component reac-
tion of 1a, 2a, and 4b to give propargylic amine, which triggers
cycloaddition/aromatization to form quinoline 3, is also not the
case. Because the reaction of benzaldehyde, 2a, and 4b under the
standard conditions did not afford the corresponding propargylic
amine (Eq. 4).
When aniline was treated with phenylacetylene (2a) without
the addition of 1a under the optimal reaction conditions, the
hydroamination product 6 was obtained in 24% yield after
hydrolysis with most of the starting materials remaining
(
Eq. 5).

H. Li et al. / Tetrahedron Letters 52 (2011) 1108–1111
1111
O
C
R2
[
Ag+]
NH2
HN
N
R3
NH
2
hydroamination
R3
Ag
R3
Ag
7
8
Ag O R2
Ag O R2
R2
Ag O R2
C
R3
N
R3
NHPh
N
H
R3 [Ag+]
N
R3
N
H
N
PhNH2
H
2
Ph
9
10
11
3
Scheme 2. A proposed reaction mechanism.
References and notes
cat. AgOTf
N
1
2
3
.
.
.
(a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223; (b) Michael, J. P. Nat. Prod. Rep.
2005, 22, 627; (c) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia, M. Eur.
J. Med. Chem. 2000, 35, 1021; (d) Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.;
Tzeng, C.-C. J. Med. Chem. 2001, 44, 2374.
(a) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances,
Synthesis, Patents, Applications; Thieme: Stuttgart, Germany, 2001; (b)
Vaitilingam, B.; Nayyar, A.; Palde, P. B.; Monga, V.; Jain, R.; Kaur, S.; Singh, P.
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Chem. 1994, 37, 2129; (b) Bilker, O.; Lindo, V.; Panico, M.; Etiene, A. E.; Paxton,
T.; Dell, A.; Rogers, M.; Sinden, R. E.; Morris, H. R. Nature 1998, 289; (c) Chen, Y.
L.; Fang, K. C.; Sheu, J.-Y.; Hsu, S. L.; Tzeng, C. J. Med. Chem. 2001, 44, 2374.
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Kulka, M. Org. React. 1953, 7, 59.
NH2
o
DCE, 80 C, 3h
6
: 24%
ð5Þ
Based on the above observations and the reported results of the
hydroamination reactions,1
0,13
a plausible reaction mechanism
was proposed (Scheme 2), which involves hydroamination of al-
kynes to produce intermediate 7 or 8, and the reaction of 8 with
o-aminoaryl ketone 1 to form intermediate 9. Then intramolecular
cycloaddition followed by aromatization gave the desired quino-
line 3. We tried the reaction at lower temperature in order to ‘ob-
serve’ intermediate 9. However, no information about 9 could be
obtained at the current stage. It seems that the transformation of
4
.
.
5
Doebner, O.; von Miller, W. Ber. Dtsch. Chem. Ges. 1881, 14, 2812.
6. Friedlander, F. Ber. Dtsch. Chem. Ges. 1882, 15, 2572.
7
8
.
.
Combes reaction: (a) Combes, A. Bull. Soc. Chim. Fr. 1883, 49, 89; (b) Bergstrom,
F. W. Chem. Rev. 1944, 35, 77.
For selected examples see: (a) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10,
2629; (b) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257; (c) Mahata, P.
K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68,
9
to the final quinoline is fast.
3966; (d) Jia, C.; Zhang, Z.; Tu, S.; Wang, G. Org. Biomol. Chem. 2006, 4, 104; (e)
In summary, we have reported an efficient silver-catalyzed cas-
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cade hydroamination–cyclization reactions of acetylenes and a
variety of o-aminoaryl compounds, such as o-aminoarylaldehydes
and o-aminoaryl ketones with the assistance of aniline. The reac-
tions proceed to afford 2- or 2,4-substitued quinoline derivatives
in good to high yields using AgOTf as the catalyst under mild reac-
tion conditions.
9
.
(a) Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett.
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Acknowledgments
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We are grateful to the National Natural Science Foundation of
China (Nos. 20572025 and 20872037) for financial support. We
also thank the Laboratory of Organic Functional Molecules, the
Sino-French Institute of ECNU for support.
6
4, 2755.
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1
1
a
Supplementary data
2
Supplementary data (experimental details and spectroscopic
characterization of all new compounds) associated with this
article can be found, in the online version, at doi:10.1016/j.tetlet.
1
2
010.12.102.