Iron-catalyzed cascade reaction of ynone with o-aminoaryl compounds: A Michael addition-cyclization approach to 3-carbonyl quinolines

Article abstract of DOI:10.1016/j.tetlet.2010.11.106

An efficient iron-catalyzed cascade Michael addition-cyclization of o-aminoaryl compounds including o-aminoaryl aldehydes, o-aminoaryl ketones, and o-aminobenzyl alcohols with ynones for the synthesis of 3-carbonyl quinolines is reported. The reactions proceed to afford 3-carbonyl quinoline derivatives with or without substituent at the C-4 position in good to high yields using Iron(III) chloride hexahydrate as the catalyst in the air.

Full text of DOI:10.1016/j.tetlet.2010.11.106

Tetrahedron Letters 52 (2011) 530–533
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron-catalyzed cascade reaction of ynone with o-aminoaryl compounds:
a Michael addition–cyclization approach to 3-carbonyl quinolines
⇑
Hongfeng Li, Xiaolei Xu, Jingyu Yang, Xin Xie, He Huang, Yanzhong Li
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 iron-catalyzed cascade Michael addition–cyclization of o-aminoaryl compounds including
o-aminoaryl aldehydes, o-aminoaryl ketones, and o-aminobenzyl alcohols with ynones for the synthesis
of 3-carbonyl quinolines is reported. The reactions proceed to afford 3-carbonyl quinoline derivatives
with or without substituent at the C-4 position in good to high yields using Iron(III) chloride hexahydrate
as the catalyst in the air.
Received 25 August 2010
Revised 15 November 2010
Accepted 19 November 2010
Available online 24 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalysis
Quinolines
Cascade reaction
Michael addition/cyclization
Quinoline derivatives are important substructures in a broad
range of natural or designed products with interesting biological
activities.1 The quinoline ring system occurs widely in a large num-
ber of drugs with activities such as antibacterial, antiinflammatory,
antifungal, and analgesic properties.1c,2 They also find application
in organic synthesis as useful ligands3 and materials.4 Several sig-
nificant methods have been reported for their construction includ-
ing Skraup, Doebner-von Miller, Friedlander, and Combes
reactions, etc.5–8 Among them, Friedlander reaction is one of the
most straightforward methods, and excellent works have been dis-
closed.9 The reported procedures usually involve acid- or base-cat-
alyzed condensation between a 2-aminoaryl ketone or aldehyde
forming reactions catalyzed or mediated by Iron have been
reported.11 During the course of our ongoing study on the
Table 1
Optimization of reaction conditions for the synthesis of 3a
O
O
Catalyst, 80oC
1,4-dioxane, air
O
Ph
H
+
Ph
N
NH2
1a
2a
3a
Entry
Catalyst (mol %)
t (h)
Yielda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
FeCl3 (20)
4
4
8
12
4
7
4
8
8
10
4
10
6
9
10
4
84%
82% (84%)
78%
and a carbonyl compound possessing a reactive
a-methylene
FeCl3ꢀ6H2O (20)
FeCl3ꢀ6H2O (10)
Fe(acac)3 (20)
None
FeCl3ꢀ6H2O (20)
FeCl3ꢀ6H2O (20)
BF3ꢀEt2 (20)
TFA (20)
group. Recently, transition metal mediated methods for the syn-
thesis of quinolines have also appeared,10 substrates used include
o-aminophenylboronates, o-aminobenzyl alcohols, and o-aminoa-
ryl iodides. Although these methods are effective, most of them
suffer from strong acid or base conditions, high reaction tempera-
tures, the use of expensive or toxic metal catalyst, or the need of
big excess amount of metal salts. These could be serious problems
from the environmental point of view and large scale production.
In recent years, the development of sustainable, environmen-
tally friendly, and low cost C–C and C–X bond forming protocols
attracted much attention in synthetic organic chemistry. As a re-
sult, many excellent works concerning direct C–C and C–X bond
Trace
—
76%b
85%c
94%
Trace
Trace
96% (82%)
Trace
NIR
Trace
Trace
78%d
HCl (20)
TsOHꢀH2O (20)
Cul (20)
CuO (1)
Znl2 (20)
CeCl3ꢀ7H2O (20)
FeCl3ꢀ6H2O (20)
a
NMR yields, isolated yields were given in parenthesis. Unless otherwise noted,
all reactions were carried out using 2 equiv of 1a in 1,4-dioxane at 80 °C.
b
Reaction was carried out in toluene.
Reaction was carried out in DCE.
1.5 equiv of 1a was used.
c
⇑
Corresponding author. Fax: +86 021 62233969.
E-mail address: yzli@chem.ecnu.edu.cn (Y. Li).
d
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.106

H. Li et al. / Tetrahedron Letters 52 (2011) 530–533
531
development of transition metal mediated heterocycle forming
O
O
protocols,12 we found that quinolines could be efficiently prepared
using Iron catalyst in the air. Herein, we would like to present our
results of the iron-catalyzed cascade Michael addition–cyclization
of o-aminoaryl compounds, including o-aminoaryl aldehydes,13 o-
aminoaryl ketones, and o-aminobenzyl alcohols, with ynones for
the synthesis of 3-carbonyl quinolines. This procedure is quite dis-
tinct from the reported Friedlander synthesis, which was based on
the condensation between ketones and the amino moiety of 2-
aminoaryl aldehydes followed by cyclization (Eq. 1). To the best
of our knowledge, this is the first example for the iron-catalyzed
synthesis of 3-carbonyl quinolines through a Michael addition–
cyclization sequence using ynones and 2-aminoaryl compounds
(Eq. 2).
O
H
H
Solvent-free
30oC, 1h
NH2
N
H
Hex
Hex
O
5a: 61%(Z/ E = 7:2)
O
FeCl3 6H2O, 80oC
1,4-dioxane, air
Hex
5a
N
3i:78%
Scheme 1. Isolation of the intermediate.
Table 2
Synthesis of quinolines from the reaction of o-aminoarylaldehydes and ynones
Entry
1
Aminoarylaldehyde
Ynone
Product
Yielda (%)
84
O
O
O
O
O
O
O
1a
H
Ph
3a
2a
NH2
N
O
2
3
4
5
6
1a
76
86
94
74
81
p-MeC6H4
3b
2b
2c
N
N
N
N
N
Me
O
1a
1a
1a
1a
3c
OMe
p-MeOC6H4
O
p-ClC6H4
3d
2d
2e
Cl
O
o-BrC6H4
3e
3f
Br
O
O
p-NO2C6H4
2f
NO2
O
S
O
O
S
7
1a
1a
1a
63
3g
2g
2h
N
N
O
8
9
82
52
67
3h
3i
O
O
O
Hex
Hex
2i
2j
N
N
O
10
1a
3j
Cyclhex
O
O
Br
Br
H
11
2a
2a
76
74
3k
NH2
N
1b
O
O
MeO
H
MeO
9
12
3l
NH2
N
1c
a
Isolated yields.

532
H. Li et al. / Tetrahedron Letters 52 (2011) 530–533
R1
N
O
R1
O
O
R3
ð1Þ
ð2Þ
Friedlander synthesis
O
+
R2
R3
R2
Condesation-cyclization
NH2
R2
R2
O
O
O
O
R3
R3
R2
Cat. Fe
O
R1
R1
R1
+
R3
NH2
N
N
H
Cascade Michael addition-cyclization
We started our investigation with 2-aminobenzaldehyde (1a),
2, entry 2), the electron-donating (-p-OMe) aryl group ynone 2c
afforded 3c in 86% yield (Table 2, entry 3). While 2d with elec-
tron-withdrawing (-p-Cl) aryl group gave rise to the corresponding
3d in 94% yield (Table 2, entry 4). When 2e with a similar electron-
withdrawing (-o-Br) aryl group was employed, the corresponding
quinoline was produced in 74% yield (Table 2, entry 5), while the
–Cl and –Br groups are well tolerated. Ynone with a much stronger
electron-withdrawing (-p-NO2) aryl group also furnished the corre-
sponding quinoline 3f in high yield (Table 2, entry 6). Other aryl
ynones are also suitable for this reaction. For example, 2-thienyl
or 1-naphthyl substituted ynone (2g and 2h) reacted smoothly
with 1a to produce 3g and 3h in 63% and 82% yields, respectively
(Table 2, entries 7 and 8). Moreover, alkyl ynones such as non-
1-yn-3-one (2i) and 1-cyclohexylprop-2-yn-1-one (2j) afforded
the desired quinolines in good yields (Table 2, entries 9 and 10).
However, when non-terminal ynone, namely 1,3-diphenylprop-
2-yn-1-one, or methyl propiolate was used under our reaction con-
ditions, no desired product was detected.
Substrate scope of the reaction could be extended to substituted
o-aminobenzaldehydes, the desired quinolines were obtained in
high yields. When 5-bromo-2-aminobenzaldehyde (1b) was used,
the reaction was completed cleanly with 2a to afford 3k in 76%
yield (Table 2, entry 11). 5-Methoxy-2-aminobenzaldehyde (1c)
furnished 3l in 74% yield (Table 2, entry 12), in which both –Br
and –OMe are well tolerated, and it offers the chance for further
diversification and amplification of the quinoline moiety.
which was synthesized according to the reported method.14 The
reaction of 2 equiv of 1a with 1-phenylprop-2-yn-1-one (2a) was
selected as a model reaction to screen the experimental conditions.
Selected results are summarized in Table 1. Firstly, the reaction
was carried out using 20 mol % of FeCl3 as catalyst in 1,4-dioxane
at 80 °C under an air atmosphere. We were happy to see that the
reaction was completed in 4 h, and the desired quinoline derivative
3a was formed in 84% NMR yield (Table 1, entry 1). FeCl3ꢀ6H2O
gave rise to 3a in much higher yield of 92% (Table 1, entry 2). Less
FeCl3ꢀ6H2O (10 mol %) resulted in lower yield (Table 1, entry 3).
However, Fe(acac)3 gave only trace amount of quinoline (Table 1,
entry 4). A controlled experiment without the addition of Iron salts
in 1,4-dioxane led to no detection of the desired product (Table 1,
entry 5). Decreasing the amount of 1a to 1.5 equiv also resulted in
much lower yield (Table 1, entry 16). Other solvents such as tolu-
ene and dichloroethane also furnished quinoline in good yields
(Table 1, entries 6 and 7). When 20 mol % of BF3ꢀEt2O was used,
the product yield was similar to that of FeCl3ꢀ6H2O with a pro-
longed reaction time (Table 1, entry 8). Brnsted acids such as TFA
and HCl gave only trace amount of the quinoline (Table 1, entries
9 and 10), yet TsOHꢀH2O afforded good result with slightly lower
isolated yield (Table 1, entry 11). 20 mol % of CuI or 1 mol % of
CuO resulted in trace amount of the desired product or no reaction
(Table 1, entries 12 and 13). It was cleared that the optimized reac-
tion condition was to use 20 mol % of FeCl3ꢀ6H2O as the catalyst
under an air atmosphere with 1,4-dioxane as the solvent.
To view insight of the interesting quinoline forming reaction,
we stopped the reaction of 2-aminobenzaldehyde (1a) with 1-phe-
nylprop-2-yn-1-one (2a) after 15 min and 1 h, unfortunately, no
Michael addition product could be isolated. It seems that once
the Michael addition product was formed, it transformed to the fi-
nal quinoline quickly. This result indicated that the Michael addi-
tion step might be the rate-determining process. Lower the
reaction temperature to 30 °C, no reaction took place between 1a
and 2a after 1 h. Then we use non-1-yn-3-one (2i) instead of 2a
Having established an effective catalytic system for the synthe-
sis of quinolines, we next examined the reaction of a variety of o-
aminoaryl aldehydes and ynones to explore the scope of the cas-
cade Michael addition–cyclization reactions under the optimized
conditions. The representative results are shown in Table 2. The
reaction was applicable to various ynones and o-aminoaryl alde-
hydes. Ynone 2b with an electron-donating (-p-Me) aryl group re-
acted smoothly with 1a to give the quinoline 3b in 76% yield (Table
-
H
O
FeCl3
Cl3Fe
O
O
O
C
O
R3
O FeCl3
R3
R3
H+
H
H
N
H2
N
N
FeCl3
H2
H2
5
6
-Cl3Fe
Cl3Fe
O
O
OH
O
O
H+
R3
R3
R3
N
N
H
N
FeCl3
H2O
H
7
8
3
Scheme 2. A proposed reaction mechanism.

H. Li et al. / Tetrahedron Letters 52 (2011) 530–533
533
Table 3
We also thank the Laboratory of Organic Functional Molecules, the
Sino-French Institute of ECNU for support.
Synthesis of quinolines from o-aminoaryl ketones or benzylic alcohols with ynone
Entry Substrates
Ynone
Product
Yielda
(%)
Supplementary data
O
O
Me
O
O
O
O
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.2010.11.106.
Me
Ph
1
2
3
4
34
53
42
58
3m
3n
2a
NH2
O
N
4a
4b
4c
Ph
Ph
References and notes
2a
NH2
OH
N
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Me
2a
3m
NH2
OH
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Ph
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NH2
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3n
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4d
a
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isolated yield after 3 h (Scheme 1).
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Based on the above observation, a plausible reaction mecha-
nism is proposed in Scheme 2.15
In order to further probe the scope of this process, we also
examined the o-aminoaryl ketones and o-amino benzylic alcohols
under the optimized reaction conditions, the results are shown in
Table 3. When o-aminoaryl ketone with a methyl group, namely
1-(2-aminophenyl)ethanone (4a) was used, the desired 4-methyl
substituted quinoline 3m was obtained in moderated yield (Ta-
ble 3, entry 1). Similarly, o-aminoaryl ketone bearing a phenyl
group afforded the corresponding 4-phenyl substituted quinoline
3n in 53% yield (Table 3, entry 2). o-Amino benzylic alcohols could
also be employed in the reaction and gave good yields of the quin-
oline derivatives. For example, 1-(2-aminophenyl)ethanol (4c) re-
acted smoothly with 1-phenylprop-2-yn-1-one (2a) to give
quinoline 3m in 42% yield (Table 3, entry 3). When (2-aminophe-
nyl)(phenyl)methanol (4d) was employed, the desired 4-phenyl
substituted quinoline could be obtained in much higher yield (Ta-
ble 3, entry 4).
In summary, we have reported an efficient iron-catalyzed cas-
cade Michael addition–cyclization of ynones and a variety of o-
aminoaryl compounds such as o-aminoarylaldehydes, o-aminoaryl
ketones, and o-aminobenzyl alcohols. The reactions proceed to af-
ford 3-carbonyl quinoline derivatives with or without substituent
at 4-position in good to high yields using Iron(III) chloride hexahy-
drate as the catalyst under mild reaction conditions. A plausible
reaction mechanism is proposed. Further application of this novel
iron-catalyzed cascade Michael addition–cyclization procedure to
extend the scope of synthetic utility of the reaction is under pro-
gress in our group.
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Nos. 20572025 and 20872037) for the financial support.
15. Yamazaki, S.; Takebayashi, M.; Miyazaki, K. J. Org. Chem. 2010, 75, 1188.