Cu(ii)-promoted three-component coupling sequence for the efficient synthesis of substituted quinolines

Article abstract of DOI:10.1039/c2ob26484f

The copper-promoted three-component coupling sequence for substituted quinoline formation from aldehydes, anilines and acetone is described. Various 2-arylquinolines were selectively obtained in good yields under mild conditions. The reaction tolerated a wide range of functionalities.

Full text of DOI:10.1039/c2ob26484f

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Cu(II)-Promoted Three-Component Coupling Sequence for the Efficient
Synthesis of Substituted Quinolines
Fuhong Xiao, Wen Chen, Yunfeng Liao, and Guo-Jun Deng*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
5
DOI: 10.1039/b000000x
The copper-promoted three-component coupling
sequence for substituted quinolines formation from
aldehydes, anilines and acetone is described. Various 2-
arylquinolines were selectively obtained in good yields
10 under mild conditions. The reaction tolerated a wide
range of functionalities.
The development of new quinoline syntheses in oneꢀpot using
readily available starting materials under mild reaction conditions
50 is highly desirable.15,16 During our recent investigation of direct
acylation of aromatic CꢀH bonds with ketones and alcohols, we
observed a small amount of quinoline adducts when Nꢀarylimines
were used as substrates.17 This unexpected result inspired us to
systematically investigate the quinoline formation using readily
55 available starting materials. Herein, we report a copperꢀpromoted
quinoline formation from readily available and nonꢀexpensive
arylamines, aromatic aldehydes and acetone, affording 2ꢀarylꢀ4ꢀ
methylꢀquinolines in good yields under mild conditions.18
Quinoline derivatives are one of the major classes of heterocycles
and the quinoline moiety is widely found in many natural
products.1 The functionalized quinolines are widely used as
15 agrochemicals,2 dyes3 and medicinal chemistry.4 2ꢀ
Arylquinolines also provide convenient precursors to chiral
dihydroꢀ and tetrahydroquinolines, which are important
biologically active structures.5 Therefore, the development of
efficient methods for rapid construction and functionalization of
20 substituted quinolines has gained much attention.6 Recently, the
activation of CꢀH bonds has received much attention for the
straightforward construction of CꢀC and Cꢀhetero bonds.7 Various
substituted quinolines especially 2ꢀarylquinolines have been
successfully synthesized by direct CꢀH activation and subsequent
25 CꢀC bond formation with aryl halides, aryl boronic acids, and aryl
metals.8
The Combes Synthesis
R3
O
O
acid
R1
R1
+
R2
R3
- 2H2O
NH2
N
R2
The Skraup Synthesis
R3
O
R3
[O]
R1
R1
+
- H2O
NH2
R2
N
R2
This W ork
The classical methods for the construction of quinoline ring
include the Combes synthesis from arylamines and 1,3ꢀ
dicarbonyl compounds,9,10 the Skraup (or DoebnerꢀMille)
30 synthesis11 from anilines and α,βꢀunsaturated carbonyl
compounds in the presence of an oxidizing agent (Scheme 1), and
the Friedländer synthesis from orthoꢀacylꢀarylamines and
aldehydes/ketones (must contain an αꢀmethylene group).12
However, these methods sometimes are limited for preparation of
35 quinolines with sensitive functional groups because of the high
reaction temperatures and the use of strong acids or bases. More
recently, the metalꢀcatalyzed cyclisation of orthoꢀsubstituted
anilines have also found to be efficient routes for assembling the
quinoline skeleton.13,14 However, these protocols need use
40 prepared starting materials, and thus require multiꢀstep procedure.
Me
CuCl2
TfOH
O
R1
R1
+
Ar
CHO
+
NH2
O2, 50 oC
N
Ar
Scheme 1 Various routes for substituted quinoline synthesis from anilines.
60
We began our study by examining the reaction of
benzaldehyde (1a), aniline (2a), and acetone (3a) in ethanol at 50
oC using trifluoromethanesulfonic acid (TfOH) as acid under an
atmosphere of oxygen. Lewis acid catalysts such as FeCl3, NiCl2
and LaCl3 were efficient catalysts for this kind of transformation
65 and the desired product 4ꢀmethylꢀ2ꢀphenylꢀquinoline (4a) was
obtained in good yields as determined by GC and 1H NMR
methods (Table 1, entries 1ꢀ3). Among the various Lewis acid
catalysts examined, CuCl2 was the most effective, and its use
resulted in the formation of 4a in 89% yield (entry 4). Other
70 copper catalysts such as CuBr2 and CuF2 were also found to be
effective for this reaction (entries 5 and 9). The choice of TfOH
Key Laboratory of Environmentally Friendly Chemistry and Application
of Ministry of Education, College of Chemistry, Xiangtan University,
Xiangtan, 411105, China.. Fax: (+86)ꢀ731ꢀ58292251; Tel: (+86)ꢀ731ꢀ
58298601; Eꢀmail: gjdeng@xtu.edu.cn
45 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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was crucial for this reaction. The use of trifluoroacetic acid
(TFA)
6). Good yields were obtained when 4ꢀchlorobenzaldehyde (1e)
and 4ꢀbromobenzaldehyde (1f) were used, and the desired
and acetic acid completely prohibited the reaction (entries 11 and 25 products were achieved in 85 and 87% yields, respectively. The
13). The solvent also played an important role for the formation
of substituted quinoline. Other solvents such as toluene,
acetonitrile, water and other alcohols all resulted lower yields
(entries 13ꢀ18). Good yield still could be achieved when the
position of the substituents on the phenyl ring of benzaldehydes
affected the reaction yield significantly, and the use of 2ꢀ
chlorobenzaldehyde resulted the product 4j in only 60% yield
(entry 10). High yields were achieved when 3,4,5ꢀ
5
reaction was carried out under an atmosphere of air (entry 19). 30 trimethoxybenzaldehyde (1l) and 2ꢀnaphthaldehyde (1m) were
However, the reaction decreased significantly when the reaction
10 was carried out under argon (entry 20). Excess acetone is
necessary to get satisfied yield for this transformation.
used (entries 12 and 13). Notably, the reaction of hetero aromatic
aldehydes such as 2ꢀfuraldehyde (1n) with 2a and 3a afforded the
desired product in moderate yield (entry 14). Unfortunately,
aliphatic aldehydes are not suitable for this kind of transformation
35 under the optimal conditions.
Table 1 Optimization of the reaction conditionsa
Table 2 Reaction of various aldehydes with aniline and acetonea
CHO
O
catalyst
+
+
Ph NH2
additive
50 oC
N
Ph
CuCl2
TfOH
ethanol
O2, 50 oC
CHO
1a
2a
3a
4a
O
+
+
Ph NH2
R
Yield (%)b
N
Solvent
Entry
Catalyst
Acid
R
1
2a
3a
4
FeCl3
NiCl2
LaCl3
CuCl2
1
2
3
4
TfOH
TfOH
TfOH
TfOH
ethanol
ethanol
ethanol
ethanol
71
75
62
89
Yield (%)b
Entry
Adehyde
CHO
Product
1
R
R = H
1a
4a
80
CuBr2
5
6
7
TfOH
ethanol
ethanol
ethanol
87
52
62
CuSO4
TfOH
TfOH
R = CH3
R = OCH3
R = F
2
3
4
1b
1c
1d
4b
4c
4d
73
71
81
Cu(OTf)2
Cu(OAc)2
8
TfOH
TfOH
ethanol
ethanol
ethanol
ethanol
64
81
68
0
9
CuF2
CuCl2
CuCl2
5
6
7
R = Cl
1e
1f
4e
4f
85
87
74
10
11
TsOH
TFA
R = Br
R = tBu
1g
4g
CuCl2
CuCl2
CuCl2
CuCl2
CH3COOH
TfOH
12
13
14
15
ethanol
neat
0
R = CH3SO2
8
9
1h
1i
4h
4i
85
72
68
70
73
toluene
CH3CN
R = NO2
CHO
TfOH
TfOH
TfOH
TfOH
10
11
1j
4j
60
78
CuCl2
CuCl2
H2O
69
82
16
17
Cl
CHO
methanol
1k
4k
isopropanol
ethanol
73
80
CuCl2
CuCl2
18
TfOH
TfOH
H3CO
H3CO
CHO
19c
20d
TfOH
12
1l
4l
81
ethanol
CuCl2
41
OCH3
CHO
a Conditions: 1a (0.3 mmol), 2a (0.2 mmol), acid (1.0 equiv), acetone (0.2
mL), solvent (0.3 mL), 50 oC, 24 h under oxygen unless otherwise noted. b
GC yield. c Under air. d Under argon.
13
14
1m
1n
4m
4n
90
51
O
CHO
15
With the optimized reaction conditions established, the scope
of the reaction with respect to aniline (2a), acetone (3a) and
various aromatic aldehydes (1) was investigated (Table 2). The
reactions with aromatic aldehydes bearing electronꢀdonating
groups (entries 2, 3 and 7) and electronꢀwithdrawing substituents
a Conditions: 1 (0.3 mmol), 2a (0.2 mmol), 3a (0.2 mL), CuCl2 (5 mol %),
TfOH (0.2 mmol), C2H5OH (0.5 mL), 50 oC, 24h, under oxygen. b Isolated
yield based on 2a.
20 at the para position (entries 4, 5 and 9) proceeded smoothly to
give the desired products in good yields. Under the optimized
conditions, halogen substituents were all well tolerated (entries 4ꢀ
To further explore the scope of the reaction, various arylamines
40 were employed to react with 1a and acetone under the optimized
conditions (Table 3). A series of functional groups including
2
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methyl, methoxy, chloro, bromo and acetyl were well tolerated
20
Scheme 2 Control experiments.
under the optimized conditions (Table 3, entries 1ꢀ6). The
position of the substituents on the phenyl ring of aniline
significantly affected the reaction yield (entries 7). The reaction
showed good selectivity when mꢀtoluidine was used, and the
products 4v and 5v were formed in 76% total yield (entry 8). The
replacement of acetone with other ketones resulted much lower
yield.
under the optimized reaction conditions. Based on these
observations, plausible mechanism to rationalize this
transformation is illustrated in Scheme 3. Condensation of
a
5
25 benzaldehyde (1a) with aniline (2a) generates an imine
intermediate A in the presence of trifluoromethanesulfonic acid.
Addition of acetone to A affords an intermediate B, which can be
Table 3 Reaction of various amines with 1a and 3aa
cyclized to form intermediate
C under acidic conditions.
CuCl2
NH2
Dehydration and deprotonation of C provides intermeidate D,
30 and oxidation of D using CuCl2 as catalyst under oxidative
conditions to give the final product 4a.
TfOH
O
R
Ph-CHO
+
R
+
ethanol
O2, 50 o
N
C
1a
2
3a
4
O
Yield (%)b
Entry
Amine
NH2
Product
acetone
Ph
+
Ph NH2
Ph CHO
N
Ph
- H2O
N
Ph
1
H
R
1a
2a
A
B
R = CH3
2b
4o
81
R = OCH3
R = F
H+
2
3
4
2c
2d
2e
4p
4q
4r
56
56
66
Me
OH
Me
Me
N
H
- H+
CuCl2
O2
R = Cl
+
- H2O
N
Ph
N
H
Ph
5
6
R = Br
2f
4s
4t
80
61
Ph
H
R = COCH3
NH2
2g
4a
D
C
7
8
63
76
2h
2i
4u
Scheme 3 A tentative mechanism.
NH2
35
In summary, we have developed a copperꢀpromoted 2ꢀarylꢀ4ꢀ
methylꢀquinoline formation from readily available and nonꢀ
expensive anilines, aromatic aldehydes and acetone. The threeꢀ
component reaction completed in oneꢀpot under relative mild
reaction conditions and gave the functionalized quinolines in
+
N
Ph
N
5v
Ph
4v
10:1
H3CO
NH2
9
2j
4w
66
40 good yields. Functional groups such as methyl, methoxy, acetyl,
chloro and bromo were all well tolerated under the optimized
reaction conditions. This method affords a cheap and efficient
alternative route for the synthesis of substituted quinolines. The
scope, mechanism, and synthetic applications of this reaction are
45 under investigation.
OCH3
a Conditions: 1a (0.3 mmol), 2 (0.2 mmol), 3a (0.2 mL), CuCl2 (5 mol %),
TfOH (0.2 mmol), C2H5OH (0.5 mL), 50 oC, 24h, under oxygen. b Isolated
yield based on 2.
10
To get more information about the reaction mechanism, several
control experiments were set up under the standard conditions.
The reaction of imine generated from its corresponding amine
and aldehyde with acetone afforded the desired product 4a in
15 81% yield (Scheme 2, 1). However, the reaction of aniline with
benzylideneacetone which can be easily generated from acetone
and benzaldehyde did not afford the desired product (Scheme 2,
2). This means the reaction did not take the Skraup pathway
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20902076, 21172185), the Hunan
Provincial Natural Science Foundation of China (11JJ1003,
50 12JJ7002), the New Century Excellent Talents in University from
Ministry of Education of China (NCETꢀ11ꢀ0974) and the
Scientific Research Foundation for Returned Scholars, Ministry
of Education of China (2011ꢀ1568)
Me
standard
conditions
O
N
+
(1)
N
Notes and references
81% yield
4a
55
1
(a) J. P. Michael, Nat. Prod. Rep., 2008, 25, 166; (b) J. P. Michael,
Nat. Prod. Rep., 2007, 24, 223.
standard
conditions
O
2
K. Grossmann, Pest Manag. Sci., 2010, 66, 113.
+
4a
(2)
NH2
trace
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