Synthesis of substituted quinoline via copper-catalyzed one-pot cascade reactions of 2-bromobenzaldehydes with aryl methyl ketones and aqueous ammonia

Article abstract of DOI:10.1016/j.tetlet.2014.09.024

In this Letter, a new version of the Friedl?nder synthesis of quinoline derivatives starting from 2-bromobenzaldehydes, aryl methyl ketones, and aqueous ammonia with copper-catalyzed amination as a key step is presented. Remarkable advantages of this new quinoline synthesis include commercially available and economical starting materials, simple operational process, and excellent efficiency.

Full text of DOI:10.1016/j.tetlet.2014.09.024

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted quinoline via copper-catalyzed one-pot
cascade reactions of 2-bromobenzaldehydes with aryl methyl
ketones and aqueous ammonia
⇑
Bin Li, Chenhao Guo, Xuesen Fan , Ju Zhang, Xinying Zhang
School of Environment, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan
Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan 453007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, a new version of the Friedländer synthesis of quinoline derivatives starting from 2-bromo-
benzaldehydes, aryl methyl ketones, and aqueous ammonia with copper-catalyzed amination as a key
step is presented. Remarkable advantages of this new quinoline synthesis include commercially available
and economical starting materials, simple operational process, and excellent efficiency.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 22 June 2014
Revised 27 August 2014
Accepted 6 September 2014
Available online xxxx
Keywords:
Quinoline
Copper catalysis
Cascade reaction
Quinoline and its derivatives have attracted tremendous
attention due to their frequent occurrence in natural products
and synthetic compounds possessing remarkable biological and
In the mean time, copper-catalyzed Ullmann-type reactions are
emerging as a highly useful approach for the formation of C–N
bond due to their high efficiency and economical sustainability.12
In recent years, along with the discovery of more efficient cop-
per/ligand catalytic systems that could be operated under mild
conditions, copper-catalyzed cross coupling reactions have been
extensively utilized in the construction of N-fused heterocycles.13
In this regard, we have revealed a one-pot cascade reaction leading
1
–5
chemical properties.
Because of their importance, several proto-
6
cols for their preparation, such as Friedländer synthesis, Combes
synthesis, Skraup synthesis,8 and Gould–Jacobs synthesis, have
7
9
been well established. More recently, a number of new methods
for the synthesis of quinolines starting from various kinds of sub-
strates have also been developed.1
0,11
Among the above mentioned
to pyrazolo[1,5-c]quinazolines and a one-pot three-component
14
1
5
strategies, Friedländer annulation, involving a condensation of 2-
aminobenzaldehyde/ketone with carbonyl compound bearing an
preparation of quinolizines, both with copper-catalyzed amina-
tion of aryl halides as an initiating step by using aqueous ammonia
as a cheap and convenient nitrogen source. The high efficiency and
easy to handle manner of this synthetic strategy encouraged us to
propose a new synthetic pathway toward substituted quinolines
by using 2-bromobenzaldehydes, acetophenones, and aqueous
ammonia as the starting materials (Scheme 1).
a-methylene functionality followed by an intramolecular cycliza-
tion of the in situ formed 2-amino chalcone intermediate, has been
frequently used due to its simple and straightforward nature. Not-
withstanding its success, this strategy still suffers from pitfalls
such as harsh reaction conditions and limited availability of sub-
strates. The required 2-aminobenzaldehyes are in most cases not
commercially available or quite expensive. Therefore, they have
to be prepared through the reduction of the corresponding o-nitro-
benzaldehyes or ketones. Thus, the development of an alternative
version of the classical Friedländer synthesis by using readily avail-
able starting materials and carried out under mild conditions is
still highly desired.
To study the feasibility of our proposed synthesis of quinoline,
the reaction of 2-bromobenzaldehyde (1a) with acetophenone
(2a) and aqueous ammonia (3) was initially studied. To our delight,
2 3
in the presence of 10 mol % CuI and 2 equiv of K CO in DMF, 1a
reacted with 2a and 3 affording 2-phenylquinoline (4a) in a yield
of 68% (Table 1, entry 1). Further effort was then made to optimize
the reaction conditions. Firstly, the effect of different solvents
including DMF, DMSO, 1-methyl-2-pyrrolidinone (NMP), and iso-
propanol was studied (entries 1–4). Among them, DMF gave the
best yield of 4a. Furthermore, experiments with different copper
⇑
Corresponding author. Tel.: +86 373 3329261; fax: +86 373 3329275.
E-mail address: xuesen.fan@htu.cn (X. Fan).
2 2
catalysts showed that CuI, Cu(OAc) , CuCl, and CuCl were inferior
http://dx.doi.org/10.1016/j.tetlet.2014.09.024
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0
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2
B. Li et al. / Tetrahedron Letters xxx (2014) xxx–xxx
CHO
O
good efficiency (entry 10). Notably, when acetone (2k) was tried
for this transformation, a complicated and unidentified mixture
was obtained (Table 2, entry 11).
NH
.H
O
copper catalysis
+
+
3
2
H C
Ph
3
Br
N
Ph
As a further aspect, the reaction of various 2-bromobenzalde-
hyde derivatives (1) with acetophenone (2a) was studied. The
results listed in Table 3 show that 2-bromobenzaldehydes bearing
diverse functional groups such as methyl, methoxy, chloro, fluoro,
and trifluoromethyl could take part in this three- component reac-
tion (Table 3). More importantly, both electron-rich and electron-
deficient substrates gave the products in almost equally excellent
yields.
Scheme 1. Proposed synthesis of substituted quinoline by using ammonia as the
nitrogen source.
to CuBr in promoting this tandem reaction (entries 1, 5–8). Studies
2 3
on the effect of different bases showed that Cs CO is superior to
K
2
CO , Na CO , KOAc, and K PO (entries 5, 9–12). Without a base,
3
2
3
3
4
the yield decreased (entry 13). Next, the reaction was tried with
some ligands including dimethylethylenediamine (DMEDA),
tetramethylethylene diamine (TMEDA), 1,10-phenanthroline
Based on the results described above, plausible pathways for
the formation of 4a were proposed in Scheme 2. Initially, an aldol
condensation between 1a and 2a occurs to give 3-(2-bromophe-
nyl)-1-phenylprop-2-en-1-one (A). Then, A condenses with ammo-
nia to give an imine intermediate (B). Under the reaction
conditions employed, B should be in equilibrium with its Z-isomer
hydrate (1,10-phen),
L-proline, and 4-dimethylaminopyridine
(
DMAP) (entries 14–18). It turned out that the addition of 1,10-
phen could improve the yield of 4a to 87% (entry 16). Tempera-
tures higher or lower than 80 °C had adverse effect (entries 19
and 20). It was also noted that when aqueous ammonia was
replaced by ammonium acetate, the yield of 4a decreased dramat-
ically (entry 21). Without a copper catalyst, the formation of 4a
was not observed (entry 22). In summary, treatment of 1a, 2a,
0
0
0
(B ) albeit the formation of B is less favorable. Once B is formed, an
intramolecular N-arylation under the catalysis of CuBr and promo-
2 3
tion of Cs CO takes place to give 4a as a final product. Along with
0
0
the consumption of B , B is continuously transformed into B to
eventually complete the process. Alternatively, A may be firstly
and 3 with 10 mol % of CuBr, 2 equiv of Cs
,10-phen in DMF at 80 °C for 20 h could afford 4a in a yield of 87%.
With the optimized conditions (Table 1, entry 16), the scope
2 3
CO , and 20 mol % of
0
1
aminated to give intermediate C. Isomerization of C affords C ,
which then undergoes an intramolecular condensation to give
6
d
and generality of this new reaction was studied. Firstly, 2-bromo-
4a.
benzaldehyde (1a) was reacted with various aryl methyl ketones
The proposed mechanisms shown in Scheme 2 were partly sup-
2
(2). The results listed in Table 2 show that the R unit in 2 can be
ported by the following control experiments. Firstly, the reaction of
1a, 2a, and 3 under standard conditions was let to run for 1 h and
workup of the resulting mixture gave A as a major product. Next, A
was re-subjected to the conditions (Table 1, entry 16) and it was
cleanly transformed into 4a (Scheme 3).
In conclusion, an efficient and straightforward synthesis of
substituted quinolines via copper-catalyzed one-pot cascade
reactions of 2-bromobenzaldehydes with aryl methyl ketones
and aqueous ammonia has been developed. This new version of
with either an electron-donating (entries 2–3) or an electron-
withdrawing nature (4–8), and can be at the ortho, para, or meta
position. A variety of functional groups, such as methyl, methoxy,
chloro, fluoro, trifluoromethyl, and nitro group were well tolerated
and installed. Moreover, 1-(naphthalene-1-yl)ethanone could
afford 2-(naphthalene-1-yl)quinoline (4i) in high yield (entry 9).
In addition, 1-(pyridin-2-yl)ethanone was found to be also a
suitable substrate affording 2-(pyridine-2-yl)quinoline (4j) with
Table 1
Optimization studies on the formation of 4aa
O
CHO
various conditions
N
NH .
H O
+
3 2
+
H C
3
Br
1a
2a
3
4a
Entry
Solvent
Catalyst
Base
Additive
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
DMF
DMSO
NMP
i-PrOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu(OAc)
K
K
K
K
K
K
K
K
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
—
—
—
—
—
—
—
—
—
—
—
—
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
68
66
50
35
75
48
56
53
50
80
45
42
33
80
72
87
80
2
CuCl
2
3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
Na
Cs
KOAc
PO
2
CO
3
1
1
1
1
1
1
1
1
2
CO
3
K
3
4
—
—
Cs
Cs
Cs
Cs
2
CO
2
CO
2
CO
2
CO
3
3
3
3
DMEDA
TMEDA
1,10-Phen
L-Proline
1
1
2
8
9
DMF
DMF
DMF
DMF
DMF
CuBr
CuBr
CuBr
CuBr
—
2
Cs CO
2
Cs CO
2
Cs CO
2
Cs CO
2
Cs CO
3
3
3
3
3
DMAP
80
60
100
80
83
64
80
52
0
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
0
c
2
1
2
2
80
a
b
c
1
a (0.5 mmol), 2a (0.6 mmol), 3 (26%, 0.5 mL), copper salt (0.05 mmol), base (1 mmol), additive (0.1 mmol), solvent (3 mL), air, sealed tube, 20 h.
Isolated yield.
NH OAc (1.5 mmol) was used instead of NH
4
3 2
ꢀH O.
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B. Li et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2
Reaction of 1a with various aryl methyl ketones (2) and 3a
O
CHO
CuBr, Cs
2
CO
3
, 1,10-Phen
+ NH .
H O
3 2
+
H C
3
R2
DMF, 80 o
C
N
R2
Br
1a
2
3
4
Entry
1
2
4
Yieldb (%)
O
N
87
91
2
a
4
a
O
N
N
2
CH3
CH3
4
b
2
b
O
O
O
3
4
93
83
OCH
3
OCH
3
2
c
4c
N
F
F
4
d
2
d
N
N
5
80
CF3
CF3
2
e
4e
O
6
7
8
76
84
81
NO2
NO2
Cl
2
f
4f
O
O
O
Cl
N
N
2
g
Cl
4g
Cl
4
h
2
h
N
9
90
82
4
i
2
i
O
O
N
1
0
1
N
N
2
j
4
j
1
—
—
2
k
a
Reactions were run with 1a (0.5 mmol), 2 (0.6 mmol), 3 (26%, 0.5 mL), CuBr (0.05 mmol), Cs
2
CO
3
(1 mmol), and
1
,10-phen (0.1 mmol) in DMF (3 mL) at 80 °C under air in a sealed tube for 20 h.
Isolated yield.
b
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4
B. Li et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 3
a
Reaction of 2a with various 2-bromobenzaldehydes (1) and 3
O
CHO
, 1,10-Phen R1
3
CuBr, Cs
2
CO
R1
+ H C
+ NH .
H O
3 2
3
o
N
DMF, 80 C
Br
1
2a
3
4
Entry
1
1
4
Yieldb (%)
92
CHO
Br
H C
N
H C
3
3
1
b
4
k
H
3
CO
CHO
3
H CO
2
3
4
Br
N
91
87
87
82
77
1
c
4
l
CHO
Br
O
O
O
O
N
1
d
4
m
Cl
CHO
Br
Cl
N
1
e
4
n
F
CHO
Br
F
F
5
6
7
N
1
f
4
o
F3C
CHO
Br
3
C
N
1
g
4
p
CHO
Br
F
N
84
F
1
h
4
q
a
Reactions were run with 1 (0.5 mmol), 2a (0.6 mmol), 3 (26%, 0.5 mL), CuBr (0.05 mmol), Cs
2
CO
3
(1 mmol), and
1
,10-phen (0.1 mmol) in DMF (3 mL) at 80 °C under air in a sealed tube for 20 h.
Isolated yield.
b
O
NH
Ph
CHO
Br
Aldol
O
reaction
Ph
NH3
+
Ph
Br
Br
Br
1a
2a
O
3
A
B
s
2C
C
,
L
r/
B
u
3
C
H
N
O
Ph
NH
Ph
Ph
CuBr/L
O
N
2 3
Ph Cs CO
NH
2
NH2
C
C'
4a
B'
Scheme 2. Plausible mechanism for the formation of 4a.
O
CuBr, Cs CO3
CuBr, Cs CO3
2
2
CHO
O
NH
3
, 1,10-Phen
3
Ph NH , 1,10-Phen
+
Ph
DMSO, air
8
DMSO, air
Br
Br
N
Ph
o
o
0
C, 1 h
80 C, 20 h
1a
2a
A, major product
4a, 92%
Scheme 3. Formation of 3-(2-bromophenyl)-1-phenylprop-2-en-1-one (A) and its transformation into 4a.
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B. Li et al. / Tetrahedron Letters xxx (2014) xxx–xxx
5
the classical Friedländer synthesis showed advantages such as
commercially available starting materials, simple synthetic proce-
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it is expected to be used as an alternative approach toward substi-
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