ZnCl2-promoted Friedl?nder-type synthesis of 4-substituted 3-aroyl quinolines from o-aminoaryl ketones and enaminones

Article abstract of DOI:10.1016/j.tetlet.2016.09.087

A practical synthesis of 4-substituted 3-aroyl quinolines via Friedl?nder-type reaction from readily available o-aminoaryl ketones and enaminones was developed. In the presence of ZnCl₂, the reaction proceeded smoothly affording the desired products with various functional groups in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2016.09.087

Accepted Manuscript
ZnCl2-promoted Friedländer-type synthesis of 4-substituted 3-aroyl quinolines
from o-aminoaryl ketones and enaminones
Laichun Luo, Zongbao Zhou, Jiayi Zhu, Xue Lu, Hong Wang
PII:
S0040-4039(16)31270-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.087
TETL 48157
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 August 2016
25 September 2016
27 September 2016
Please cite this article as: Luo, L., Zhou, Z., Zhu, J., Lu, X., Wang, H., ZnCl2-promoted Friedländer-type synthesis
of 4-substituted 3-aroyl quinolines from o-aminoaryl ketones and enaminones, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.09.087
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ZnCl2-promoted Friedländer-type synthesis
of 4-substituted 3-aroyl quinolines from o-
aminoaryl ketones and enaminones
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Laichun Luo∗, Zongbao Zhou, Jiayi Zhu, Xue Lu, Hong Wang

1
Tetrahedron Letters
journal homepage: www.elsevier.com
ZnCl2-promoted Friedländer-type synthesis of 4-substituted 3-aroyl quinolines from
o-aminoaryl ketones and enaminones
Laichun Luo∗, Zongbao Zhou, Jiayi Zhu, Xue Lu, Hong Wang
College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A practical synthesis of 4-substituted 3-aroyl quinolines via Friedländer-type reaction from
readily available o-aminoaryl ketones and enaminones was developed. In the presence of ZnCl2,
the reaction proceeded smoothly affording the desired products with various functional groups
in moderated to good yields.
Received in revised form
Accepted
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Quinoline
o-Aminoaryl ketone
Enaminone
ZnCl2
Friedländer reaction
1. Introduction
required to prepare substrates 6 from corresponding o-aminoaryl
ketones 1 beforehand. Besides, compound 5 was also synthesized
from substituted quinolines through 1,4-addition/oxidation,32
Quinoline scaffold is prevalent in various natural and
synthetic products, including several important clinically used
drugs and pharmaceutical candidates.1–6 Due to their important
applications, a variety of synthetic methods have been developed
to construct quinolines over the past decades. 6–12 Among them,
the classic Friedländer synthesis represents one of the most
widely used methods, which involves the reaction of o-aminoaryl
aldehyde/ketone 1 with a carbonyl compound 2 containing a
reactive α-methylene group (Scheme 1a).12 Recently, modified
Friedländer reactions and related cascade reactions of 1 with
various other substrates, such as alkynes,13–16 alkenes,17 alkenyl
iodides,18 alcohols,19 α-enolic dithioesters,20 α-oxoketene dithio-
acetals,21 and 3-amino acrylontrile,22 were intensively explored,
which provided efficient approaches to qulinolines with
structural diversity.
Palladium-catalyzed
1,2-addition/oxidation,33
or
Suzuki
coupling.34 Despite the presence of these established methods,
practical, direct and more efficient synthetic route to 4-
substituted 3-aroyl quinolines from simple and readily available
starting material is still in demand.
R2
O
O
R3
acid or base
R2
R3
R1
R1
R1
R1
R1
+
(a)
R4
Ar
Ar
Friedländer reaction
N
R4
O
NH2
O
2
1
3
R2
O
FeCl3. 6H2O
R2
Ar
Ar
Ar
R1
+
+
+
(b)
(c)
(d)
1,4-dioxane, 80 or 100 o
C
NH2
O
N
1
4
5
R2
O
O
O
R2
NHTs
1) PPh3, CH3CN, rt
2) 1N HCl
R1
However, to the best of our knowledge, there is no report on
the direct reaction of o-aminoaryl ketones 1 with enaminone 7,23
a versatile and readily obtainable reagent for heterocyclic
synthesis.23–30 We envisioned that a Friedländer-type reaction
would occur, affording 4-substituted 3-aroyl quinoline 5.
Although compound 5 was successfully achieved via an iron-
catalyzed cascade Michael addition–cyclization of 1 (R2 = CH3,
Ph) with ynone 4 by Li et al. previously (Scheme 1b),16 this
protocol had some drawbacks, such as the requirement of 2 equiv
of substrates 1, long reaction times, and moderate yields. In 2012,
Khong and Kwon reported a mild one-pot PPh3-catalyzed
synthesis of quinolines from o-tosylamidophenones 6 (R2 = CH3,
N
4
5
6
O
R2
O
R2
ZnCl2
R1
Ar
N
1,4-dioxane, reflux
NH2
R2 = aryl, alkyl
N
This work
1
7
5
Scheme 1. Synthesis of substituted quinolines.
As part of our continuing interest in the synthesis of fused-
pyridines,35 herein we reported a ZnCl2 promoted Friedländer-
type synthesis of 4-substituted 3-aroyl quinolines 5 from o-
aminoaryl ketones 1 (R2= aryl, alkyl) and enaminons 7 (Scheme
1d).
Ph) and substrates 4 (Scheme 1c).31 However, tosylation was
———
∗ Corresponding author. Tel.: +86-027-68890101; fax: +86-027-68890113; e-mail: laichunluo@163.com

2
Tetrahedron
2. Results and discussion
group appeared less reactive, but still afforded product 5m in
42% yield after prolonged reaction time (Table 2, entry 13).
Besides, 2- aminophenones bearing methyl (1h), sterically bulky
isopropyl (1i) or cyclohexyl (1j) groups were successfully
converted to 4-alkyl quinolines 5q-s in 66–73% yields under the
optimized conditions (Table 2, entries 17–19).
Initially, we chose 2-aminobenzophenone 1a and enaminone
7a as the model substrates to optimize the reaction conditions
(Table 1). Attempts with common acidic (1.0 equiv of
concentrated sulfuric acid in ethanol) or basic conditions (1.0
equiv of KOH in ethanol) under reflux failed to yield the
quinoline product 5a (Table 1, entries 1 and 2). Then ZnCl2 was
employed as an additive enlightened by our previous study.35,36 In
the presence of 1.0 equiv of ZnCl2, the reaction of 1a with 7a in
ethanol under reflux for 4 h gave the desired product 5a in 24%
yield (Table 1, entry 3). A solvent screen revealed that 1,4-
dioxane was the optimal solvent (Table 1, entries 3–8), affording
5a in 43% yield (Table 1, entry 8). Other Lewis acids, such as
FeCl3.6H2O, CuCl, ZnSO4, and Zn(OAc)2, proved less effective
(Table 1, entries 9–12). However, Zn(OTf)2 was found more
effective than ZnCl2. In the presence of 1.0 equiv of Zn(OTf)2,
the reaction gave product 5a in 78% yield (Table 1, entry 13).
Unfortunately, the reaction did not work well with 0.5 equiv of
Zn(OTf)2 (Table 1, entry 14). Beacuse ZnCl2 was more readily
available and economically attractive, and it had a much lower
molecular weight, it was still chose as optimal additive for this
reaction instead of Zn(OTf)2. When the amount of ZnCl2 was
increased, the yield was enhanced remarkably and the reaction
time was also reduced (Table 1, entries 8, 15 and 16). And the
best result was achieved in 81% yield with 3.0 equiv of ZnCl2
(Table 1, entry 16).
Table 1.
Optimization of reaction conditionsa
Entry
1
Additive (equiv)
H2SO4 (1.0)
KOH (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
Solvent
Time (h)
Yieldb (%)
C2H5OH
4
4
4
4
4
4
4
4
4
4
4
4
4
4
3
2
trace
0
2
C2H5OH
3
C2H5OH
24
0c
4
DMF
5
DMSO
0c
6
CH3CN
32
27
43
25
18
trace
0
7
THF
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
.
FeCl3 6H2O (1.0)
9
With the optimal condition in hand, the reaction scope was
subsequently explored (Table 2). A variety of enaminones 7b–h
bearing both electron-donating and electron-withdrawing groups
reacted with 1a smoothly, affording products 5b–k in 62–87%
yields (Table 2, entries 2–8). Enaminone with a naphthalen-1-yl
(7i), naphthalen-2-yl (7j) or thiophen-2-yl (7k) substituent also
furnished the corresponding products in moderate yields (Table
2, entries 9–11), although a longer reaction time was required for
7i presumably due to the steric hindrance (Table 2, entries 9).
Then the substrate scope of o-aminoaryl ketones 1 was examined.
A series of substituted 2-aminobenzophenones 1b–f were
subjected to the reaction, and the corresponding products 5l–p
were obtained in 42–81% yields (Table 2, entries 12–16). Among
them, substrate 1c containing a strong electron-withdrawing nitro
10
11
12
13
14
15
16
CuCl (1.0)
ZnSO4 (1.0)
Zn(OAc)2 (1.0)
Zn(OTf)2 (1.0)
Zn(OTf)2 (0.5)
ZnCl2 (2.0)
78
35
73
81
ZnCl2 (3.0)
a Reaction conditions: 1a (5.0 mmol), 7a (5.0 mmol), and an additive in
refluxing solvent (5.0 mL).
b Isolated yields.
c Reaction occurred at 110 oC.
Table 2.
Synthesis of 4-substituted 3-aroyl quinolines 5 from o-aminoaryl ketones 1 and enaminones 7a
O
R2
O
O
R2
NH2
ZnCl2
Ar
R1
R1
+
(d)
Ar
N
1,4-dioxane, reflux
N
5
7
1
Entry
Substrate 1
R = H, R = Ph
Substrate 2
Time (h)
Product
5a
Yieldb (%)
1
Ar = Ph
2
2
2
2
2
2
2
2
5
3
2
81
75
72
65
87
82
62
75
60
67
75
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
7a
7b
7c
7d
7e
7f
1
2
2
Ar = 4-F-Ph
Ar = 4-Cl-Ph
Ar = 4-Br-Ph
Ar = 4-Me-Ph
Ar = 4-MeO-Ph
5b
5c
3
4
5d
5e
5
6
5f
7
Ar = 4-NO -Ph
2
7g
7h
7i
5g
8
Ar = 3-Cl-Ph
5h
5i
9
Ar = naphthalen-1-yl
Ar = naphthalen-2-yl
Ar = thiophen-2-yl
10
11
7j
5j
7k
5k

3
12
13
14
15
16
17
18
19
R = 5-Cl, R = Ph
1
3
5
2
2
2
3
3
3
63
42
75
81
80
66
73
71
1b
1c
1d
1e
1f
7a
7a
7a
7a
7a
7a
7a
7a
5l
2
R = 5-NO , R = Ph
2
5m
5n
5o
5p
5q
5r
5s
1
2
R = H, R = 4-F-Ph
1
2
R = H, R = 4-Me-Ph
1
2
R = H, R = 4-MeO-Ph
1
2
R = H, R = Me
1
1g
1h
1i
2
R = H, R = CH(CH )
3 2
1
2
R = H, R = Cyclohexyl
1
2
a Reaction conditions: 1 (5.0 mmol), 7 (5.0 mmol), and ZnCl2 (15 mmol) in 1,4-dioxane (5.0 mL), reflux.
b Isolated yields.
Furthermore, the substrate scope was extended to enaminone
analogues 8 bearing a chloro or ethoxy group.37,38 In the presence
of 1.0 equiv of ZnCl2, the reaction of 1a with 8a or 8b gave the
expected product 5a in 75% and 82%, respectively (Scheme 2).
By contrast, more amount of ZnCl2 was required for enaminone
substrate 7a to achieve a good yield of 5a (Table 1, entries 15
and 16), which was probably due to the affinity of dimethylamine
byproduct for ZnCl2.39
This work was supported by Doctoral Starting up Foundation
of Hubei University of Chinese Medicine and Qingmiao Plan
Project of Hubei University of Chinese Medicine.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/
O
Ph
O
O
ZnCl2 (1 equiv)
References and notes
Ph
NH2
1a
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Ph
X
1,4-dioxane, reflux, 4 h
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According to the results and previous literatures, a plausible
Friedländer-type mechanism for the reaction was proposed
(Scheme 3). Initially, condensation of o-aminoaryl ketone 1 with
enaminone 7 afforded the enamine intermediate 9 via a Michael
addition/elimination process,24,25 in which ZnCl2 could serve a
catalyst40,41 and a Lewis acid to bind the dimethylamine
byproduct. Subsequently, enamine
catalyzed intramolecular aldol reaction to give intermediate 10.
9 underwent a ZnCl2-
21,35
Finally, the quinoline product 7 was formed by elimination
of a water molecule. Secondary amine, quinoline and water could
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fact that an excess amount of ZnCl2 was beneficial for this
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O
O
R2
ZnCl2
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N
R1
NH2
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N
H
Ar
1
7
9
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N
O
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R2
HO
Ar
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Scheme 3. Plausible reaction mechanism.
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In summary, we have developed
a ZnCl2 promoted
Friedländer-type reaction of o-aminoaryl ketones with
enaminones. This cascade protocol provides an efficient and
straightforward access to 4-substituted 3-aroyl quinolines in
moderate to good yields from easily available starting materials,
which may find practical applications in the synthesis and
discovery of bioactive quinoline derivatives.
Acknowledgments
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4
Tetrahedron
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5
Highlights
1. Friedländer-type reaction of o-aminoaryl ketones with
enaminones.
2. An efficient and straightforward approach to 4-substituted
3-aroyl quinolines.
3. Using ZnCl2 as a cheap and effective additive.
4. Readily available starting materials, and short reaction
times.