Synthesis of 2-trifluoromethyl quinoline by the reaction of fluorinated imine with alkyne catalyzed by indium(III) triflate

Article abstract of DOI:10.1055/s-0030-1258770

Preparation of 2-trifluoromethyl-4-aryl quinolines from a variety of readily available alkynes and N-aryl trifluoroethylimine has been achieved via indium(III) triflate catalyzed Diels-Alder reactions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258770

LETTER
2659
Synthesis of 2-Trifluoromethyl Quinoline by the Reaction of Fluorinated
Imine with Alkyne Catalyzed by Indium(III) Triflate
S
ynthesis of 2-Trif
a
luoromethy
i
l
Q
uin
b
oline o Xie,a Jiangtao Zhu,a Zixian Chen,a,b Shan Li,a Yongming Wu*a
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 LingLing Road, Shanghai 200032, P. R. of China
Fax +86(21)54925192; E-mail: ymwu@sioc.ac.cn
Department of Chemistry, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P. R. of China
b
Received 13 July 2010
trifluoromethyl quinoline was the Combes’ method.8 Till
recently, several methods have been developed.9 In 2001,
Uneyama et al. reported a one-pot synthesis of highly sub-
stituted fluorinated quinolines by Rh(I)-catalyzed cycliza-
tion of N-aryl trifluoroacetimidoyl chlorides with
alkynes.10 In 2009, Likhar et al. reported a method for the
synthesis of highly substituted 2-perfluoroalkyl quino-
lines by electrophilic iodocyclization of perfluoroalkyl
propargyl imines or amines.11 Recently, our group devel-
oped a process for synthesis of multisubstituted 2-trifluo-
romethyl quinolines via palladium-catalyzed domino
Sonogashira–alkyne carbocyclization of b-trifluorometh-
ly b-enamino ketones with alkyne.12 The drawbacks of
many of these methods are either the limited availability
of starting materials or poor substrate scope. Consequent-
ly, the development of an efficient and facile synthesis of
2-perfluoroalkyl-substituted quinolines using mild reac-
tion conditions remains an active research area. Herein we
wish to report a versatile method for synthesis of multi-
substituted 2-trifluoromethyl quinolines by the reaction of
fluorinated imine with alkyne under catalysis of indi-
um(III) triflate.
Abstract: Preparation of 2-trifluoromethyl-4-aryl quinolines from
a variety of readily available alkynes and N-aryl trifluoroethylimine
has been achieved via indium(III) triflate catalyzed Diels–Alder re-
actions.
Key words: alkynes, quinolines, indium, Diels–Alder reaction,
imines
The performance of organofluorine compounds in all as-
pects of chemicals industry, such as materials, pharma-
ceuticals, agrochemicals, and fine chemicals, is
phenomenal. Organofluorine compounds are rare in natu-
ral products, but 20–25% of drugs in the pharmaceutical
pipeline contain at least one fluorine atom. As the incor-
poration of fluorine and/or fluorine-containing groups
into an organic molecule often drastically alters the chem-
ical, physical, and biological properties of the parent com-
pound, it is only logical to conclude that such
modifications necessitate the invention of novel reagents
and materials endowed with fluorine imparting properties.
For example, 2-trifluoromethyl quinolines are of signifi-
cant pharmacological interest for their use as potent anti-
malarial agents (mefloquine, 1),1 PDE4 inhibitors 2,2
antituberculosis agents 3 (Figure 1),3 DPP-IV inhibitors,4
and leishmanicidal agents.5
Initially, we chose phenylacetylene 5a and N-aryl trifluo-
roethylimine 4a which was obtained by the condensation
of the commercial trifluoroacetaldehyde ethyl hemiacetal
with arylamine, as the model substrates to optimize the re-
action conditions at 60 °C in toluene. As shown in
Table 1, when CuOTf was used as the catalyst, 27% of de-
sired 2-trifluoromethyl quinoline 6a was obtained after
column chromatography (Table 1, entry 1). Switching to
Cu(OTf)2 as the catalyst, the yield of 6a was raised to 35%
(Table 1, entry 2). Under this condition, N-p-methox-
yphenyl trifluoroethylamine was also formed. It was rea-
soned that 5a reacted with 4a to form dihydroquinoline
firstly, which was then oxidized to 6a. At the same time
some 4a was reduced to N-p-methoxyphenyl trifluoroeth-
ylamine. So we supposed that the yield of this reaction
may be improved by adding an oxidant to the reaction sys-
tem. As expected, the yield of 6a was increased to 64%,
when two equivalents of 2,3-dichloro-5,6-dicyanoquino-
ne (DDQ) was added. Subsequently, other catalysts were
further scanned. It was found that when CuI or La(OTf)3
was used as catalyst, product 6a was formed in trace
amount (Table 1, entries 5, 6). However, when In(OTf)3
was used as the catalyst, the yield of 6a was improved to
88% (Table 1, entry 7), the yield of 6a was further raised
Since Skraup reported the synthesis of quinoline in 1880
for the first time,6 there have been great achievements in
this area.7 However, the usual method for synthesis of 2-
O
O
O
O
N
H2N
N
O
NEt
O
N
HO
N
H
O
H
N
CF3
N
CF3
CF3
N
CF3
OMe
CF3
1
2
3
Figure 1 Representative of 2-trifluoromethyl quinoline in medi-
cinal chemistry
SYNLETT 2010, No. 17, pp 2659–2663
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258770; Art ID: W11010ST
© Georg Thieme Verlag Stuttgart · New York

2660
H. Xie et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
Ph
N
catalyst
OMe
MeO
oxidant
+
Ph
toluene, 60 °C
N
CF3
5a
6a
F3C
4a
Entry
Catalyst
CuOTf
Oxidants
–
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Yield (%)b
1
2
3
4
5
6
7
8
27
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
–
35
DDQ
BQ
64
64
DDQ
DDQ
DDQ
BQ
trace
trace
88
La(OTf)3
In(OTf)3
In(OTf)3
92
a Unless otherwise specified, reactions were performed on a 1.0 mmol scale of N-aryl trifluoroethylimine, alkyne (2.0 mmol), toluene (5 mL).
b Isolated yield calculated on the basis of N-aryl trifluoroethylimine.
to 92%, when two equivalents of para-benzoquinone Friedel–Crafts-type addition affording dihydroquinoline,
(BQ) was used as oxidant (Table 1, entry 8). Then the op- which was then oxidized to the desired products by BQ.
timization conditions were ascertained as In(OTf)3 (10 To confirm this proposed mechanism (Scheme 1), the in-
mol%), BQ (2 equiv) in toluene at 60 °C.
termediate propargylic amine
7 was synthesized
(Scheme 2). But the experiment revealed that propargylic
amine 7 did not react under the same reaction conditions.
This result provided a concrete evidence to exclude this
mechanism.
Having established suitable reaction conditions, the scope
and generality of this methodology were explored. As
shown in Table 2, most substrates examined provided
moderate to excellent yields under the standard reaction
conditions. In an effort to understand the scope of the re-
action, the effect of various substituents on the benzene
ring of the imine was scrutinized. Generally, electron-do-
nating substitutent on the benzene ring of the imine, such
as methoxy (Table 2, entry 1) and methyl (Table 2, entry
3) proceeded well. On the other hand, electron-withdraw-
ing substituted on the benzene ring of the imine, including
chloro (Table 2, entry 4), fluoro (Table 2, entry 5), and tri-
fluoromethyl (Table 2, entry 5) would reduce the yield.
Next, the effect of various substituents on the aryl ring of
the alkynes was examined.
OMe
OMe
OMe
OMe
N
HN
HN
F3C
F3C
F3C
C
Ph
In3+
In3+
Ph
Ph
7
OMe
BQ
N
HN
F3C
Ph
F3C
Ph
The substituents on the aryl ring of the alkynes such as
methoxy (Table 2, entries 7, 11), methyl (Table 2, entry
8), and chloro (Table 2, entries 9, 12) also proceeded well,
while 4-fluorophenylacetylene provided lower yield
(Table 2, entry 10). Notably, it was interesting to note that
2-naphthylacetylene (Table 2, entry 13) or 2-thienylacet-
ylene (Table 2, entry 14) could also afford 6 in excellent
yield.
Scheme 1 Possible stepwise mechanism
OMe
OMe
n-BuLi
+
Ph
HN
N
THF, –78 °C
F3C
F3C
Ph
OMe
7
In(OTf)3 (10 mol%)
BQ (2 equiv)
There are two possible reaction routes for this reaction.
The first one was a stepwise mechanism (Scheme 1). In
this case, propargylic amine 7 which was produced via an
intermediate that was formed by successive complexation
of substrates to the metal center was formed firstly.7g,h,13
Subsequent cyclization step may occur directly through a
HN
no reaction
toluene, 60 °C, 3 h
F3C
Ph
Scheme 2 The synthesis of intermediate propargylic amines 7 and
its reaction
Synlett 2010, No. 17, 2659–2663 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Trifluoromethyl Quinoline
2661
Table 2 In(OTf)3-Catalyzed Synthesis of 2-Trifluoromethyl Quino-
Table 2 In(OTf)3-Catalyzed Synthesis of 2-Trifluoromethyl Quino-
linesa
linesa (continued)
Ar
Ar
In(OTf)3 (10 mol%)
In(OTf)3 (10 mol%)
R
R
R
R
BQ (2 equiv)
BQ (2 equiv)
Ar
+
Ar
+
toluene, 60 °C, 3 h
toluene, 60 °C, 3 h
N
Rf
N
N
N
Rf
5
6a–n
5
6a–n
Rf
4
Rf
4
Entry
1
Product
Yield (%)b
Entry
Product
Yield (%)b
Me
6a
6b
6c
6d
6e
6f
92
MeO
8
6h
93
MeO
N
CF3
N
CF3
CF3
CF3
Cl
2
3
4
5
6
94
91
85
75
66
MeO
Me
Cl
9
6i
82
60
N
CF2Br
MeO
N
F
N
CF3
10
6j
MeO
N
MeO
N
CF3
11
12
6k
6l
92
91
MeO
N
CF3
Cl
F
N
CF3
MeO
N
CF3
F3C
N
CF3
OMe
13
14
6m
6n
90
90
MeO
MeO
7
6g
93
MeO
N
N
CF3
N
CF3
S
CF3
Synlett 2010, No. 17, 2659–2663 © Thieme Stuttgart · New York

2662
H. Xie et al.
LETTER
Table 2 In(OTf)3-Catalyzed Synthesis of 2-Trifluoromethyl Quino-
OMe
linesa (continued)
Ph
D
In(OTf)3 (10 mol%) MeO
BQ (2.0 equiv)
N
Ar
+
In(OTf)3 (10 mol%)
D
Ph
R
R
toluene, 60 °C
BQ (2 equiv)
F3C
N
CF3
Ar
+
6o
toluene, 60 °C, 3 h
N
Rf
N
5
6a–n
OMe
OMe
OMe
BQ
Rf
4
6o
N
N
HN
Entry
15
Product
Yield (%)b
H
Ph
In3+
F3C
F3C
Ph
F3C
Ph
D
D
D
Scheme 3 Deuterium-labeled reaction
6o
91
MeO
D
N
CF3
References
a Reaction conditions: N-aryl trifluoroethylimine (1.0 mmol), alkyne
(2.0 mmol), In(OTf)3 (0.1 mmol), BQ (2.0 mmol), toluene (5mL), 60
°C.
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the catalyst of In(OTf)3, which was then oxidized to the
desired product by BQ. To gain further evidence for this
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corresponding product’s NMR spectrum showed that
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(Scheme 3). This kind of reaction belongs to the IEDDA
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an organic reaction described as a formal cycloaddition
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In summary, a facile and efficient method for synthesis 2-
trifluoromethyl-4-aryl quinolines from a variety of readily
available alkynes and N-aryl trifluoroethylimine was de-
veloped. The reaction proceeded under mild conditions
and gave the desired quinoline products in high yields.
Through intermediate propargylic amines and deuterium-
labeling studies, a Diels–Alder reaction mechanism was
proposed.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
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The authors gratefully acknowledge generous financial support
from National Science Foundation of China (No. 20772145).
(12) Chen, Z.; Zhu, J.; Xie, H.; Li, S.; Wu, Y.; Gong, Y. Chem.
Commun. 2010, 46, 2145.
Synlett 2010, No. 17, 2659–2663 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Trifluoromethyl Quinoline
2663
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Synlett 2010, No. 17, 2659–2663 © Thieme Stuttgart · New York

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