Efficient synthesis of 2-fluoromethylated qninolines via copper catalyzed alkynylation and cyclization of fluorinated imidoyl iodides

Article abstract of DOI:10.1002/adsc.201000180

2-Fluoromethylated quinolines were synthesized through the reaction of N-aryl-fluorinated imidoyl iodides with terminal alkynes in good yields by the catalysis of copper(I) iodide (CuI) alone.

Full text of DOI:10.1002/adsc.201000180

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DOI: 10.1002/adsc.201000180
Efficient Synthesis of 2-Fluoromethylated Quinolines via Copper-
Catalyzed Alkynylation and Cyclization of Fluorinated Imidoyl
Iodides
Shan Li,a Yafen Yuan,a Jiangtao Zhu,a Haibo Xie,a Zixian Chen,a,b
and Yongming Wua,*
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry. Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; phone: (+86)-21-54925190; e-mail: ymwu@mail.sioc.ac.cn
Department of Chemistry, Huazhong University of Science and Technology, Wuhan, Hubei 430074, Peopleꢀs Republic of
b
China
Received: March 8, 2010; Revised: May 6, 2010; Published online: June 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000180.
Abstract: 2-Fluoromethylated quinolines were syn-
thesized through the reaction of N-aryl-fluorinated
imidoyl iodides with terminal alkynes in good yields
by the catalysis of copper(I) iodide (CuI) alone.
yields, however, only moderate regioselectivity was
achieved. Herein, we wish to report a Cu(I)-catalyzed
coupling reaction and subsequent cyclization to con-
struct 2-fluoromethylated quinolines.
During the course of our study on the reactivity of
fluorinated alkynylimines,[12] it was found that 2-bro-
modifluoromethylated N-aryl-alkynylimines could be
readily converted to quinolines via an intramolecular
cyclization reaction catalyzed by CuI. And it was also
found in our previous work that fluorinated imidoyl
halides could react with terminal alkynes in the pres-
Keywords: copper; coupling reactions; cyclization;
fluorinated alkynylimines; fluorinated quinolines
Quinolines are important heterocycles that are fre- ence of CuI.[13] We envisioned that these two reac-
quently found in natural products.[1] The quinoline tions might be combined into a one-pot protocol. The
skeleton is often used in the design of many synthetic reaction of N-(p-methylphenyl)-2-bromo-2.2-difluoro-
compounds with pharmacological properties.[2,3] Re-
ACHTUNGTRENaNGNU cetimidoyl iodides with 1-hexyne was selected as the
cently, the fluorine-containing quinolines have been model system. Et3N was the base, several Lewis acids
attracted much attention due to their interesting bio- such as ZnBr2, AlCl3, CuI were used as the catalyst
logical activities.[4] It was considered that the fluorine separately to test this transformation, and the results
atom or fluorinated substituent plays a pivotal role in are listed in Table 1. Gratifyingly, CuI could indeed
bioactive compounds, and that they provide an catalyze this transformation. Extensive investigations
avenue for further structural elaboration.[5,6] The 2-tri- indicated that, in the presence of 10 mol% of CuI, the
fluoromethylated quinolines, mefloquine, for example, 2-bromodifluoromethylated quinoline was isolated in
are of significant pharmacological interest for their 93% yield while the two-step one-pot reaction was
use as potent antimalarial agents.[7]
conducted in Et3N/MeCN at 508C. In addition, when
Although the synthesis of various quinolines has inorganic bases like K3PO4, K2CO3 were used, alkynyl-
been largely described in the literature through many imine (3aba) was afforded as the final product, and
different strategies,[8] methods leading to the trifluoro- K3PO4 is superior to K2CO3.
methylated substrates are limited.[9] The conventional
To investigate the scope of the established strategy,
method is based on a trifluoromethylated building a number of fluorinated imidoyl iodides and terminal
blocks strategy. Some of them can be prepared in alkynes were tested (Table 2). Both electron-donating
good yields.[10] In 2001, Uneyama et al reported a and electron-withdrawing groups on the arene of the
one-pot method for the synthesis of 2-trifluoromethy- imidoyl iodides were tolerated in this reaction. It was
lated quinolines from N-aryl-trifluoroacetimidoyl interesting to note that electron-donating groups on
chlorides and alkynes catalyzed by an Rh complex.[11] the benzene ring of the imidoyl iodides could raise
This procedure gave the desired products in good the yields of the isolated products (Table 2, entries 2,
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Efficient Synthesis of 2-Fluoromethylated Quinolines
Scheme 1. CuI-catalyzed the coupling reaction of unfluorinated imidoyl chloride with 1-hexyne. Reaction conditions: imidoyl
chlorides (1.0 mmol), 1-hexyne (1.2 mmol), CuI (30 mol%), KI (1.0 equiv.), K3PO4 (a) or Et3N (b) (1.2 mmol), CH3CN
(3.0 mL), 608C.
4, 8, 14, 17, 20, 24, 26, 27, 30, and 31). Electron-with- al groups on the alkynes, such as hydroxy (Table 2,
drawing groups would lead to lower yields of the iso- entries 17, 18, and 26–28) and carboxylate groups
lated products (Table 2, entries 3, 6, 9, 11, 12, 16, 18, (Table 2, entries 8–12, 22, 23, and 31) albeit with
23, and 25). If a strong electron-withdrawing group lower yields. In this reaction, CF2Br, CF2Cl, CF3 ex-
(Table 2, entry 7) was involved in the substrate, no hibit a similar reactivity.
product could be obtained and the alkynylimines
It was very interesting to note that, when non-fluo-
were found to undergo decomposition in the presence rinated alkynylimines were used as starting material,
of triethylamine. The protocol gave equally good pyrroles were formed as the sole product under the
yields with substances bearing the para, meta, and same conditions.[14] This might be due to the strong
ortho substituents. For instance, 6-methylquinoline electron-withdrawing effect of the Rf group, whereby
and 8-methylquinoline were obtained in almost the the electronic density and nucleophilicity of nitrogen
same yields (Table 2, entries 2 and 4). Regretfully, this in fluorinated alkynylimine was reduced dramatically,
reaction was also suffered from moderate regioselec- so that the allene is attacked by the benzene ring in-
tivity. For the benzene ring with a substituent at the stead of the N atom (Scheme 1).
meta-position, two isomers (5- and 7-substituted qui-
It was found that the presence of the terminal
nolines) were obtained (Table 2, entries 5 and 11). alkyne a-H was essential for the success of the reac-
The reaction was compatible with a range of function- tion. For example, no quinoline could be obtained
Table 1. CuI-catalyzed the coupling reaction of imidoyl iodide with 1-hexyne.[a]
Entry
Catalyst
Base
Temperature [8C]
3aba[b] [%]
4aba[b] [%]
1
2
3
4
5
6
7
8
9
AlCl3 (1.2 equiv.)
ZnBr2 (1.2 equiv.)
CuI (1.2 equiv.)
CuI (0.3 equiv.)
CuI (0.1 equiv.)
CuI (0.1 equiv.)
CuI (0.1 equiv.)
CuI (0.1 equiv.)
CuI (0.1 equiv.)
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
K3PO4
KO-t-Bu
r.t.
r.t.
r.t.
70
70
50
50
50
50
–
–
–
–
–
–
40
92
–
–
-
50
86
70
93
–
–
–
[a]
Reaction conditions: imidoyl iodide (1.0 mmol), 1-hexyne (1.2 mmol), and base (1.2 mmol) under nitrogen.
Isolated yields.
[b]
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Shan Li et al.
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Table 2. CuI-catalyzed the coupling reaction to synthesize quinolines.[a]
Entry
Rf
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
BrCF2
H
p-CH3
p-Cl
o-CH3
m-CH3
o-Cl
p-NO2
p-OCH3
p-Cl
n-Pr
4aaa
4aba
4aca
4ada
4aea
4afa
–
82.7
92.4
82.6
86.4
83.9 (10:3)[c]
72.1
–
90.9
70.7
OCOCH3
4aab
4abb
4acb
4adb
4aeb
4aac
4abc
4acc
4adc
4aad
4abd
4baa
4bba
4bca
4bab
4bbb
4bac
4bbc
4bad
4bbd
4bcd
4caa
4cba
4cab
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
o-CH3
m-Cl
o-Cl
72.6
66.5 (1:1)[c]
60.0
H
Ph
81.7
87.8
88.7
p-CH3
o-CH3
p-Cl
p-CH3
o-Cl
H
p-CH3
p-Cl
p-OCH3
p-Cl
p-OCH3
o-Br
p-OCH3
p-CH3
o-CH3
H
p-CH3
p-OCH3
62.9
CH(OH)
(CH2)2CH3
66.5[d]
41.3[d]
86.9
CF3
n-Pr
90.0
83.4
82.5
70.5
OCOCH3
Ph
75.8
74.4
CH(OH)
(CH2)2CH3
75.1[d]
56.2[d]
64.6[d]
85.4
ClCF2
n-Pr
91.8
89.5
OCOCH3
[a]
Reaction conditions: fluorinated imidoyl iodides (1.0 mmol), alkynes (1.2 mmol), CuI (10 mol%), Et3N (1.2 mmol),
CH3CN (3.0 mL), T=50 8C, and under nitrogen.
Isolated yield.
[b]
[c]
[d]
Estimated by 19F NMR.
CuI (30 mol%).
when phenylacetylene was used as substrate, while al- allene intermediate C. Intermediate C is expected to
kynylimine was formed in high yield (Scheme 2). undergo a nucleophilic attack by the carbon atom of
Based on above study, the mechanism of this reac- the benzene ring to the central carbon of the allene
tion was proposed as shown in Scheme 3. Copper al- moiety. This process is similar to the Friedel–Crafts
À
kynide inserted to the C I bond of imidoyl iodides by reaction. As mentioned earlier, the presence of the a-
oxidant addition to form an intermediate A. After the H of the triple bond in the substrate was a key factor
reductive elimination, alkynylimine 3 was formed. for the success of the current transformation, which
When triethylamine was used as the base, the solubili- supports the proposed mechanism. After protonation
ty of the copper salt was increased by the complexa- and isomerization, quinoline 4 was formed.
tion effect of Et3N, which in turn allowed the forma-
In conclusion, we have developed a convenient and
tion of the intermediate B. Then B underwent a base- efficient approach for the one-pot synthesis of fluori-
induced propargyl-allenyl isomerization to form an nated quinolines catalyzed by CuI. The absence of
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Efficient Synthesis of 2-Fluoromethylated Quinolines
Scheme 2. Effect of terminal alkynes.
Scheme 3. Proposed mechanism for the synthesis of quinolines.
noble metals (such as Pd, Rh) and expensive ligands atmosphere. Then the system was heated to 508C, the con-
sumption of imidoyl iodides being monitored by TLC until
the corresponding spot was no longer observable. When the
reaction had finished, the solvent was removed under re-
duced pressure and the residue was purified by column
chromatography on silica gel to give the desired products.
renders this approach highly attractive for the further
development of fluorinated quinolines.
Experimental Section
General Procedure
Acknowledgements
To a Schenk tube, CuI (20 mg, 0.1 mmol), CH3CN (3.5 mL),
Et3N (1.2 mmol), imidoyl iodides (1.0 mmol), and terminal
alkyne (1.2 mmol) were added successively under a nitrogen
This work was supported by the National Science Foundation
of China No 20772145.
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asc.wiley-vch.de
1585

Shan Li et al.
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