Cu-catalyzed tandem reactions of fluorinated alkynes with sulfonyl azides en route to 2-trifluoromethylquinolines

Article abstract of DOI:10.1039/c3ob41658e

A novel method for the synthesis of 2-trifluoromethylquinolines via Cu-catalyzed tandem reactions was reported. A strong electronic effect was observed, but the steric effect was negligible.

Full text of DOI:10.1039/c3ob41658e

Organic &
Biomolecular Chemistry
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Cu-catalyzed tandem reactions of fluorinated
alkynes with sulfonyl azides en route to
Cite this: Org. Biomol. Chem., 2013, 11,
7267
2-trifluoromethylquinolines†
Received 14th August 2013,
Accepted 17th September 2013
Yajun Li,a,b Lisi Zhang,a Li Zhang,a,c Yongming Wu*a and Yuefa Gong*b
DOI: 10.1039/c3ob41658e
www.rsc.org/obc
A novel method for the synthesis of 2-trifluoromethylquinolines reported. 2-Trifluoromethylquinolines could be achieved in
via Cu-catalyzed tandem reactions was reported. A strong elec- excellent yields under mild conditions.9a In the same year, a
tronic effect was observed, but the steric effect was negligible.
milder way to obtain 2-trifluoromethylquinolines catalyzed by
cheap and abundant copper metal was disclosed.9b This strat-
egy was proposed to undergo a tandem reaction mechanism
that involves isomerization to form allene, followed by a
Friedel–Crafts reaction to give the products. However, despite
the significant progress, the reactions suffer from harsh con-
ditions (high reaction temperature), limited availability of
starting materials, and poor functional-group compatibility.
Methods that feature mild conditions and easy operation with
easily accessible starting materials are still required to be
developed.
As part of our continuous studies on the synthesis of fluori-
nated heterocyclic compounds, herein we report a copper-
catalyzed azide–alkyne cycloaddition (CuAAC)10 to synthesize
2-trifluoromethylquinolines through tandem reactions of
fluorinated terminal alkynes with sulfonyl azides at room
temperature.11,12
As shown in Table 1, fluorinated terminal alkyne 1a and
tosyl azide 2a were chosen as the model substrates to screen
the optimal reaction conditions. An initial experiment was per-
formed using 1.2 equiv. of tosyl azide 2a and 1.5 equiv. of Et3N
with 10 mol% of CuI in CH3CN at room temperature under a
nitrogen atmosphere for 24 h. Substrate 1a was consumed
completely, and no corresponding product 3aa was observed
(Table 1, entry 1). When an inorganic base K2CO3 was used,
substrate 1a was also fully converted, and only a trace amount
of product 3aa was detected (Table 1, entry 2). To our delight,
the product 3aa was obtained in 11% yield when THF was
used as the solvent, although 1a was fully consumed (Table 1,
entry 3). However, almost all of substrate 1a remained when
CH2Cl2 was used as the solvent (Table 1, entry 4). An encoura-
ging result was achieved when toluene was used, yielding 36%
of the product and recovering 58% of the substrate (Table 1,
entry 5). These results suggest that non-polar solvents benefit
the transformation. Other inorganic bases were also studied
and no better results were achieved (Table 1, entries 6–8).
Then copper catalysts were studied. To our satisfaction, an
Quinolines are common structural motifs and appear in a
wide range of natural products and drug molecules.1,2 Among
them, 2-trifluoromethylquinoline derivatives have attracted
great attention in drug design because of the unique pro-
perties of the fluorine atom.3 For example, Mefloquine which
contains a 2-trifluoromethylquinoline skeleton is one of the
main drugs for anti-malaria.4
Although 2-trifluoromethylquinoline derivatives are of great
interest, methods for the synthesis of these compounds are
limited.5 The most frequently utilized strategy is the Combes’
method.6 Recently, transition-metal-catalyzed synthesis of
2-trifluoromethylquinolines has become increasingly attrac-
tive.7,8 For example, in 2001, Uneyama et al. reported an
intermolecular synthesis of 2-trifluoromethylquinolines by
rhodium-catalyzed cyclization of trifluoroacetimidoyl chlorides
with alkynes at an elevated temperature.8e In 2008, the same
group developed an altered method to access 2-trifluoro-
methylquinolinesbypalladium-catalyzedintramolecularchloro-
imination reactions.8c In order to avoid or reduce the use of
noble metals and to enrich the strategies for the synthesis of
2-trifluoromethylquinolines, our group has developed several
routes to 2-trifluoromethylquinolines.9 In 2010, a palladium-
catalyzed tandem Sonogashira–alkyne carbocyclization of
β-trifluoromethyl β-enaminoketones with aryl alkynes was
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: ymwu@mail.sioc.ac.cn
bSchool of Chemistry and Chemical Engineering, Huazhong University of Science and
Technology, 1037 Luoyu Road, Wuhan 430074, China.
E-mail: gongyf@mail.hust.edu.cn
cDepartment of Chemistry, School of Science, Shanghai University, 99 Shangda Road,
Shanghai 200444, China
†Electronic supplementary information (ESI) available. CCDC 946895. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob41658e
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Table 1 Reaction condition optimizationa
Table 2 Scope and limitations of Cu-catalyzed tandem reactions between
fluorinated terminal alkynes and sulfonyl azidesa
Entry
Cu(I)X
Base
Solvent
Yieldb/%
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Et3N
CH3CN
CH3CN
THF
0
Entry
R1
R2
R3
Yieldb/%
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
Trace
11
Trace
36
21
14
1
2
3
4
5
6
7
8
H
H
H
H
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
p-Me-Ph
Ph
p-Cl-Ph
p-NO2-Ph
Me
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
3aa, 94
3ab, 90
3ac, 82
3ad, 93
3ae, 44
3ba, 94
3ca, 89
3da, 46
3ea, 42
3fa, 33
3ga + 3ga′, 75
3ha + 3ha′, 45
3ia, 21
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
H
6-Me
6-NMe2
6-Br
6-I
6-CO2Et
5-Me : 7-Me (1 : 1.7)
5-Cl : 7-Cl (1 : 1.8)
10
9
10
11
CuCl
CuBr
CuCN
98(94)c
64
23
9
10
11
12
13
14
15
a Reaction condition: 1a, 1.2 equiv. of 2a, 1.5 equiv. of base, 10 mol%
of Cu(I)X, in solvent at room temperature under a nitrogen atmosphere
for 24 h. b Yields were determined by 19F NMR using α,α,α-
trifluorotoluene as an internal standard. c Isolated yield in
parentheses.
8-F
8-Me
8-Ph
3ja, 83
3ka, 91
16
3la, 96
almost quantitative yield (98%) was detected when CuCl was
used as the catalyst (Table 1, entry 9). Other copper catalysts
such as CuBr and CuCN were less efficient compared to CuCl
(Table 1, entries 10 and 11). Finally, the optimized reaction
conditions were identified as 1a, 1.2 equiv. of 2a, 10 mol% of
CuCl, and 1.5 equiv. of K2CO3 in toluene at room temperature
under a nitrogen atmosphere.
To investigate the scope and limitations of the established
strategy, a number of fluorinated terminal alkynes 1 and sulfo-
nyl azides 2 were tested. The results are summarized in
Table 2. It should be noted that the electronic effect of substi-
tuents on the N-aromatic moiety of substrates 1 significantly
affects the yield of desired products, while the steric effect has
little effect on that.
As can be seen from Table 2, the reaction occurs smoothly
in toluene at room temperature, reaching completion within
24 h. The method has a broad scope and good functional-
group compatibility. Firstly, we studied various sulfonyl azides
2a–e. Both electron-rich aryl sulfonyl azides and electron-poor
aryl sulfonyl azides gave excellent results (Table 2, entries 1–4).
Even alkyl sulfonyl azides afforded the desired product in
moderate yield (Table 2, entry 5). Then the effect of substitu-
ents on the N-aromatic moiety of substrates 1 was studied.
Many different substituents were tolerated in the reactions,
such as alkyl groups (Table 2, entries 6, 11 and 14), amino
group (Table 2, entry 7), halides (Table 2, entries 8, 9, 12 and
13), ester group (Table 2, entry 10) and aryl groups (Table 2,
entries 15 and 16). The halides could be used for further trans-
formation. However, while electron-rich substituents afforded
excellent results, electron-poor substituents only delivered
moderate results. These results suggest that the electronic
effect of substituents on the N-aromatic moiety of substrates 1
has a great influence on the yield of desired products. For
17
18
19
20
21
H
H
6-OMe
6-OMe
H
C2F5
C3F7
CF2Cl
CF2Br
CF2H
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
p-Me-Ph
3ma, 84
3na, 81
3oa, 62
3pa, 54
3qa, trace
a Reaction condition: 1, 1.2 equiv. of 2, 1.5 equiv. of K2CO3, 10 mol%
of CuCl, in toluene at room temperature under a nitrogen atmosphere
for 24 h. b Isolated yields.
substrates containing substituents at the m-position on the
N-aromatic moiety, both electron-rich and electron-poor sub-
stituents gave approximately 2 : 1 regioisomeric products in
75% (Me) and 45% (Cl) yield, respectively. For substrates con-
taining substituents at the o-position on the N-aromatic
moiety, even the Ph group could afford excellent product yield
up to 91% (Table 2, entry 15 vs. entries 13, 14 and 16). More-
over, the structure of 3ka was confirmed by X-ray crystal diffr-
action studies (Fig. 1).13 These results implied that the steric
Fig. 1 X-ray crystal structure of 3ka.
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effect has little effect on the yield of desired products. In
This work was supported by the National Science Foun-
addition, other fluoroalkyl groups were also examined. Per- dation of China (no. 21172239).
fluoroalkyl groups were more efficient than others during the
transformation (Table 2, entries 1, 17, and 18 vs. entries
19–21). When the CF2H group was employed in the reaction,
only a trace amount of the desired product was detected, pre-
Notes and references
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