Synthesis of fluorinated aryl ethers via selective C-F functionalization with polyfluorobenzenes and carbonates under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2015.06.032

Abstract A facile and efficient method to synthesize fluorinated aryl ethers with polyfluorobenzenes and carbonates without metal catalyst has been developed. Selective C-F bond and aryl fragment of carbonate participate in the reaction. The desired produ

Full text of DOI:10.1016/j.tetlet.2015.06.032

Tetrahedron Letters 56 (2015) 4689–4693
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of fluorinated aryl ethers via selective C–F
functionalization with polyfluorobenzenes and carbonates
under mild conditions
⇑
Guanghui Yang, Zhiqun Yu, Xinpeng Jiang, Chuanming Yu
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Chao Wang Road
18th, Hangzhou 310014, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient method to synthesize fluorinated aryl ethers with polyfluorobenzenes and
carbonates without metal catalyst has been developed. Selective C–F bond and aryl fragment of carbonate
participate in the reaction. The desired products were obtained in moderate to excellent yields with good
substrates compatibility.
Received 22 April 2015
Revised 8 June 2015
Accepted 11 June 2015
Available online 17 June 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Fluorinated aryl ethers
C–F bond functionalization
Polyfluorobenzene
Carbonate
Introduction
co-workers have reported palladium-catalyzed cross coupling
reaction between pentafluorobenzene and phenols.3b Shortly after
The carbon–oxygen bond-forming reaction has gained signifi-
cant attention during past few years and is widely applied in
organic and pharmaceutical chemistry.1 The most straightforward
procedures to synthesize these ethers includes classic Ullmann
coupling,2 palladium catalyzed coupling reaction of aryl halides
with phenols,3 Williamson ether synthesis,4 and some other
methods.5 However, these strategies often require high tempera-
tures, expensive metal catalysts, long reaction times, and mostly
used to active aryl halides, such as chloride, bromide, and iodide,6
with low selectivity. While fluorine atom can increase the biologi-
cal activity, the bioavailability, and the potency of biologically
active molecules.7 Perfluoro- or polyfluoro-substituted aryl ethers
have drawn great interest especially in materials science,8 agricul-
tural and pharmaceutical areas due to their unique chemical and
physiological properties,9,10 such as lapatinib and crizotinib
(Scheme 1). The activation and functionalization of carbon–
fluorine bonds by transition metals is an effective method for
synthesizing these compounds.
that, Adonin and Bardin found the reaction also could be achieved
without palladium catalysis.11 Inevitably, it still needs a higher reac-
tion temperature. Zhang has reported a transition metal-free
method of synthesizing polyfluoroaryl ethers by using pentafluo-
robenzene with phenols and benzyl alcohols.12
Moreover, our group engaged in the research of fluorochemicals
and has successfully developed some useful methods to synthesize
fluorinated thioethers, tetrafluorophenoxathiins, biphenyl com-
pounds by using copper catalysis, and fluorinated nitriles and
diaryl ketones via selective C–F bond functionalization.13
As mentioned above, it is meaningful to synthesize these aryl
ethers via functionalization of C–F bond with higher selectivity
under milder conditions. Herein, we report another convenient
and effective procedure to synthesize fluorinated aryl ethers via
selective C–F functionalization of polyfluorobenzenes with carbon-
ates without metal catalyst.
Results and discussion
Recently, Cao and co-workers found a new method of preparing
unsymmetrical biaryl ethers using polyfluoroarenes and
arylboronic acids through nickel catalysts.5b Later, Weng and
At the early stage of our research, we intended to selectively
active C–H bond of pentafluorobenzene under metal catalyzed.
However, when the alkalinity of base was enhanced, we found
the existence of benzyl ether products even when the temperature
dropped to room temperature. So we found another easy way to
⇑
Corresponding author. Fax: +86 571 88320867.
E-mail address: ycm@zjut.edu.cn (C. Yu).
http://dx.doi.org/10.1016/j.tetlet.2015.06.032
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4690
G. Yang et al. / Tetrahedron Letters 56 (2015) 4689–4693
NH
N
N
N
N
O
Cl
CH3
O
F
N
HN
O
S
O
NH
NH2
Cl
O
Cl
Lapatinib
Crizotinib
F
Scheme 1. Representative drugs of fluorinated aryl ethers.
Table 1
Optimization of selective C-F functionalization to synthesize fluorinated aryl ethersa
OMe
F
O
F
F
F
F
H
F
Base
F
O
O
O
+
solvent
MeO
H
F
F
r.t. 0.5h
3b
1a
2b
Entry
Base
Solvent
Yield%b
1
2
3
t-BuOLi
NaH
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
THF
DMF
DMA
DMSO
1,4-Dioxane
CH3CN
NR
NR
57
93
76
85
81
40
37
31
68
16
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
4
5c
6
7
8
9
10
11
12
a
b
c
Reaction condition: 1a (2 mmol), 2b (1 mmol), solvent (3 mL), base (1.5 mmol), rt, 0.5 h.
Isolated yield base on 2b.
1 equiv t-BuOK.
Table 2
Substrate scope of carbonatesa
F
F
R1
O
F
O
F
F
H
F
t-BuOK
R2
R1
O
O
+
toluene
r.t., 0.5 h
H
F
R1 = Ar, Het, Alkyl
2 = ethyl, isopropyl
F
F
R
3
1a
2
Entry
1
Carbonate
Product
Yield%b
86
O
F
F
O
F
O
O
H
F
3a
O
OCH3
F
F
O
F
O
O
2
3
93
90
H3CO
H
F
3b
OCH3
O
F
F
O
F
O
O
OCH3
H
F
3c

G. Yang et al. / Tetrahedron Letters 56 (2015) 4689–4693
4691
Table 2 (continued)
Entry
Carbonate
Product
Yield%b
O
CH3
F
F
O
F
O
O
4
5
6
84
95
90
H3C
H
F
F
3d
3e
O
Cl
F
O
F
O
O
Cl
H
F
F
O
O
F
O
F
O
O
O
O
Cl
H
Cl
F
F
3f
Cl
Cl
F
O
Cl
7
77
H
F
Cl
F
F
3g
O
O
F
O
F
O
O
8
94
83
85
80
H
F
F
3h
O
F
O
F
O
O
9
H
F
F
3i
O
F
O
F
O
O
O
O
10
11
H
F
F
3j
O
O
N
F
O
F
O
N
H
F
3k
O
F
F
O
F
O
12
13
87
H
F
F
3l
O
O
F
O
F
O
O
93
90
H
F
F
3m
O
F
O
F
O
14
H
F
3n
a
Reaction condition: 1a (2 mmol), 2 (1 mmol), solvent (3 mL), base (1.5 mmol), rt, 0.5 h.
Isolated yield base on 2.
b
form C–O bond via selective C–F functionalization of polyfluo-
robenzenes with carbonates under mild conditions without metal
catalyst.
Pentafluorobenzene (1a) and isopropyl (4-methoxybenzyl) car-
bonate (2b) were chosen as the substrates in our following
exploration. The reaction did not proceed when t-BuOLi and NaH
were used in this reaction (Table 1, entries 1 and 2). While
t-BuONa was used as the base with toluene as the solvent, corre-
sponding product 3b was obtained in 57% yield (Table 1, entry
3). When the base was changed to t-BuOK, the yield was increased

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G. Yang et al. / Tetrahedron Letters 56 (2015) 4689–4693
Table 3
Substrate scope of polyfluorobenzenesa
OMe
O
t-BuOK
O
O
O
+
Fn-1
Fn
toluene
r.t. 0.5 h
MeO
n=1-5
4
1
2b
Entry
1
Fluorobenzene
Product
Yield%b
F
OMe
F
F
F
Br
F
F
O
F
92
Br
F
F
4b
F
F
OMe
F
F
F
O
2
3
4
85
81
F
F
4c
F
OMe
OMe
OMe
F
F
F
F
F
F
O
F
F
4d
4e
F
F
O
F
62
55
F
O
NC
5
NC
4f
a
Reaction condition: 1 (2 mmol), 2b (1 mmol), solvent (3 mL), base (1.5 mmol), rt, 0.5 h.
Isolated yield base on 2b.
b
to 93% (Table 1, entry 4).14 The yield was reduced to 76% as the
quantity of base was decreased to 1 equiv. (Table 1, entry 5). A
variety of solvents (e.g., xylene, THF, DMF, DMSO, 1,4-dioxane,
etc.) were screened, and toluene was found to be the best solvent
(Table 1, entries 6–12). Xylene, THF, and 1,4-dioxane also gave
good yields with 85%, 81%, and 68%.
heterocyclic substrates, such as furan and pyridine, were also
investigated and the corresponding products were obtained in
good yields (Table 2, 3j 85% and 3k 80%).
To expand the scope of the substrates, we proceeded to examine
a series of fluorobenzenes. When bromopentafluorobenzene was
used, selective C–F functionalization product was obtained in
92% (Table 3, 4b). 1,2,3,4-Tetrafluorobenzene and 1,2,3,5-tetrafluo-
robenzene could also undergo the reaction to afford the corre-
sponding products 4c and 4d in good yields. The yields were in
decline as the number of fluorine atoms in polyfluorobenzenes
decreased. As shown in Table 3, the desired products 4e and 4f
of 1,2,4-trifluorobenzene and 4-fluorobenzonitrile were generated
in moderate yields. Unfortunately, we did not observe the ether
products when 1,2-difluorobenzene and 1,3-difluorobenzene were
examined.
We further examined the scope and limitations of substituted
carbonates with the optimal reaction conditions in hand, the
representative results are summarized in Table 2. As described,
various carbonates were found to participate in the reaction, and
the electronic nature showed no pronounced effect on the effi-
ciency of the reaction. When the aryl group had no substituent,
the reaction proceeded smoothly and 86% yield of the product
was obtained (Table 2, 3a). Carbonates with electron-donating sub-
stituents afforded the corresponding products in 93%, 90%, and 84%
(Table 2, 3b–3d). Electron-withdrawing groups on different posi-
tions of the aromatic ring could also react well, the yields of
desired products were 95% and 90% (Table 2, 3e–3f). It was worth
mentioning that the yields were decreased a little due to the effect
of steric hindrance (Table 2, 3g and 3i). The reaction proceeded
well when phenylethyl and 4-phenylbutyl carbonates were used
instead of benzyl carbonate (Table 2, 3h and 3n). Alkyl carbonates
also showed good activity and provided the desired products in
87% and 93% yields (Table 2, 3l and 3m). Furthermore, other
Conclusion
In conclusion, we have developed a facile and efficient route to
synthesize fluorinated aryl ethers with polyfluorobenzenes and
carbonates. Various functional groups are tolerated in this reaction
with moderate to excellent yields. Moreover, selective C–F bond
and aryl fragment of carbonate participated in the reaction.
Further investigation and its application are in progress.

G. Yang et al. / Tetrahedron Letters 56 (2015) 4689–4693
4693
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Acknowledgments
7. (a) Wang, F.; Luo, T.; Hu, J. B.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.;
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Chem. 2011, 123, 7291; (b) Itoh, T. In Fluorine in Medicinal Chemistry and
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334.
The authors gratefully acknowledge financial support from the
National Natural Science Foundation of China (NSFC) (grant
number 21176222) and the Public Projects of Zhejiang Province
(grant number 2014C31133).
8. Cargill, M. R.; Sandford, G.; Tomlinson, D. J.; Hollfelder, N.; Pleis, F.; Nelles, G.;
Kilickiran, P. J. Fluorine Chem. 2011, 132, 829.
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10. Behniafar, H.; Sedaghatdoost, M. J. Fluorine Chem. 2011, 132, 276.
11. Adonin, N. Y.; Bardin, V. V. J. Fluorine Chem. 2013, 153, 165.
12. Liu, C. B.; Cao, L. M.; Yin, X. G.; Xu, H. L.; Zhang, B. J. Fluorine Chem. 2013, 156,
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13. (a) Yu, C. M.; Zhang, C. L.; Shi, X. J. Eur. J. Org. Chem. 2012, 1953; (b) Yu, C. M.;
Hu, G. B.; Zhang, C. L.; Wu, R.; Ye, H. W.; Yang, G. H.; Shi, X. J. J. Fluorine Chem.
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14. Procedure for the synthesis of compounds 3 and 4 (3b as an example): In a 15 mL
sealed tube, isopropyl (4-methoxybenzyl) carbonate (0.224 g, 1 mmol), t-
BuOK (0.168 g, 1.5 mmol), were added to toluene (3 mL) at room temperature.
10 min later, pentafluorobenzene (0.336 g, 2 mmol) was following added in
one portion. The reaction mixture was monitored by TLC until the carbonate
compound was consumed, and then poured into water (10 mL). The mixture
was extracted with EtOAc (3 Â 10 mL). The combined organic phases were
washed with saturated aqueous NaCl, dried with anhydrous Na2SO4, and
concentrated. The crude product was purified by flash chromatography on a
silica gel column (petroleum ether/EtOAc, 32:1 v/v) to afford the desired pure
product.
Supplementary data
Supplementary data (characterization of the products and
copies of spectras) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
032.
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