Visible-light-induced installation of oxyfluoroalkyl groups

Article abstract of DOI:10.1039/c7cc08067k

(Hetero)aryloxytetrafluoroethylation of heteroaromatics and alkenes has been achieved by visible-light photocatalysis utilizing readily synthesized oxyfluoroalkyl reagents. The mild reaction conditions and the high diversity on both substrates and oxyfluoroalkyl reagents make this a useful method for late-stage modifications in the development of various functional molecules.

Full text of DOI:10.1039/c7cc08067k

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Visible-light-induced installation of oxyfluoroalkyl groups
Gwi-Rim Park, Jisu Moon and Eun Jin Cho*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
(
Hetero)aryloxytetrafluoroethylation of heteroaromatics and the harsh reaction conditions. Recently, visible-light
alkenes, have been achieved by visible-light photocatalysis photocatalysis has emerged as a powerful preparative tool
utilizing readily synthesized oxyfluoroalkyl reagents. The mild owing to its environmental benignity and mechanistic
reaction conditions and the high diversity on both substrates and versatility in promoting a large number of synthetically
7
oxyfluoroalkyl reagents make this a useful method for late-stage important reactions with high levels of selectivity.
modifications in the development of various functional molecules.
O
H
N
O
H
O
Cl
H
N
N
S
Fluorine has the unique ability to alter the biological, physical,
and chemical properties of organic molecules, mainly due to
its high electronegativity, small size, and high C−F bond
dissociation energy. In particular, fluoroalkylated compounds
are characterized by superior lipophilicity, binding selectivity,
bioavailability, and metabolic stability as compared to their
nonfluoroalkylated analogues.1 Thus, extensive research
F
O
F
F F
N
H
N
O
Cl
MeO
OMe
Roflumilast
Anti-inflammatory Drug)
Cl
Pantoprazole
(
(Drug of acid-peptic disease)
F
F
OMe
F
F
O
O
F
O
O
H
F
O
F
O
F
F
F F
N
N
Cl
N
N
Cl
H
H
H
H
F
Hexaflumuron
Termiticide)
US Patent 4737509
(Insecticide)
efforts have been devoted for the preparation of
(
pharmaceutical and agrochemical agents bearing fluoroalkyl
moieties.2
Fig. 1 Aryloxyfluoroalkyl structural motifs in pharmacological compounds.
Oxygen is also an important element in drug development. In
particular, when connected to fluoroalkyl groups, oxygen can
significantly affect the biological and physical properties of
organic molecules, for example, by inducing higher
a) Fluoroalkylation of ROH6
(
F
F
O
R
R'
3
lipophilicity. Accordingly, molecules containing a fluoroalkyl
F
F
group connected to oxygen have been of great interest,
especially in medicinal chemistry, and many biologically active
work)
(
(
this
b) Visible-light-induced
installation of
oxyfluoroalkyl
groups
molecules such as roflumilast, pantoprazole, and Fig. 2 Strategies for oxyfluoroalkylation
4
hexaflumuron contain aryloxyfluoroalkyl groups (Figure 1).
Because of the importance of both fluoroalkyl and oxygen Our group has developed various visible-light-induced
moieties, various methods have been developed for their fluoroalkylation methods under mild conditions
including
which enabled simultaneous
8
installation, and the most common approach involves the direct arylthiofluoroalkylation
9
5
fluoroalkylation of alcohols [Figure 2(a)]. Considering the use installation of sulfur and fluoroalkyl moieties. As
a
of both moieties in drug development,
oxyfluoroalkylation reaction could offer an efficient strategy photocatalytic fluoroalkylations, we envisioned the visible
for late-stage modifications.
light-induced simultaneous introduction of alkoxy group and
a
direct continuation of our interest and inspired by our success on
However, only a few direct oxyfluoroalkylation methods have fluoroalkyl groups into organic molecules such as
been developed,4
(a),6
and their application is limited because of heteroaromatics and alkenes by utilizing readily available
oxyfluoroalkyl reagents. We expected their incorporation into
organic molecules to be easier than the fluoroalkylation of
Department of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu,
Seoul 06974, Republic of Korea. E-mail: ejcho@cau.ac.kr
alcohols via the corresponding fluoroalkyl radical, which would
be generated regardless of the presence of the alkoxy moiety
under mild reaction conditions [Figure 2(b)].
†
Electronic Supplementary Information (ESI) available: Experimental procedures,
1
13
additional experimental data, analytical data, and H and C NMR spectra of
aryloxytetraethylated compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2017
Chem. Commun., 2017, 00, 1-3 | 1
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Table 1 Optimization table of heteroaromaticsa
reaction of indole 1b showed high regioselectivity, providing
View Article Online
DOI: 10.1039/C7CC08067K
3
3% of the 2-substituted product 3ba without the formation of
Me
Me
N
photocatalyst (1 mol%)
11
the 3-substituted product (entry 2).
Interestingly, the
N
base (2 eq)
+
2OPh
eq)
2 2
(CF )
OPh
2
Br(CF )
reaction of 1d having an acetyl substituent provided indoline
3da' as the major product under the standard conditions
solvent, rt
CFL (23 W), 24 h
1a
2a
3aa
(1.2
Entry Photocatalyst
Base
Solvent (Conc.)
MeCN (0.2 M)
MeCN (0.2 M)
MeCN (0.2 M)
MeCN (0.2 M)
MeCN (0.2 M)
DMF (0.2 M)
Variations
Yield (%)b
(entry
4).
Instead,
the
desired
1
2
3
4
5
6
7
8
[Ru(Phen)
3
]Cl
2
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
46
43
31
phenyloxytetrafluoroethylatedindole (3da) could be obtained
1
2
3]Cl
2
4 2 2 8
by using (NH ) S O as the oxidant additive. In addition,
[
Ru(bpy)
fac-Ir(ppy)
bioactive compounds such as 5-aminouracil 1g and caffeine 1h
were suitable substrates for the oxyfluoroalkylation, proving
the utility and practicality of our method. The reaction
conditions were amenable to a large-scale reaction such that
3
fac-Ir(dFppy)
28
-
3
Nile red
[Ru(Phen)
[Ru(Phen)
3
]Cl
2
67
3aa could be prepared on a 5 mmol scale with yield similar to
3
]Cl
]Cl
2
2
TMEDA
TMEDA
DMSO (0.2 M)
DMSO (0.2 M)
71
that of a 0.3 mmol scale reaction. Reactions of other
heterocycles such as thiophenes, benzothiophenes,
benzofurans, and benzoxazoles were also tried, but did not
show good reactivity, giving low yields of products with several
side products. In addition, aromatic compounds were not
reactive under the standard conditions.
[Ru(Phen)
-
3
no hv
trace
9
TMEDA
TMEDA
TMEDA
TMEDA
DMSO (0.2 M)
DMSO (0.3 M)
DMSO (0.3 M)
trace
76
1
0
1
2
[Ru(Phen)
[Ru(Phen)
3
]Cl
]Cl
2
2
1
3
2 equiv 2a
82
1
[Ru(Phen)
3
]Cl
2
DMSO
(0.3
M)
3 equiv 2a
87
aReaction scale: 1a (0.1 mmol); byield (%) was determined by GC spectroscopy
Table 2 Substrate scope of heteroaromatics
a
using dodecane as internal standard.
[
Ru(Phen)
3
]Cl
2
(1 mol%)
X
X
TMEDA (2 eq)
We began our study by using N-methylpyrrole 1a and 2-
bromo-1,1,2,2-tetrafluoroethoxybenzene, Br(CF
model substrates (Table 1, and the full optimization details can
be found in Table S1 in the electronic supplementary
Br(CF
2
)
2
OPh
2 2
(CF )
OPh
X'
C, N,
DMSO (0.3 M),
rt
X'
2
)
2
OPh 2a, as
X,
X' =
S
CFL (23 W), 24-60 h
1
2a
3
Entry
Substrate
Product
Yield (%)b
Me
N
Me
N
information). Br(CF
2 2
) OPh could be easily synthesized from
1
(CF
2
)
2
OPh
82
1
0
phenol and dibromotetra-fluoroethane, Br(CF
reaction of 1a with 1.2 equiv of 2a proceeded in the presence
of 1 mol% of the photocatalyst and 2 equiv of TMEDA in MeCN
2
)
2
Br.
The
1a
3aa
H
H
N
N
2
3
33
(
CF
2
)
)
2
OPh
OPh
(
0.2 M) under the irradiation from a 23 W compact fluorescent
lamp (CFL) (entries 1-5) to give the
phenyloxytetrafluoroethylated product 3aa. [Ru(Phen) ]Cl
1b
3ba
H
H
N
N
3
2
(CF
2
2
72
40
was the best photosensitizer among those tested and was
chosen for subsequent studies. Solvent screening showed that
DMF and DMSO provided higher efficiencies, whereas MeOH,
THF, and 1,4-dioxane did not work at all for the reaction
Me
Me
3ca
1c
H
H
N
N
(
CF
Me
2
)
2
OPh
(Indoline,
3
da'
)
4
37
(
entries 1, 6, and 7). Changing the base from TMEDA to other
amine bases or inorganic bases, including TEA, DBU, DIPEA,
,6-lutidine, K CO , and Cs CO resulted in lower efficiencies.
3da c
Me
(
Indole,
)
O
O
1d
3da, 3da'
H
2
2
3
2
3
H
N
O
N
O
Control experiments indicated that the transformation
required both visible light and the photocatalyst (entries 8 and
5
6
60
OEt
OPh
OEt
(
CF
2
)
2
9). Thorough further screening of the reaction concentration
1e
S
3ea
S
H N
H N
2 2
(CF )
OPh
and stoichiometry of the reagents (entries 10-12) revealed the
best reaction conditions that provided 3aa in 87% yield as
follows: 1a, 1 mol% of [Ru(Phen) ]Cl , 3 equiv of 2a, and 2
3 2
equiv of TMEDA in DMSO (0.3 M) (entry 12).
With the optimized conditions in hand, we next investigated
the scope of various hetero-aromatic substrates with
2
2
88
44
N
N
O
1
f
3fa
O
NH2
NH2
HN
HN
7
8
O
N
O
N
H
2
(CF )
2OPh
H
1g
3ga
Me
O
O
N
Me
Br(CF
indole, and thiazole derivatives worked well under the
optimized conditions to give the corresponding
2 2
) OPh 2a (Table 2). N-heteroaromatics including pyrrole,
Me
O
Me
O
N
N
N
N
21
2
(CF )
2OPh
N
N
N
Me
Me
phenyloxytetra-fluoroethylated products (entries 1-6). Despite
the moderate yield and the formation of some side products,
1h
3ha
a
b
c
Reaction scale: 1 (0.3 mmol), 2a (0.9 mmol); isolated yield; (NH4)2S2O8 (4 equiv)
including
phenyloxytetrafluroethylindole,
small
amounts
of
2-bromo-3-
3-bromo-2-
was added as oxidizing additive.
phenyloxytetrafluoroethylindole, and 2-bromoindole, the
2
| Chem. Commun., 2017, 00, 1-3
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Table 3 Substrate scope of aliphatic and aromatic alkenesa
13
general, aromatic alkenes showed low reactivity ; thus,
View Article Online
DOI: 10.1039/C7CC08067K
reactions of styrene provided low yields of the corresponding
fac-Ir(ppy)3 (1 mol %)
products except of disubstituted styrene derivatives.
Interestingly, reactions of 1,1-disubstituted styrene derivative
4h and 1,2-disubstituted styrene derivative 4i proceeded well
to yield oxyfluoroalkylated alkene 5ha and 5ia as the major
product, respectively (entries 8 and 9), while those of aliphatic
alkenes provided the alkane products. Despite the lower
reactivity, internal alkene 4j also underwent the
transformation to give hydrophenyloxytetra-fluoroethylated
product 5ja (entry 5).
TMEDA (2 eq)
R
R
+
2OPh
2
(CF )
2OPh
Br(CF
2
)
DMF (0.1 M), rt
CFL (23 W), 12-24 h
4
2a
- 2 eq)
5
(1.2
Yield (%)b
Entry
Substrate
Product
8
4
1
2 2
(CF )
OPh
c
7
7
(
18:1)
4a
5aa
2
3
O
52
O
3
2 2
(CF )
OPh
3
O
O
4b
5ba
5ca
OH
OH
Scheme 1 Diversity of the (hetero)aryloxytetrafluoroethylationa,b
65
(
2 2
CF )
OPh
1
a
+
3
2
[Ru(Phen) (1
]Cl
mol%)
R
4c
R
F
F
F
F
TMEDA eq)
O
O
(2
(
a) Br
N
O
O
DMSO
rt
0.3 M),
23 W),
(
4
5
N
H
N
2OPh 60
F F
(
CF
2
)
F
F
CFL
24 - 48 h
Me
H
(
R = Ph (2b)
R = Ph (3ab), 78%
Me 3ac 75%
Cl
4d
Cl
5da
2c
OMe (2d)
CN (2e)
Me
(
)
(
),
OMe (3ad), 74%
CN (3ae), 72%
O
O
75
N
N
2OPh
fac
mol %)
(1
TMEDA (2 eq)
(
CF
2
)
4a
-Ir(ppy)
3
R
4
4
H
H
F
F
4e
5ea
(b)
+
O
O
O
DMF
rt
7
2
b - 2e
(
0.1 M),
F
F
6
64
80
CFL (23 W), 12 -24 h
=
Ph 5ab 82%
N
H
N
(CF
)
OPh
R
( ),
2
2
H
Me (5ac), 81%
OMe (5ad), 77%
4f
5fa
O
O
1
a +
Me
Me
2
(CF )
2OPh
[Ru(Phen)
3
]Cl
2
(1 mol%)
7d
N
N
(c)
TMEDA (2 eq)
N
F
F
N
F F
Br
rt
48 h
DMSO (0.3 M),
4g
O
N
Me
N
O
N
Me
5
ga
CFL
(23 W),
F F
F
F
Me
6
7
, 66%
6
0
a
Reaction scale: 1a or 4a (0.3 mmol), 2b
-
2e or 6 (0.9 mmol with 1a and 0.6 mmol
(
CF
2
)
2
OPh
c
b
8d
(1:5)
with 4a); isolated yield or GC yield due to the volatility of products.
To prove the diversity and potential application of this
transformation, other oxyfluoroalkyl reagents were employed
(Scheme 1). Reactions of 1a and 4a were conducted with
various (hetero)aryloxytetrafluoroethyl reagents containing
either electronwithdrawing (EWG) substituents (2e) or
electrondonating (EDG) substituents (2b, 2c, 2d). The
moderate to good yields of corresponding products 3ab-3ae
4
h
5
ha
HO
Me
HO
Me
2 2
(CF )
OPh
74
9d
e
(
2.5:1)
O
Me
O
Me
4i
5ia
10
30
(
CF
5
2
)
2
OPh
4j
ja
a
Reaction scale: 4 (0.3 mmol); bisolated yield; cratio between the alkane and and 5ab-5ad indicated that the method is applicable to the
d
alkene form of the product. (NH4)2S2O8 (4 equiv) was added as oxidizing additive;
synthesis of various aryloxyfluoroalkylated products [Scheme
(a) and 1(b)]. A heterocycle containing a dimethylpyrimidine
eE/Z ratio of 5ia.
1
moiety (6) was also synthesized and successfully utilized for
the reaction with 1a to provide 7 in 66% yield [Scheme 1(c)].
Based on the results of our studies, a proposed mechanism is
shown in Scheme 2 for the aryloxytetrafluoroethylation of
Oxyfluoroalkylation reactions of alkenes proceeded more
efficiently than that of heteroaromatics (Table 3). After the
optimization process using 1-dodecene 4a as the model
substrate with 2a, we found that the transformation worked
best with 1.2 equiv of 2a, 2 equiv of TMEDA, and 1 mol% of
heteroaromatics and alkenes using [Ru(Phen)
3
2
]Cl or fac-
Ir(ppy)
3
as the photocatalyst. The catalyst in its normal state,
3
fac- Ir(ppy) in DMF (0.1 M) to give hydrophenyloxytetrafluoro-
n
[M L
x
], is photoexcited under visible-light irradiation using a 23
ethylated product 5aa as the major compound (entry 1). The
full optimization details can be found in Table S2 in the
electronic supplementary information. Under the optimal
conditions, aliphatic and aromatic alkenes containing various
functional groups, including ester (entry 2), alcohol (entry 3),
and amide (entries 4-6), underwent oxyfluoroalkylation. The
reaction of lactam substrate 4g produced a mixture of
phenyloxytetra-fluoroethylated alkene and alkane products
under the standard conditions; the alkene product 5ga could
W compact fluorescent light (CFL) and is converted into
n+1 •−
[M
L
x
] through a metal-to-ligand charge-transfer (MLCT)
n+1 •−
transition. Then, [M
electron transfer to Br(CF ] , a
bromide ion, and the key intermediate ·(CF ) OAr. The radical
x
L ] is oxidatively quenched by a one-
n+1
+
2
)
2
OAr, generating [M
L
x
1
4
2 2
intermediate is then added to substrate 1 or 4 to generate
aryloxytetrafluoroethylated radical species A. Radical species A
can then proceed through three possible pathways.
Tetrafluoroethylated alkane product 5 would be generated by
4 2 2 8
be selectively obtained by using 4 equiv of (NH ) S O . In
This journal is © The Royal Society of Chemistry 20xx
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Medicinal Chemistry and Chemical Biology, WiVleieyw-BArltaicclekOwnelinlle,
N
N
A
pathway (b)
2009; (f) V. Gouverneur, and K. Müller, Fluorine in
DOI: 10.1039/C7CC08067K
pathway (a)
B
N
n
Pharmaceutical and Medicinal Chemistry, From Biophysical
N
[M L
x
]
M = Ru or Ir
Aspects to Clinical Applications, World Scientific Publishing
Company, 2012.
Hydro-
oxytetrafluoroethylation
n+1L
OAr
[MnL
L
= Phen or
ppy
[
M
x
]
x
]
Br(CF
2
)
2
pathway (a)
3
The properties of oxyfluoroalkyl compounds, see: (a) C.
Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani and E. J.
Lien, J. Med. Chem., 1973, 16, 1207; (b) C. Hansch, A. Leo, R.
W. Taft, Chem. Rev., 1991, 91, 165; (c) F. Leroux, P. Jeschke
and M. Schlosser, Chem. Rev., 2005, 105, 827; (d) P. Jeschke,
E. Baston, and F. R. Leroux, Mini-Rev. Med. Chem., 2007, 7,
n+1L
H-abstraction
[
M
x
]
-
H
Br
N
N
N
N
R
3
R
3
(CF
2
)
2
OAr
R
3
2 2
(CF )
OAr
(CF
2
)
2
OAr
R
1
R
2
R
1
R
2
R
1
R
2
A
1
or 4
5
pathway (b)
R
3
(CF
2
)
2
OAr
OAr
1027.
pathway (c)
radical propagation
Br-abstraction)
Br(CF
OAr
deprotonation
Photocatalytic
oxidation
R
1
R
2
4
5
6
Examples of aryloxyfluoroalkyl structural motifs in drugs and
biological active compounds, see: (a) J. Zhu, C. Ni, B. Gao and
J. Hu, J. Fluorine Chem., 2015, 171, 139; (b) T. Khotavivattana,
S. Calderwood, S. Verhoog, L. Pfeifer, S. Preshlock, N. Vasdev,
T. L. Collier and V. Gouverneur, Org. Lett., 2017, 19, 568.
Examples of fluoroalkylation reactions of alcohols, see: (a) J.
B. Liu, C. Chen, L. Chu, Z. H. Chen, X. H. Xu and F. L. Qing,
Angew. Chem. Int. Ed., 2015, 54, 11839; (b) J. B. Liu, X. H. Xu
and F. L. Qing, Org. Lett., 2015, 17, 5048; (c) J. W. Lee, D. N.
Spiegowski and M. -Y. Ngai, Chem. Sci., 2017, 8, 6066.
Examples on direct oxyfluoroalkylations, see: (a) F. R. Leroux,
B. Manteau, J. -P. Vors and S. Pazenok, Beilstein J. Org.
Chem., 2008, 4, 13; (b) T. Besset, P. Jubault, X. Pannecoucke
and T. Poisson, Org. Chem. Front., 2016, 3, 1004; (c) A. Tlili, F.
Toulgoat and T. Billard, Angew. Chem. Int. Ed., 2016, 55,
11726; (d) K. N. Lee, J. W. Lee and M. -Y. Ngai, Synlett, 2016,
27, 313.
(
- H
B
2 2
)
R
3
(CF
2
)
2
R3
2
(CF )
2OAr
Br
- HBr
R
1
R
2
R1 R2
HBr-elimination 3 or 5'
Oxytetrafluoroethylation
Scheme 2. Proposed mechanism for aryloxytetrafluoroethylation of heteroaromatics
and alkenes.
the hydrogen abstraction from ammonium radical cations,
which are formed from the corresponding tertiary amines via a
one-electron transfer to [M
cycle]. On the other hand, tetrafluoroethylated product 3 or 5'
would be generated from A by pathway (b) or (c). A one-
electron transfer from A to [M
carbocation intermediate B, which is deprotonated by TMEDA
to complete the reaction, providing product 3 or 5' [pathway
b)]. Alternatively, 3 or 5' can be generated by Br-abstraction
and HBr elimination processes, which involve radical
propagation to produce the key radical intermediate
n+1
+
x
L ] [pathway (a) in the catalytic
n+1
+
x
L ] produces the oxidized
7
For some recent reviews on visible-light-induced photo-
catalysis, see: (a) J. M. Narayanam, C. R. Stephenson, Chem.
Soc. Rev., 2011, 40, 102; (b) C. K. Prier, D. A. Rankic and D. W.
MacMillan, Chem. Rev., 2013, 113, 5322; (c) D. M. Schultz, T.
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(
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́
C.
·
(CF
2 2
) OAr [pathway (c)].
In summary, we have developed a practical visible-light-
̈
induced (hetero)aryloxytetrafluoroethylations of hetero-
aromatics and alkenes under mild reaction conditions. Two
functional groups consisting of oxygen and fluoroalkyl moieties
could be simultaneously installed into unactivated hetero-
aromatics and alkenes, demonstrating the potential use of the
method for late-stage modifications in the development of
functional molecules. In addition, this method can be utilized
for the fine-tuning of properties in drug development by
modifying the oxyfluoroalkyl reagent.
This research was supported by the Chung-Ang University
Graduate Research Scholarship in 2017 for Jisu Moon. We
gratefully acknowledge the National Research Foundation of
Korea [NRF-2012M3A7B4049657, NRF-2014-011165, NRF-
8
Accounts on our previous visible-light-induced fluoroalkyl-
ation reactions, see: (a) E. J. Cho, Chem. Rec., 2016, 16, 47; (b)
T. Chatterjee, N. Iqbal, Y. You and E. J. Cho, Acc. Chem. Res.,
2
016, 49, 2284.
Y. Choi, C. You, J. S. Kim and E. J. Cho, Org. Lett., 2016, 18,
246.
0 Synthesis of Br(CF
9
1
3
2 2
) OAr derivatives, see: J. Li, J. X. Qiao, D.
Smith, B. -C. Chen, M. E. Salvati, J. Y. Roberge and B. N.
Balasubramanian, Tetrahedron Lett., 2007, 48, 7516.
1
1 Previous examples on the formation of regioisomers in
visible-light-induced fluoroalkylations of indole, see: (a) D. A.
Nagib, D. W. MacMillan, Nature, 2011, 480, 224; (b) N. Iqbal,
S. Choi, E. Ko and E. J. Cho, Tetrahedron Lett., 2012, 53, 2005;
(c) J. Jung, E. Kim, Y. You and E. J. Cho, (d) N. J. W. Straathof,
H. P. L. Gemeots, X. Wang, J. C. Schouten, V. Hessel and T.
Noёl, Chemsuschem, 2014, 7, 1612.
2
016K1A3A1A19945930, and NRF-2017R1A2B2004082].
1
2 Used as an oxidizing additive for recovering aromaticity of
heteroaromatics, see: I. Abdiaj, C. Bottecchia, J. Alcazar and T.
Noёl, Synthesis, 2017, DOI: 10.1055/s-0036-1588527.
3 X. -J. Wei, W. Boon, V. Hessel and T. Noёl, ACS Catal., 2017, 7,
Notes and references
1
1
7136.
1
The properties of fluoroalkylated compounds, see: (a) M.
4 The results of Stern–Volmer experiments, conducted in our
previous fluoroalkylation works, showed that the
corresponding fluoroalkyl radicals were generated by
oxidative quenching pathways, see: ref. 11(c) and W. J. Choi,
S. Choi, K. Ohkubo, S. Fukuzumi, E. J. Cho and Y. You, Chem.
Sci., 2015, 6, 1454.
Shimizu and T. Hiyama, Angew. Chem. Int. Ed., 2004, 44, 214;
(
b) D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308.
2
The applications of fluoroalkylated compounds in medical
fields, see: (a) K. Mu
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ller, C. Faeh and F. Diederich, Science,
007, 317, 1881; (b) W. K. Hagmann, J. Med. Chem. 2008, 51,
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Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H.
Liu, Chem. Rev., 2014, 114, 2432; (d) K. P. S. Cheung and G. C.
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4
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