Single C?F Bond Cleavage of Trifluoromethylarenes with an ortho-Silyl Group

Article abstract of DOI:10.1002/anie.201604776

The transformation of a single C?F bond of trifluoromethylarenes bearing a hydrosilyl group at the ortho position was achieved. The activation of the hydrosilyl group with a trityl cation in the presence of nucleophiles allowed for selective C?F bond func

Full text of DOI:10.1002/anie.201604776

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604776
German Edition: DOI: 10.1002/ange.201604776
À
C F Activation
Hot Paper
À
Single C F Bond Cleavage of Trifluoromethylarenes with an
ortho-Silyl Group
Suguru Yoshida,* Ken Shimomori, Youngchan Kim, and Takamitsu Hosoya*
À
Abstract: The transformation of a single C F bond of
trifluoromethylarenes bearing a hydrosilyl group at the ortho
position was achieved. The activation of the hydrosilyl group
with a trityl cation in the presence of nucleophiles allowed for
À
selective C F bond functionalization, for example, by allyla-
tion, carboxylation, or chlorination. Further derivatization of
the resulting fluorosilylarenes afforded various aromatic
difluoromethylene compounds.
O
rganofluorine compounds are an important class of
molecules that are widely used in various fields, including
the pharmaceutical sciences, agrochemistry, and materials
science.[1] The increasing demand for fluorinated compounds
has prompted the development of a variety of methods for
introducing a fluorine atom or a fluorinated functional group
into organic frameworks. In particular, with the increasing
availability of convenient reagents in recent years, various
methods for fluorination and trifluoromethylation have been
developed.[2,3] However, methods for synthesizing complex
fluorinated compounds are still limited, and new approaches
are highly sought-after.
À
Figure 1. Transformation of an aromatic trifluoromethyl group by C F
À
bond cleavage. A) Bond lengths and dissociation energies of C X
bonds for homolytic bond cleavage.[4] B) Bond lengths and dissociation
À
energies of C F bonds in H4ÀnCFn (n=1–4) for homolytic bond
cleavage.[5] C) Reported transformation of an aromatic trifluoromethyl
group with a silylium intermediate.[8a] D) Strategy proposed herein.
In principle, a diverse range of fluorinated compounds can
be straightforwardly prepared from trifluoromethylated com-
pounds by the selective transformation of one of the three
À
C F bonds of the trifluoromethyl group. However, the high
that is triggered by the generation of a silyl cation at the ortho
position in the presence of an appropriate nucleophile
(Figure 1D). We also anticipated that the resulting products
could be transformed into a wide range of difluoromethylene
compounds because the hydrosilyl group of the starting
material is converted into a base-activatable fluorosilyl group
during this transformation.[11]
À
stability of the C F bond has rendered this transformation
difficult to achieve (Figure 1A).[4–7] Furthermore, previous
studies regarding the transformation of C F bonds stressed
the difficulty of performing single C F bond cleavage with an
À
À
À
aromatic trifluoromethyl group; all of the three C F bonds of
the trifluoromethyl group were cleaved in these cases.[8–10] The
À
reason behind this difficulty is that the C F bonds of the di-
After an extensive screening of reaction conditions for the
À
and monofluorinated intermediates are likely to be more
reactive than those of the trifluoromethyl-substituted starting
material (Figure 1B). For example, Ozerov and co-workers
reported the reduction of an aromatic trifluoromethyl group
transformation of trifluoromethylarenes by single C F bond
cleavage, we found that defluorinative mono-allylation of
2-(diphenylsilyl)benzotrifluoride (1a)[12] proceeded upon
treatment with a trityl cation source in the presence of
allyltrimethylsilane (3a) to afford gem-difluorinated 2a
(Table 1). The best result was obtained when a mixture of
1a and 3a was treated with triphenylmethylium tetrafluor-
oborate in a 1:1 mixture of dichloromethane and 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) at 08C for 10 minutes, which
afforded 2a in 86% yield (entry 6). The diallylated product,
À
to the corresponding methyl group by C F bond cleavage
with a silylium species (Figure 1C).[8b] We assumed that
a pinpoint transformation of the aromatic trifluoromethyl
À
group could be achieved through a single C F bond cleavage
[*] Dr. S. Yoshida, K. Shimomori, Y. Kim, Prof. Dr. T. Hosoya
Laboratory of Chemical Bioscience
À
which would result from further C F bond cleavage, was not
detected. Product 2a contains a fluorosilyl group, which
indicates that the reaction proceeded by hydride abstraction
from the silyl group in 1a with the trityl cation,[13] followed by
migration of a fluoride to the silyl group. Performing the
reaction in dichloromethane, toluene, acetonitrile, or nitro-
methane furnished a complex mixture that included triphe-
nylmethane (entries 1–4). These results indicate that using
Institute of Biomaterials and Bioengineering
Tokyo Medical and Dental University
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
E-mail: s-yoshida.cb@tmd.ac.jp
thosoya.cb@tmd.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604776.
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Table 1: C F bond allylation of 1a in various solvents.
methoxy, para-anisyl, para-tolyl, or 3-thienyl groups, were
smoothly allylated to afford the corresponding products 2b–
2e in high yields. The allylation of substrates bearing electron-
deficient groups also afforded difluoromethylated products
2 f–2j, some of which contained chloro, bromo, or ester
moieties for further transformation. Notably, as demonstrated
À
by the synthesis of 2i and 2j, the C F bond cleavage of
substrates having two trifluoromethyl groups occurred only at
the trifluoromethyl group adjacent to the silyl group.
2-(Dimethylsilyl)benzotrifluorides also participated in the
reaction, providing the allylated products, such as 2k and 2l,
in moderate yields.
A variety of substituted allylsilanes, such as 3b–3e, were
also suitable for this transformation (Table 3). Methallylation
and 2-bromoallylation afforded the corresponding products
Entry
Solvent
2a [%][a]
1
2
3
4
5
6
7
CH2Cl2
toluene
CH3CN
CH3NO2
CH2Cl2/(CF3)2CHOH (9:1)
CH2Cl2/(CF3)2CHOH (1:1)
CH2Cl2/(CF3)2CHOH (1:9)
trace
0
0
0
34
86[b]
58
1
À
Table 3: C F bond allylation using various allylsilanes.
[a] Yields determined by H NMR analysis, unless otherwise noted.
[b] Yield of isolated product.
a solvent such as HFIP that strongly stabilizes cationic
intermediates was crucial to the efficiency of this trans-
formation.[14]
The optimized conditions were applicable to the defluor-
inative allylation of various benzotrifluorides 1 (Table 2).
Benzotrifluorides bearing electron-rich substituents, such as
Entry Allylsilane
1
3
Product
2
Yield [%]
42
3b
2m
À
Table 2: C F bond allylation of various benzotrifluorides.
2
3
3c
3d
2n
2o
61
50
4
3e
2p
41
2m and 2n in moderate yields (entries 1 and 2). In the case of
À
g-substituted allylsilanes 3d and 3e, C C bond formation
selectively occurred at the g-position (entries 3 and 4).[15]
Notably, 4,4-difluoro-1-butene derivative 2p was obtained
À
by C F bond cleavage of the trifluoromethyl group of
benzotrifluoride 1a without damaging the trifluoromethyl
group of allylsilane 3e.
The fluorodiphenylsilyl and fluorodimethylsilyl groups in
the allylated products are more reactive than the correspond-
ing hydrosilyl groups, thereby allowing for further trans-
formations into a diverse range of difluorinated compounds
(Scheme 1). For example, desilylprotonation of 2c or 2l with
tetra(n-butyl)ammonium fluoride (TBAF) smoothly pro-
À
ceeded to afford 4 in high yields. C C bond formation by
Hiyama cross-coupling with an iodoarene using silver(I)
oxide as an activator afforded para-terphenyl derivative
5.[16,17] Modification of the allyl group under Heck arylation
conditions in the presence of TBAF afforded desilylproto-
nated styrene derivative 6.
[a] Allylsilane (10 equiv) was used.
2
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Scheme 1. Further transformations of the fluorosilyl group.
Scheme 3. Plausible reaction mechanisms.
To gain insight into the mechanism of the defluorinative
allylation reaction, we performed several experiments. The
reaction of benzotrifluoride 1m, which bears a hydrosilyl
group at the para position, did not afford the desired allylated
product 2q; a complex mixture was obtained, and the
formation of triphenylmethane was observed (Scheme 2A).
This result indicates the importance of the proximity of the
hydrosilyl and trifluoromethyl groups to achieve the trans-
formation, which most likely proceeds by intramolecular
fluoride migration. Furthermore, a competition experiment
using equimolar amounts of 1a, 1j, and a trityl cation source
resulted in the preferential production of 2a over 2j,
indicating that more electron-rich substrates are favored by
this reaction (Scheme 2B).
However, a concerted mechanism involving hydride abstrac-
À
tion and C F bond cleavage without generation of silylium
intermediate I cannot be excluded (Scheme 3B).
Nucleophiles other than allylsilane were also applicable to
the defluorinative transformation (Scheme 4). For example,
using benzoic acid 7 or anhydrous hydrogen chloride as the
nucleophile, carboxylation and chlorination of benzotrifluor-
ide 1a took place to afford ester 8 and chlorodifluoromethyl-
arene 9, respectively.
On the basis of the experimental results, we currently
believe that the reaction is triggered by hydride abstraction
from the hydrosilyl group of benzotrifluoride 1a with a trityl
cation, followed by the transfer of one fluoride of the
trifluoromethyl group to generate carbocationic intermediate
II (Scheme 3A). Subsequent allylation of carbocation II with
allylsilane 3a would then furnish the desired product 2a by
a mechanism similar to that of the Hosomi–Sakurai allylation.
À
Scheme 4. C F bond carboxylation and chlorination.
In summary, we have described the transformation of
À
a single C F bond of benzotrifluorides with an ortho-hydro-
silyl group upon treatment with a trityl cation in the presence
of various nucleophiles. Through further transformations of
the resulting fluorosilylarenes, this method allows for the
synthesis of various difluoromethylene compounds. Further
studies to expand the scope of this reaction are currently
underway.
Acknowledgements
This work was supported by the JSPS KAKENHI Grants
24310164 (T.H.) and 26350971 (S.Y.) and the Platform for
Drug Discovery, Informatics, and Structural Life Science
from MEXT and AMED, Japan.
Scheme 2. Mechanistic studies.
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Keywords: allylation · C F Activation · fluorine · silanes ·
trityl cation
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Received: May 16, 2016
Published online: && &&, &&&&
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À
C F Activation
One of the three: The transformation of
À
a single C F bond of trifluoromethylar-
S. Yoshida,* K. Shimomori, Y. Kim,
T. Hosoya*
enes bearing an ortho-hydrosilyl group is
described. The activation of the hydrosilyl
group with a trityl cation in the presence
&&&& — &&&&
À
À
Single C F Bond Cleavage of
Trifluoromethylarenes with an ortho-Silyl
Group
of nucleophiles enabled selective C F
bond functionalization, for example, by
allylation, carboxylation, or chlorination.
Further derivatization of the resulting
fluorosilylarenes afforded various
difluoromethylated arenes.
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