Siladifluoromethylation and Difluoromethylation onto C(sp3), C(sp2), and C(sp) Centers Using Ruppert-Prakash Reagent and Fluoroform

Article abstract of DOI:10.1021/acs.orglett.6b01476

Siladifluoromethylations and difluoromethylations on sp³, sp², and sp carbons of lithiated carbamates, arenes, and terminal alkynes, respectively, have been attained by employing the Ruppert-Prakash reagent (CF₃TMS) and fl

Full text of DOI:10.1021/acs.orglett.6b01476

Letter
pubs.acs.org/OrgLett
Siladifluoromethylation and Difluoromethylation onto C(sp3), C(sp2),
and C(sp) Centers Using Ruppert−Prakash Reagent and Fluoroform
Kohsuke Aikawa, Kenichi Maruyama, Junki Nitta, Ryota Hashimoto, and Koichi Mikami*
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology,
O-okayama, Meguro-ku, Tokyo 152-8552, Japan
S
* Supporting Information
ABSTRACT: Siladifluoromethylations and difluoromethyla-
tions on sp3, sp2, and sp carbons of lithiated carbamates,
arenes, and terminal alkynes, respectively, have been attained
by employing the Ruppert−Prakash reagent (CF3TMS) and
fluoroform (CF3H) as the CF2 sources. The advantage of this
reaction is that the (sila)difluoromethylated compounds can be obtained by simple treatment of easily accessible substrates,
lithium bases, and CF3TMS or CF3H. Furthermore, the products bearing the TMS group can be transformed into the valuable
compounds with the CF2 fragment via the carbon−carbon bond forming reactions.
rganofluorine chemistry has become a major research
field in the discovery of new bioactive molecules and
Table 1. Siladifluoromethylation Using CF3TMS
O
materials,1 and major efforts have focused on the introduction
of a fluorine atom2 and various perfluoroalkyl groups
containing the CF3 group.3 Furthermore, attraction for
organofluorine compounds possessing difluoromethylene
(−CF2−) and difluoromethyl (−CF2H) groups is growing in
pharmaceutical and agrochemical industies.4 Actually, it has
been proposed that the CF2 fragment can be employed as an
oxygen surrogate.4
b
entry
base
x
y
solvent
THF
yields of 2a/3a (%)
1
2
3
4
5
6
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
s-BuLi
MeLi
1
2
2
2
2
2
2
2
2
2
2
5
21/5
42/22
31/32
43/21
0/18
50/26
44/49
23/1
20/9
0/0
5
THF
2
THF
The synthesis of compounds containing the CF2 fragment
can be conventionally performed via the deoxofluorination
reaction5 with harsh reagents such as N,N-diethylaminosulfur
trifluoride (DAST) and derivatives of DAST or the building
block method6 using fluorinated starting materials. However,
introduction of the CF2 fragment based on the carbon−carbon
bond formation has been less explored, in sharp contrast to the
development of various methods to fluorofunctionalize.
Recently, we succeeded in the α-difluoromethylations and α-
siladifluoromethylations of carbonyl and nitrile compounds in
the presence of a lithium base by using fluoroform (CF3H)3a,7,8
and the Ruppert−Prakash reagent (CF3TMS)9 as CF2
sources.10−12 We herein report the siladifluoromethylations
and difluoromethylations on C(sp3), C(sp2), and C(sp) centers
with lithiated carbamates, arenes, and terminal alkynes. The
advantage of the reaction is that the simple combination of
substrate, lithium base, and CF3TMS or fluoroform can be
converted to valuable compounds with the CF2 fragment.
Siladifluoromethylation on a C(sp3)13 center was initiated by
employing carbamate 1a,14 which was subjected to reaction
conditions similar to those attained by our previous works10b,c
(Table 1). Upon treatment with n-BuLi (1.0 equiv) in THF, the
reaction of lithiated 1a and CF3TMS (5 equiv) provided the
expected product 2a in 21% yield,15 along with gem-
difluoroolefinated byproduct 3a in 5% yield (Table, entry 1).
Additionally, employment of 2 equiv of n-BuLi was found to
enhance the yield of 2a, although 3a was also increased (Table
10
5
THF
Et2O
5
THF/Et2O
THF/Et2O
THF
a
7
5
8
5
9
5
THF
10
11
LDA
5
THF
LHMDS
5
THF
b
0/0
a
Reaction temperature was −20 °C. Yields were determined by 19F
NMR analysis using benzotrifluoride as an internal standard.
1, entries 2 and 3). An excess amount of CF3TMS (10 equiv)
could not improve the yield (Table 1, entry 4). While the
selection of Et2O instead of THF as a solvent led to no product
(Table 1, entry 5), the mixed solvent of THF and Et2O in a 1:1
ratio improved slightly the yield (50%) (Table 1, entry 6). The
reaction was sensitive to lithium bases, and n-BuLi gave the best
results (Table 1, entry 6 vs 8−11). The reaction of isolated 2a
and n-BuLi in THF at −40 °C did not afford 3a, but 2a in the
presence of KF smoothly underwent the transformation into
3a. The results strongly indicate that difluoromethyl lithium
species (RCF2Li) as the intermediate, which can lead to 2a and
3a via the trimethylsilylation by CF3TMS and the β-elimination
Received: May 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01476
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Organic Letters
Letter
of carbamate group, respectively, is involved in the reaction
mechanism.10c
With the optimized reaction conditions in hand, we explored
the scope of substrates (Figure 1). The yields in the range of
We next envisioned that this method would be adaptable to
siladifluoromethylation on the C(sp2)16 center using the
Ruppert−Prakash reagent (Scheme 3). The reaction by
Scheme 3. Siladifluoromethylation on sp2 Carbon
Figure 1. Siladifluoromethylation on sp3 carbon. Reaction conditions:
After reaction of n-BuLi (0.2 mmol) and 1 (0.1 mmol) in THF/Et2O
(0.5/0.5 mL) for 30 min at −78 °C, CF3TMS (0.5 mmol) was added
at −78 °C, and then the reaction mixture was stirred for 2 h at −40 °C.
Isolated yields. a THF as a solvent was used. b Reaction temperature
was −78 °C after addition of CF3TMS.
a
Reaction conditions: After reaction of n-BuLi (0.2 mmol) and 6 (0.2
mmol) in THF (1.0 mL) for 2 h at −78 °C, CF3TMS (2.2 mmol) was
added at −78 °C, and then the reaction mixture was stirred for 5 min
at −78 °C. Yields were determined by 19F NMR analysis using
b
20−50% (2a−e) were obtained for substrates bearing different
carbamate moieties. Additionally, the reaction of carbamates
with not only electron-donating but also electron-withdrawing
substituents on the aryl rings was allowed to furnish the
products 2f−h, while the yields were not good.
β,γ-Unsaturated carbamate 1i readily derived from the
corresponding allyl alcohol was also suitable in the present
reaction. The reaction led to γ-siladifluoromethylated product
γ-2i in 50% yield, along with α-siladifluoromethylated product
α-2i in 18% yield (Scheme 1). The deprotection with TMSOTf
of γ-2i, which was separated by silica-gel column chromatog-
raphy, afforded the corresponding ketone 4 in 80% yield.
benzotrifluoride as an internal standard. n-BuLi (2 equiv) was used.
treatment of aromatic substrates 6 bearing an alkoxyl
directing-group proceeded to provide the corresponding arenes
7, although the yields were not sufficiently high.17 In contrast to
the reaction with carbamate 1, it was demonstrated that
employment of 1 equiv of n-BuLi was optimal.15 Under the
reaction conditions, phenols 6a−f protected by MOM, MEM,
and CH2OEt led to moderate yields (36−57%). The reaction of
4-(trifluoromethyl)phenol without MOM under the same
reaction conditions resulted in recovery of the substrate.
Phenol and naphthol derivatives 6g−j bearing the electron-
withdrawing substituents in the m- and/or p-positions was
examined to afford the siladifluoromethylated arenes. Unfortu-
nately, phenols protected by MOM bearing the electron-
donating substituents, such as tert-butyl and methoxy groups, in
the p-positions were transformed not to the desired products
but to the trimethylsilylated arenes as sole products under the
same reaction conditions. In addition, the reaction of 6a with
CF3H in lieu of CF3TMS in the presence of n-BuLi (1.0−2.0
equiv) resulted in the complete recovery of 6a, because the
protonation of aryl lithium species by CF3H is preferred rather
than the desirable C−C bond formation.
Scheme 1. Siladifluoromethylation on the γ-Position
The success of aromatic siladifluoromethyaltion prompted us
to investigate the transformation of the product into the
difluoromethylated compounds with a variety of functional
groups (Scheme 4). The methylation and esterification of 7a
employing MeI and ethyl chloroformate as electrophiles
proceeded through the activation of silyl functionality in the
presence of KF, providing the corresponding products 8 and 9,
respectively. Compound 7a was also converted to the
corresponding alcohol 10 and thioether 11, by treatment of
benzaldehyde and disulfide, respectively. Moreover, it was
found that hexafluorobenzene underwent the pentafluoroar-
ylation to give the unique polyfluoroarylated product 12 in 69%
yield.
Furthermore, the difluoromethylation using fluoroform
(CF3H) instead of CF3TMS as the CF2 sources was conducted
(Scheme 2). As expected, the bubbling operation of fluoroform
to a THF solution of 1a and n-BuLi (2 equiv) provided the
desired α-difluoromethylated product 5a in 28% yield, in spite
of production of 3a in 29% yield.
Scheme 2. Difluoromethylation on sp3 Carbon Using CF3H
Finally, our method was also successfully applied to
siladifluoromethylation on the C(sp)18,19 center with terminal
alkynes 13 (Scheme 5). After the best reaction conditions were
B
DOI: 10.1021/acs.orglett.6b01476
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Organic Letters
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Scheme 4. Applications to Transforming Reactions
Scheme 6. Difluoromethylation on sp Carbon of Alkyne
a
Reaction conditions: After reaction of LHMDS (0.2 mmol) and 13
Scheme 5. Siladifluoromethylation on sp Carbon
(0.1 mmol) in THF (1.0 mL) at −78 °C under excess amounts of
CF3H (1 atm: balloon), the reaction mixture was stirred for 2 h at −78
°C. Yields were determined by 19F NMR analysis using benzotri-
b
c
fluoride as an internal standard. LHMDS (1 equiv) was used. n-BuLi
(2 equiv) instead of LHMDS was used.
building blocks. At the same time, we have also demonstrated
that the difluoromethylations onto C(sp3) and C(sp) took
place by employing the same lithium species and fluoroform.
Development of novel catalytic (sila)difluoromethylations using
the transition metal is ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01476.
Reaction conditions: After reaction of n-BuLi (0.2 mmol) and 13 (0.2
mmol) in THF (1.0 mL) for 5 min at −78 °C, CF3TMS (0.2 mmol)
was added at −78 °C, and then the reaction mixture was stirred for 5
min at −78 °C. Yields were determined by 19F NMR analysis using
Experimental procedures and compound characterization
data (PDF)
b
benzotrifluoride as an internal standard. n-BuLi (2 equiv) was used.
c
LHMDS (1 equiv) instead of n-BuLi was used at rt for 1 h.
AUTHOR INFORMATION
Corresponding Author
■
surveyed, the siladifluoromethylation using 1 equiv of n-BuLi
and the Ruppert−Prakash reagent was found to give the highest
yield of products.15 Aromatic alkynes 13a−c led to the
corresponding products 14a−c in less than 5 min. Additionally,
the yields of 14d−e endowed with sterically more demanding
silyl-substituents increased to more than 60%. We were
delighted to find that the difluoromethylation of 13 under a
fluoroform atmosphere worked well with LHMDS (2 equiv)
instead of n-BuLi as a lithium base (Scheme 6).12 A variety of
lithium bases such as LDA, LTMP, NHMDS, and KHMDS
were also investigated, but no reaction proceeded. Moreover,
the reaction method by bubbling of fluoroform to a THF
solution of lithium acetylide, as shown in Scheme 2, led to a
decrease in the yield. Under the reaction conditions at −78 °C,
terminal alkynes 13 possessing not only (hetero)aryl groups
but also a silyl one underwent the difluoromethylation to
provide the corresponding products 15 in 43−72% yields. It is
widely accepted that the alkynes 14 and 15 can be readily
converted to various difluoromethylated building blocks.19,20
In summary, we have disclosed that the direct siladifluoro-
methylations onto C(sp3), C(sp2), and C(sp) centers by
combination of carbanions with lithium as a countercation and
the Ruppert−Prakash reagent can proceed through simple
operations, providing the siladifluoromethylated carbamates,
arenes, and alkynes, respectively. Especially, siladifluoro-
methylated arenes were exchanged to valuable difluoromethyl
*E-mail: mikami.k.ab@m.titech.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by a grant
program “Advanced Catalytic Transformation program for
Carbon utilization (ACT-C)” from the Japan Science and
Technology Agency (JST). We thank TOSOH F-TECH, INC.
for the gift of fluoroform (CF3H) and Ruppert−Prakash
Reagent (CF3TMS). These results have been in part reported
in the ACT-C second meeting (Koichi Mikami, June 5-6, 2013)
and 249th ACS National Symposium (Koichi Mikami, Denver,
Colorado (USA): March, 22-26, 2015).
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D
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Org. Lett. XXXX, XXX, XXX−XXX