C?F Arylation of Polyfluorophenols by Means of Sigmatropic Dearomatization/Defluorination Sequence

Article abstract of DOI:10.1002/chem.202001158

Selective C?F arylation of polyfluorophenols with aryl sulfoxides has been accomplished by means of a sigmatropic dearomatization/defluorination sequence. This sequence consists of three processes: 1) interrupted Pummerer reaction to form S?O-tethered sulfonium salt; 2) C?C-forming [3,3] sigmatropic rearrangement with dearomatization; and 3) Zn-mediated defluorinative rearomatization. The present biaryl construction provides a facile access to polyfluorinated biaryls that is difficult to synthesize by other methods. The synthetic utility of the strategy is clearly demonstrated by the synthesis of a fluorinated analogue of Maxipost, a potassium channel modulator.

Full text of DOI:10.1002/chem.202001158

A Journal of
Accepted Article
Title: C–F Arylation of Polyfluorophenols by Means of Sigmatropic
Dearomatization/Defluorination Sequence
Authors: Koichi Okamoto, Keisuke Nogi, Jun Shimokawa, and Hideki
Yorimitsu
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To be cited as: Chem. Eur. J. 10.1002/chem.202001158
Link to VoR: http://dx.doi.org/10.1002/chem.202001158
Supported by

10.1002/chem.202001158
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COMMUNICATION
C–F Arylation of Polyfluorophenols by Means of Sigmatropic
Dearomatization/Defluorination Sequence
Koichi Okamoto, Keisuke Nogi, Jun Shimokawa, and Hideki Yorimitsu*
Abstract: Selective C–F arylation of polyfluorophenols with aryl
sulfoxides has been accomplished by means of a sigmatropic
dearomatization/defluorination sequence. This sequence consists of
three processes: (1) interrupted Pummerer reaction to form S–O-
tethered sulfonium salt, (2) C–C-forming [3,3] sigmatropic
rearrangement with dearomatization, and (3) Zn-mediated
defluorinative rearomatization. The present biaryl construction
provides a facile access to polyfluorinated biaryls that is difficult to
synthesize by other methods. The synthetic utility of the strategy is
clearly demonstrated by the synthesis of a fluorinated analogue of
Maxipost, a potassium channel modulator.
Then, C–C-bond forming charge-accelerated [3,3] sigmatropic
rearrangement occurs with dearomatization of the phenol ring to
afford dearomatized intermediate B.[12] Subsequent addition of Zn
induces reductive defluorination to form phenol C. Assisted by
rearomatization, the reductive defluorination proceeds with the
moderate reducing agent under mild reaction conditions. Finally,
addition of TFA promotes cyclization and elimination of
methanethiol to give desired fluorinated benzofurans.
We envisioned that this strategy is applicable to the C–F
arylation of polyfluorophenols by employing aryl sulfoxides
instead of KDM (Scheme 1b). In the presence of acid anhydride,
S–O-tethered sulfonium A' can be generated from
a
polyfluorophenol and an aryl sulfoxide (step a). Subsequent
sigmatropic rearrangement would generate dearomatized
intermediate B' (step b), which can be converted to the desired
biaryl via Zn-mediated defluorinative rearomatization (step c).
Although this reaction contains a challenging step: concomitant
dearomatization of two aromatic rings, we tackled to develop the
C–F arylation encouraged by our previous C–H arylation of
phenols with aryl sulfoxides.[12c] Herein, we report a novel
approach to C–F arylation of polyfluorophenols with aryl
sulfoxides via the sigmatropic dearomatization/defluorination
sequence.
An increasing attention to fluorinated molecules in the fields of
pharmaceuticals, agrochemicals, and optoelectronics has been
leading the development of diverse methods for the synthesis of
these molecules.[1–4] Among the present methods, selective and
controlled C–F transformations of polyfluorinated arenes of high
availability have been considered as a powerful strategy. The
divergence of such transformations has been expanded with the
aid of transition metals such as Pd and Ni.[3] However, due to the
strength of C–F bonds, highly electron-rich transition metals are
necessary, which confines functional group compatibility. In
addition, supply risk[5] and contamination issues[6] associated with
the use of precious transition metals should be concerned.
To address these concerns, development of transition-metal-
free methods other than conventional SNAr reactions[4] should be
in high demand. Especially, we focused on C–F arylation that
provides polyfluorinated biaryl structures of high value. In 1993,
Kobrina reported ortho-selective arylation of polyfluorophenols
although the use of toxic aryllead compounds would be
problematic.[7] Recently, Peshkov achieved C–F arylation of
polyfluorobenzonitriles with benzonitrile radical anions although
strongly reducing conditions (with Na in liq. NH3) are necessary to
generate the radical anions.[8] Further development of new,
complementary methods for selective C–F arylation without
transition metal should be desirable.
(a) Our previous work
SMe
Ar
F
SMe
OH
F
TFA
TFAA
O
F
Ar
KDM
+
Fn
SMe
then Zn powder
Fn
O
interrupted
Pummerer reaction
TFAA
cyclization
TFA
SMe
SMe
SMe
H
Ar
F
Ar
Ar
SMe
O
SMe
SMe
O
Zn
F
OH
Fn
Fn
defluorinative
rearomatization
Fn
[3,3] with
dearomatization
F
F
F
C
A
B
Recently,
we
have
demonstrated
a
sigmatropic
(b) This work
dearomatization/defluorination sequence as a new strategy for
F
X
TFAA
Zn powder
SMe
OH
selective C–F transformations of polyfluorophenols for annulative
O
+
SMe
OH
F
X
[9,10]
synthesis of fluorinated benzofurans (Scheme 1a).
In the
Fn
presence of trifluoroacetic anhydride (TFAA), polyfluorophenols
undergo interrupted Pummerer reaction[11] with ketene
dithioacetal monoxide (KDM) to form S–O-tethered sulfonium A.
F
Fn
interrupted
Pummerer reaction
step a
TFAA
X
X
SMe
O
SMe
O
Zn
H
F
[*]
K. Okamoto, Dr. K. Nogi, Prof. Dr. J. Shimokawa, Prof. Dr. H.
Yorimitsu
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo-ku, Kyoto, 606-8502 (Japan)
E-mail: yori@kuchem.kyoto-u.ac.jp
defluorinative
rearomatization
step c
[3,3] with
dearomatization
step b
F
F
F
Fn
Fn
A’
B’
Scheme 1. Sigmatropic dearomatization/defluorination sequence for selective
C–F transformations of polyfluorophenols.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.202001158
Chemistry - A European Journal
COMMUNICATION
X
yield of 3aa (Scheme 2a). This biaryl construction accommodates
a gram scale synthesis: 1.21 g (83%) of 3aa was obtained from
5.0 mmol of 1a. Instead of 2a, the reaction with 2,3,5,6-
tetrafluorophenol (2b) smoothly proceeded to afford 3ab in 82%
yield. Pentafluorophenol (2c) and 4-chloro-2,6-difluorophenol
(2d) also underwent the reaction to provide 3ac and 3ad,
respectively, in moderate yields. Of note, the reaction with
heptafluoro-2-naphthol (2e) took place at the C1 position in a
regioselective manner, resulting in formation of 3ae in 85% yield.
We then explored the reaction scope with respect to aryl
sulfoxides (Scheme 2b). Instead of benzothienyl sulfoxide 1a, 2-
benzofuryl and 2-indolyl sulfoxides 1b and 1c were also
applicable to the reaction to furnish 3ba and 3ca in 77% and 58%
yields, respectively. Unfortunately, 3-benzothienyl sulfoxide 1d
did not react with 2,6-difluorophenol (2a) to afford a complex
product mixture. On the other hand, with perfluoronaphthol 2e,
sulfoxide 1d smoothly underwent the reaction to provide biaryl
3de in 65% yield. The lower aromaticity of the naphthyl ring of 2e
would facilitate the doubly dearomatizing [3,3] sigmatropic
rearrangement. Instead of benzo-fused heteroaromatics,
monocyclic 2-thienyl, 2-furyl, and 2-pyrrolyl sulfoxides 1e–g also
underwent the reaction to afford the corresponding biaryls 3ee–
ge in good yields. Gratifyingly, the iodo group on thienyl sulfoxide
1h that is potentially reactive under transition metal catalysis was
well tolerated. In addition to heteroaryl sulfoxides, 2-naphthyl
sulfoxide 1i underwent the reaction to furnish 1,1'-binaphthyl 3ie
in 85% yield. Unfortunately, phenyl sulfoxide 1j was not applicable
to the reaction probably owing to the stronger aromaticity of the
benzene ring, and only 2e, 1j and the corresponding sulfide were
observed after the reaction. These imply that the weaker
aromaticity of heteroaryl and naphthyl sulfoxides than that of the
phenyl sulfoxide would be important for the sigmatropic
dearomatization step.
F
2.0 equiv TFAA
0.05 equiv TFA
5.0 equiv Zn powder
SMe
OH
O
OH
F
X
ArF
SMe +
MeCN 0.05 M
–40 ºC, 30 min
ArF
F
3
1
0.50 mmol
2
2.0 equiv
a) fluorophenols
S
S
S
SMe
SMe
SMe
OH
OH
OH
F
F
F
F
F
F
F
3ab: 82%
F
3ac: 61%
3aa: 82%, 83%[a]
S
S
SMe
OH
SMe
OH
F
F
F
F
Cl
F
F
3ad: 55%[b]
F
3ae: 85%
b) aryl sulfoxides
Ts
N
O
SMe
OH
SMe
SMe
OH
S
F
OH
F
F
F
3de: 65%
F
F
F
3ba: 77%
3ca: 58%[c]
F
Ts
N
S
O
SMe
SMe
SMe
OH
OH
OH
F
F
F
F
F
F
F
F
F
F
(a)
S
F
OH
F
F
F
SMe
OH
F
F
F
optimized
conditions
SMe
S
OH
F
F
F
+
1a
+
3ge: 67%
3ee: 70%
3fe: 78%
I
2f
2.0 equiv
S
SMe
SMe
OH
SMe
OH
3af: 52%
3aa: 40%
OH
F
F
F
F
F
(b)
S
F
Cl
F
F
SMe
OH
F
F
optimized
conditions
OH
Cl
F
S
F
+
1a
+
SMe
F
F
F
F
F
F
Cl
3ie: 85%[d]
3je: 0%
3he: 53%
2g
2.0 equiv
Scheme 2. Substrate scope. [a] 5 mmol scale. [b] 0.10 equiv of TFA was used.
[c] 3.0 equiv TFAA was used. [d] 1.5 equiv of 1i and 1.0 equiv of 2e were used.
3ag: 19%
4: 8%
Scheme 3. Reactions with 2-fluorophenol and with 2,6-dichlorophenol.
With benzothienyl sulfoxide 1a and 2,6-difluorophenol (2a) as
model substrates, we optimized the reaction conditions based on
our previous defluorinative transformation.[9] Optimization study
revealed that TFAA (2.0 equiv) and Zn powder (5.0 equiv) are
found to be optimal as an activator and as a reductant,
respectively.[13] Moreover, an addition of a small amount of
trifluoroacetic acid (TFA) was crucial for the reproducibility of the
reaction. In the presence of these reagents, the reaction of 1a with
2a smoothly proceeded in MeCN at –40 °C to provide an 82%
To gain insight into the reaction mechanism, especially for the
[3,3] sigmatropic rearrangement, we performed the reaction with
2-fluorophenol (2f). The reaction yielded
a
mixture of
defluorinated product 3af and deprotonated product 3aa in a ratio
of 1.3:1 (Scheme 3a). This non-regioselective sigmatropic
rearrangement is consistent with our previous report on the
reaction of KDM with 2-fluorophenol.[9] The lack of the
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10.1002/chem.202001158
Chemistry - A European Journal
COMMUNICATION
regioselectivity highlights the necessity of 2,6-difluorophenol (2a)
for the selective synthesis of fluorinated biaryl 3aa.
phenolic hydroxy moiety and deprotection of the Boc group were
conducted in one pot to give 2-sulfanylindole 6 in a satisfactory
yield. Finally, treatment of 6 with Selectfluor promoted C3-
fluorination with concomitant dearomatization,[18] and subsequent
in situ hydrolysis of the iminium intermediate afforded desired
fluorinated rac-Maxipost 7 in 79% yield.
In conclusion, we have developed C–F arylation of
polyfluorophenols with aryl sulfoxides based on the sigmatropic
dearomatization/defluorination sequence. The reaction proceeds
under mild conditions, and various fluorinated biaryls could be
synthesized. We also achieved the synthesis of a fluorinated
analogue of Maxipost, which demonstrates the synthetic utility of
the biaryl construction presented herein.
Instead of the defluorinative reaction, a dechlorinative variant by
means of 2,6-dichlorophenol (2g) was not successful, and only a
19% yield of desired biaryl 3ag was obtained accompanied by 2-
benzothienyl methyl sulfide (4) and several byproducts (Scheme
3b). The formation of 4 suggests that the chloro substituent bigger
than fluoro atom would hamper the sigmatropic rearrangement,
which results in reductive decomposition of the sulfonium A' to 4.
In addition to the Zn-mediated defluorination, the dearomatized
intermediates generated in situ can be involved in 1,2-aryl
migration leading to non-trivial meta selective arylation of
phenol.[14,15] Treatment of a mixture of 1a and 2a with TFAA to
generate dearomatized intermediate like B' followed by an
addition of BF3·Et2O induced 1,2-aryl migration via D to afford 3-
aryl-2,6-difluorophenol 5aa along with a trace amount of C4-
arylated isomer 5aa' (Scheme 4a). Similarly, 2a underwent the
meta-arylation with benzofuryl sulfoxide 1b to provide 5ba in 41%
yield without detectable formation of the corresponding para-
arylated product 5ba' (Scheme 4b). Unfortunately, indolyl
sulfoxide 1c gave rather complex mixture containing a small
amount of the desired meta-arylation product.
H
N
H
N
F3C
F3C
commercially
available
O
F
OMe
1. Boc2O, DMAP, MeCN, rt
2. LiTMP, THF, –78 ºC
then MeSSO2Me, rt
Maxipost
F3C
Cl
3. mCPBA, CH2Cl2, rt
2.0 equiv 2d
Boc
N
3.0 equiv TFAA
0.20 equiv TFA
5.0 equiv Zn powder
2.0 equiv TFAA
MeCN 0.1 M
–20 ºC, 15 min
SMe
F
Boc
F
S
SMe
OH
O
N
F3C
1a
+
OH
F
SMe
OH
F
a)
+
MeCN 0.05 M
–40 ºC, 30 min
then
1.0 equiv BF3•Et2O
–20 ºC, 3 h
2a
1.5 equiv
1k
Ar
F
5aa
5aa’
3kd: 82%
72% (>20:1)
Cl
S
H
N
F3C
SMe
1.1 equiv MeI
3.0 equiv K2CO3
MeCN, rt, 12 h
SMe
OMe
F
O
BF3
F
then MeOH
50 ºC, 2 h
F
D
H
N
Cl
6: 82%
F3C
O
O
O
2.0 equiv TFAA
MeCN 0.1 M
–40 ºC, 15 min
SMe
1b
SMe
F
O
F
5.0 equiv Selectfluor
OMe
OH
b)
+
MeCN/H2O = 1/1
60 ºC, 4 h
F
then
1.0 equiv BF3•Et2O
–40 ºC, 6 h
F
7: 79%
OH
F
Cl
5ba: 41%
F
1.5 equiv
Scheme 5. Synthesis of fluorinated analogue of Maxipost 7.
2a
Scheme 4. meta-Arylation of 2,6-difluorophenol via 1,2-aryl migration from
dearomatized intermediate.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP16H04109, JP18H04254, JP18H04409, JP19H00895, and
JP18K14212 as well as JST CREST Grant Number
JPMJCR19R4. H.Y. thanks The Mitsubishi Foundation for
financial support.
Finally, to demonstrate the synthetic utility of the present
defluorinative coupling, we attempted to synthesize a potentially
useful fluorinated molecule, a fluorinated analogue of Maxipost[16]
known as a competent potassium channel modulator (Scheme 6).
Boc-protected indolyl sulfoxide 1k was prepared in three steps
from commercially available 6-(trifluoromethyl)indole. Under
slightly modified conditions, indolyl sulfoxide 1k successfully
underwent the biaryl construction with 2d to afford 3kd in 82%
yield. The choice of a Boc group for N-protection was important:
the N-Ts analogue failed to efficiently deliver the corresponding
biaryl[17] possibly because strong electron-withdrawal hampered
the sigmatropic rearrangement. Subsequent methylation of the
Keywords: biaryls · C-F transformation· interrupted Pummerer
reaction · sigmatropic rearrangement
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COMMUNICATION
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10.1002/chem.202001158
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
K. Okamoto, K. Nogi, J. Shimokawa, H.
Yorimitsu*
X
X
F
SMe
OH
SMe
O
(CF3CO)2O
Zn powder
O
X
OH
F
SMe
via
ArF
F
+
Page No. – Page No.
ArF
H
F
F
C–F Arylation of Polyfluorophenols
by Means of Sigmatropic
Dearomatization/Defluorination
Sequence
Selective C–F arylation of polyfluorophenols with aryl sulfoxides has been
accomplished by means of a sigmatropic dearomatization/defluorination sequence:
interrupted Pummerer reaction, [3,3] sigmatropic rearrangement with
dearomatization, and Zn-mediated defluorinative rearomatization. The utility of the
strategy is demonstrated by the synthesis of a fluorinated analogue of Maxipost.
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