Synthesis of Diverse Aromatic Ketones through C?F Cleavage of Trifluoromethyl Group

Article abstract of DOI:10.1002/chem.202001816

An efficient synthetic method of aromatic ketones through C?F cleavage of trifluoromethyl group is disclosed. The high functional group tolerance of the transformation and the remarkable stability of trifluoromethyl group in various reactions enabled mult

Full text of DOI:10.1002/chem.202001816

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Accepted Article
Accepted Article
Title: Synthesis of Diverse Aromatic Ketones through C–F Cleavage of
Trifluoromethyl Group
Authors: Mai Ikeda, Tsubasa Matsuzawa, Takamoto Morita, Takamitsu
Hosoya, and Suguru Yoshida
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To be cited as: Chem. Eur. J. 10.1002/chem.202001816
Link to VoR: https://doi.org/10.1002/chem.202001816
01/2020

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COMMUNICATION
Synthesis of Diverse Aromatic Ketones through C–F Cleavage of
Trifluoromethyl Group
Mai Ikeda, Tsubasa Matsuzawa, Takamoto Morita, Takamitsu Hosoya, and Suguru Yoshida*
Abstract: An efficient synthetic method of aromatic ketones through
C–F cleavage of trifluoromethyl group is disclosed. The high
functional group tolerance of the transformation and the remarkable
stability of trifluoromethyl group in various reactions enabled
multisubstituted aromatic ketone synthesis in an efficient route
involving useful transformations such as ortho-lithiation, aryne
chemistry, and cross-couplings.
a strong Lewis or Brønsted acid. On the basis of recent our study
for the mild C–F transformation,[6] we at first envisioned that an
arylation and carbonyl formation of the trifluoromethyl group of
benzotrifluorides
will
furnish
aromatic
ketones.
The
transformation of trifluoromethyl group as a robust C1 unit under
the mild reaction conditions would allow for an efficient synthetic
route involving useful transformations such as ortho-lithiation,
aryne chemistry, and cross-couplings. Considering the good
affinity between boron and fluorine and the gentle reactivity of
boron tribromide used in various natural product synthesis,[7] we
attempted a reaction between 4-methylbenzotrifluoride (1a) and
mesitylene (2a) using boron tribromide at 25 °C (Figure 1D). As a
result, we found that the reaction followed by adding methanol
provided diaryl ketone 3a in high yield through the cleavage of
three C–F bonds.[8] When water was used instead of methanol,
the desired ketone 3a was not obtained.
Aromatic ketones are of great importance in a wide range of
disciplines including photochemistry, materials chemistry,
pharmaceutical sciences, and chemical biology.[1] Despite
enormous efforts to develop facile synthetic methods of aromatic
ketones, it is not easy to prepare highly functionalized aromatic
ketones in a multi-step manner due to the electrophilic carbonyl
group. In particular, accessible ketones are quite limited in the
conventional Friedel–Crafts reaction owing to the harsh
conditions and the low functional group tolerance in the
preparation of reactive acyl chlorides (Figure 1A).[1] Recent
significant achievements have expanded the available aromatic
ketones by virtue of the significant accessibility of starting
materials and mild conditions.[2] For instance, a palladium-
catalyzed diaryl ketone synthesis using esters and arylboronic
acids developed by Newman, Houk, and coworkers enhanced the
accessibility of aromatic ketones (Figure 1B).[2d] However, a multi-
step synthesis involving these transformations toward highly
functionalized ketones still require protecting groups or functional
group transformations into the carbonyl group to avoid undesired
bond formations at the electrophilic carbonyl carbon. Thus, a
facile method to prepare aromatic ketones using a robust C1 unit
is expected to achieve the synthesis of highly functionalized
aromatic ketones in an efficient synthetic route involving reactive
intermediates such as carbanions. Herein, we describe an
efficient method to prepare aromatic ketones through C–F
cleavage of the trifluoromethyl group (Figure 1C).
A Conventinal ketone synthesis
H
O
O
Ar2
AlCl3
harsh conditions
limited scope
Cl
Ar1
Ar1
Ar2
✔
✔
labile C1 unit for the carbonyl group
transformations of functional groups,
protection, etc. for the multi-step synthesis
B
Cross-coupling approach
B
O
O
Ar2
OPh
Ar1
Ar1
Ar2
cat. Pd
✔
✔
limited scope
labile C1 unit for the carbonyl group
C
This work: ketone synthesis from benzotrifluoride derivatives
H
O
Ar2
CF3
Ar1
Ar1
Ar2
BBr3;
then, MeOH
Since trifluoromethyl group is a robust functional group in the
presence of a broad range of compounds such as acids or
nucleophiles, the C–F transformation of the trifluoromethyl group
is a challenging issue in synthetic organic chemistry.[3–6] The
synthesis of highly functionalized aromatic ketones from
benzotrifluorides is not easy owing to the harsh conditions using
✔
✔
broad scope
robust C1 unit for the carbonyl group
enabling an efficient synthetic route
through carbanion intermediates
D
Me
O
Me
MeOH
Me
Me
25 °C, 2 h
2a
Me
Me
Me
CF3
(5.0 equiv)
3a
84%
BBr3
(2.0 equiv)
CH2Cl2
Me
[*]
Ms. M. Ikeda, Mr. T. Matsuzawa, Dr. T. Morita, Prof. Dr. T. Hosoya,
Assoc. Prof. Dr. S. Yoshida
1a
H2O
3a
not detected
25 °C, 3 h
Laboratory of Chemical Bioscience, Institute of Biomaterials and
Bioengineering, Tokyo Medical and Dental University (TMDU)
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan)
E-mail: s-yoshida.cb@tmd.ac.jp
25 °C, 2 h
Figure 1. Ketone syntheses. (A) Conventional methods. (B) Ketone synthesis
from esters. (C) This work. (D) Initial attempts.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http ://dx.doi.org/10.1002/anie.xxxxxxxxx.
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groups, an advantage of this synthetic method was clearly shown.
For example, the ketone synthesis using CF3-substituted
benzo[b]thiophenes, prepared from CF3-substituted ketene
dithioacetal monoxide with triflic anhydride,[9] successfully
underwent to furnish 3f–3h in good to excellent yields leaving
reactive methylthio, iodo, silyl, and triflyloxy groups untouched.
On the other hand, transformations of the benzo[b]thiophene
having various functional groups under reported Lewis or
Brønsted acid conditions resulted in failure.[10]
A
H
Ar2
2
(5.0 equiv)
O
BBr3 (2.0 equiv)
CH2Cl2, 25 °C, 3 h;
CF3
Ar1
Ar1
Ar2
then, MeOH
25 °C, 2 h
1
3
B
O
Me
O
Me
Me
O
Me
MeO
Me
3b 82%
Me
Me
Me
A broad range of aromatic compounds were applicable to the
diaryl ketone synthesis (Figures 2A and 2C). For example,
2,3,4,5,6-pentamethylphenyl 4-tolyl ketone (3i) was efficiently
prepared by treatment of benzotrifluoride 1a and 1,2,3,4,5-
pentamethylbenzene with boron tribromide followed by addition of
methanol. In addition, the reactions of 1a with o-xylene,
cyclobutabenzene, and 3,3’,5,5’-tetramethylbiphenyl also took
place to afford the corresponding diaryl ketones 3j–3l in moderate
yields. Furthermore, 4-hydroxyphenyl 4-tolyl ketone (3m) was
synthesized from benzotrifluoride 1a and phenol with a modified
procedure.[8] It is worth noting that the synthesis of highly
functionalized benzo[b]thiophenes 3n–3p was accomplished by
Me
Me
X = Me (3c) 60%[a]
Cl (3d) 73%[a]
X
3e 55%
Me
Me
Me
Me
Me
Me
O
Me
O
Me
Me
O
SMe
SMe
S
3g quant.[b]
SMe
S
S
TfO
TfO
3f 79%[b]
I
3h 98%[b]
SiMe3
C
O
Me
O
O
Me
Me
Me
the
(triflyloxy)benzo[b]thiophene with boron tribromide followed by
adding phenol, N,N-dimethylaniline, and 1,3,5-
reaction
of
7-iodo-2-methylthio-3-trifluoromethyl-6-
Me
Me
Me
Me Me
Me
3j 47%
3i 76%
3k 34%
O
Me
trimethoxybenzene with methanol (Figure 2D).[11] Compared to
the defluoroarylation using aromatic compounds as a solvent
reported by Hu and coworkers,[5d] the broad scope is a benefit of
our method.
O
Me
Me
Me
Me
OH
3m 66%[c]
3l 37%
Me
D
O
HO
Et2N
MeO
MeO
BBr3 (2.0 equiv)
CH2Cl2, 25 °C, 3 h;
CF3
OR
Ar1
Ar1
OH
OMe
O
then, ROH
25 °C, 2 h
1
4
O
O
O
MeO
S
MeO
O
SMe
TfO
SMe
TfO
SMe
TfO
3o 55%[d]
SMe
O
O
O
S
S
S
S
TfO
OMe
OMe
HO
3p 40%[d]
I
I
I
I
3n
3n’
SMe
67%[d]
(3n:3n’ = 3:2)
Me
S
HO
4a 86%
4b 82%[a]
4c 88%
4d 88%[b]
MeO
O
Figure 2. Synthesis of diaryl ketones 3 from benzotrifluoride derivatives 1. See,
the Supporting Information for the structures of 1 and 2. (A) General scheme.
(B) Reactions between various benzotrifluoride derivatives 1 with 2a. (C)
Reactions between 1a with various arenes 3. (D) Synthesis of various
benzo[b]thiophenes 3n–3p. [a] Reaction time for the first step was 12 h. [b]
Reaction time for the first step was 21 h. [c] The procedure was changed as
follows: 1. 1 (1.0 equiv), BBr3 (2.0 equiv), CH2Cl2, 25 °C, 3 h; 2. 2 (5.0 equiv),
25 °C, 2 h; 3. MeOH, 25 °C, 2 h. [d] The procedure was changed as follows: 1.
1 (1.0 equiv), BBr3 (2.0 equiv), CH2Cl2, 25 °C, 21 h; 2. 2 (5.0 equiv), 25 °C, 2 h;
3. MeOH, 25 °C, 2 h.
MeO
MeO
O
O
SMe
4g 38%[b]
SMe
SMe
O
S
S
TfO
TfO
TfO
I
4e 90%[b]
4f 49%[b]
SiMe3
I
EtO
iPrO
O
S
O
O
O
SMe
SMe
SMe
S
S
TfO
TfO
TfO
4h 94%[b]
4i 93%[b]
4j 85%[b]
I
I
I
A wide range of diaryl ketones were synthesized from various
benzotrifluorides and aromatic compounds (Figures 2A and 2B).
Indeed, 4-anisyl mesityl ketone (3b) was obtained through the C–
F cleavage of 4-methoxybenzotrifluoride without demethylation of
the methoxy group. Ketones 3c and 3d were also prepared by
treating 4-trifluoromethylbiphenyl derivatives. The reaction using
bulky 2-methylbenzotrifluoride uneventfully took place to afford
mesityl 2-tolyl ketone (3e) in moderate yield. Since
benzo[b]thiophenes having a trifluoromethyl group participated in
synthesizing ketones 3f–3i without damaging various functional
Figure 3. Synthesis of esters from benzotrifluoride derivatives 1. See, the
Supporting Information for the structures of 1. [a] The procedure was changed
as follows: 1. 1 (1.0 equiv), BBr3 (2.0 equiv), CH2Cl2, 50 °C, 3 h (sealed tube);
2. MeOH, 50 °C, 2 h. [b] Reaction time for the first step was 21 h.
Various aromatic esters possessing functional groups were
also synthesized through the C–F cleavage (Figure 3). For
instance, esters 4a and 4b were efficiently prepared by treatment
of 4-methylbenzotrifluoride and 1-trifluoromethylnaphthalene,
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respectively, with boron tribromide followed by addition of
4B-c).[14] Addition of mesitylene (2a), boron tribromide, and
methanol to tribromide 5 in dichloromethane afforded ester 4a,
and diaryl ketone 3a was not detected (Figure 4B-d).[15] These
results in Figures 4A and 4B clearly showed that the synthesis of
diaryl ketone 3a was accomplished by the reaction between
tribromide 5 and mesitylene (2a) with an in situ generated
activator such as FnBBr(3-n). Thus, we postulated a reaction
mechanism shown in Figure 4C.[16] Firstly, a reaction between
benzotrifluoride 1a with boron tribromide provided tribromide 5
through the three-times defluorobromination. Then, transient
generation of acyl bromide I by the reaction of tribromide 5 with
methanol and Friedel–Crafts reaction between I and mesitylene
(2a) triggered by the in situ generated FnBBr(3-n) would furnish
diaryl ketone 3a (path a). Alternatively, the formation of
dibromomethylene IV through the activation of C–Br bond by
FnBBr(3-n) and subsequent transformation into the diaryl ketone 3a
is also possible (path b).
methanol.[12]
When
6-methoxy-3-
trifloromethylbenzo[b]thiophenes were used, esters 4c and 4d
were obtained via the C–F cleavage and demethylation. Similar
to the ketone synthesis, the good functional group tolerance
achieved the preparation of benzo[b]thiophene 4e or 4f having o-
iodo- or o-silylaryl triflate moiety. Benzo[b]furan-type ester 4g was
also synthesized in moderate yield. Furthermore, ester formation
using a range of alcohols, that is, ethanol, 2-propanol, and
cyclopentanol, took place smoothly to provide esters 4h–4j in high
yields without lacking iodo, triflyloxy, and methylthio groups.
A
2a (5.0 equiv)
BBr3 (2.0 equiv)
O
Me
CBr3
+ 2a
CD3OD
1a
CD2Cl2
25 °C, 3 h
25 °C, 2 h
Me
Me
Me
Me
5
3a
B
1a
2a (5.0 equiv)
BBr3
A
3a not detected + 5 82% (recovery)
3a 5% + 5 76% (recovery)
(2.0 equiv)
25 °C, 8 h;
then, isolation
CH2Cl2
25 °C, 3 h
CF3
CF3
Li
CF3
S
(b)
TsSTol
25 °C
LDA
THF
–78 °C
Me
2a (5.0 equiv)
BBr3 (2.0 equiv)
CBr3
(c)
Br
Br
Br
7 63%
6
V
B(OH)2
CH2Cl2
25 °C, 3 h
Me
cat. Pd(PPh3)4
Na2CO3
5 quant.
DME, H2O
80 °C
MeOH
25 °C, 2 h
2a (5.0 equiv)
BBr3 (2.0 equiv)
(a)
O
(d)
R = Me (8a)
Cl (8b)
R
3a not detected + 4a 86%
O
S
MeOH
CH2Cl2
25 °C, 3 h
CF3
Me
BBr3
OMe
4a quant.
CH2Cl2, 25 °C;
Me
S
Me
then,
MeOH,25 °C
R = Me (9a) quant.
Cl (9b) 81%
C
O
MeBr
HBr
R = Me (10a) 62%
Cl (10b) 50%
O
Me
R
R
p-Tol
p-Tol
Br
MeOH
2a
BBr3
FnBBr(3-n)
I
II
Me
B
path a
path b
Me
Me
1.
O
3a
5
Me
Me
1a
Me
Me
Me
13
Br
MeBr
HBr
N
Me3SiCH2MgCl
THF, –78 °C;
76%
Br Br
p-Tol Br
FnBBr(3-n)
Me
O
Me
O
cat. Pd [a]
Br Br
F
F
Me
p-Tol
III
Br
MeOH
Mes
KN(SiMe3)2
p-Tol
p-Tol
F
Me
3g
14
IV
BBr3
62%
2. NaI, Me3SiCl
MeCN, CH2Cl2
25 °C; 86%
n-octane
100 °C
Me
Me
SMe
Me
Me
S
S
11
Figure 4. Control experiments to clarify the reaction mechanism. (A) NMR
experiment. (B) Reactions using 4-(tribromomethyl)toluene (5). (C) Plausible
reaction mechanisms.
Me
Me
N
N3CH2C6H4-4-CO2Me
Me3SiCH2MgCl
THF, –78 °C
1. MeOTf, DME, 65°C
2. NaBPh4, cat. Pd2(dba)3, cat. SPhos
THF, 80 °C
Me
Me
Me
Me
To clarify the reaction mechanism of the diaryl ketone
synthesis involving the C–F cleavage, we then conducted a
reaction of benzotrifluoride 1a with boron tribromide in the
presence of mesitylene using dichloromethane-d2 as a solvent
(Figure 4A). As a result, we observed 4-(tribromomethyl)toluene
Me
O
Me
O
Me
O
MeO2C
Me
Me
N
SMe
Ph
SMe
12
60%
(single isomer)
Me
S
S
S
N
15
71%
VI
N
1
Me
with unreacted mesitylene (2a) in the H NMR analysis of the
resulting solution.[5c] Then, diaryl ketone 3a was observed by the
1H NMR analysis after an addition of methanol-d4 to the reaction
mixture. We then performed several control experiments using 4-
(tribromomethyl)toluene (5) prepared from benzotrifluoride 1a
with boron tribromide (Figure 4B). While methanolysis of 5
quantitatively afforded ester 4a (Figure 4B-a),[13] no direct reaction
of 5 with mesitylene (2a) occurred (Figure 4B-b). When tribromide
5 was treated with boron tribromide in the presence of mesitylene
(2a), only a small amount of diaryl ketone 3a was obtained (Figure
Figure 5. Multisubstituted aromatic ketone synthesis. (A) Synthesis of
thioxanthones. (B) Synthesis of benzo[b]thiophenes. [a] Pd = SingaCycle-A1.
See the Supporting Information for the details.
An advantage of the diaryl ketone synthesis using the robust
trifluoromethyl group as a C1 unit was showcased by the
thioxanthone synthesis[17] through carbanion intermediates
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