Efficient Synthesis of α-Trifluoromethyl Carboxylic Acids and Esters through Fluorocarboxylation of gem-Difluoroalkenes

Article abstract of DOI:10.1002/anie.201902779

A facile synthetic procedure for the preparation of α-trifluoromethyl carboxylic acids and esters was achieved through multicomponent coupling reactions between gem-difluoroalkenes, cesium fluoride, and carbon dioxide. The products were generated in moderate to excellent yields, and the synthetic utility of this method was demonstrated through the preparation of trifluoromethylated versions of popular nonsteroidal anti-inflammatory drugs (NSAIDs).

Full text of DOI:10.1002/anie.201902779

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Accepted Article
Title: Efficient Synthesis of α-Trifluoromethyl Carboxylic Acids and
Esters via Fluorocarboxylation of gem-Difluoroalkenes
Authors: Woo-Jin Yoo, Junpei Kondo, José A Rodríguez-Santamaría,
Thanh Nguyen, and Shu Kobayashi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201902779
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10.1002/anie.201902779
Angewandte Chemie International Edition
COMMUNICATION
a
Efficient Synthesis of -Trifluoromethyl Carboxylic Acids and
Esters via Fluorocarboxylation of gem-Difluoroalkenes
Woo-Jin Yoo,*[a] Junpei Kondo,[b] José A. Rodríguez-Santamaría,[b] Thanh V. Q. Nguyen,[b] and Shū
Kobayashi*[a,b]
Dedication ((optional))
CO2X
hydrolysis
Abstract: A facile synthetic procedure for the preparation of a-
trifluoromethyl carboxylic acids and esters was achieved through
multi-component coupling reactions between gem-difluoroalkenes,
cesium fluoride, and carbon dioxide.
R
R
R
CF3
path a
CO2H
CF3
CHO
fluorocarboxylation
oxidation
path b
R
CF2
path d
R
CF3
The introduction of fluorine into biologically active molecules has
emerged as a key strategy in the discovery of pharmaceuticals
and agrochemicals since organofluorine compounds often
possess improved metabolic stability, increased cell membrane
permeability and/or enhanced binding properties compared to its
non-fluorinated counterparts.[1] An important privileged fluoroalkyl
group is the trifluoromethyl (CF3) moiety, and numerous synthetic
protocols that employ either nucleophilic or electrophilic sources
of CF3 have been disclosed for the synthesis of CF3-containing
molecules.[2] Among them, a-CF3 carboxylic acids are of interest
since these class of organofluorines have been studied as
bioactive compounds[3] and have served as versatile building
blocks for the synthesis of a variety of complex trifluoromethyl
molecules.[4] Typically, a-CF3 carboxylic acids are obtained from
their related carbonyl counterparts, such as esters and amides
(Scheme 1, path a) or aldehydes (path b), which in turn were
prepared through trifluoromethylation of enolates,[5] aldehydes,[6]
electrochemical
carboxylation
This work
Br
path c
CF3
Scheme 1. Synthesis of a-trifluoromethyl carboxylic acids.
1,1-Difluoroalkenes are versatile intermediates for the
preparation of complex organofluoro compounds, and it was
found that these substrates could undergo regioselective
nucleophilic fluorination with fluoride sources to generate the key
a-CF3 radical or anionic intermediates for the synthesis of various
organofluorine compounds.[12] We hypothesized that these
intermediates could be intercepted by CO2 and would lead to an
effective synthetic method for the preparation of a-CF3 carboxylic
acids (path d). Although carboxylation reactions of stabilized sp3-
hybridized carbanions are challenging, due to facile
decarboxylation of the carboxylate intermediate,[13] nevertheless
and
diazo
esters,[7]
decarboxyalkyation-fluorination
of
malonates,[8] or hydrogenation of fluorinated precursors.[9]
However, these synthetic methods suffer from several drawbacks,
such as long synthetic sequences, the use of rare transition metal
catalysts, and/or the use of expensive electrophilic fluorinating
reagents.
Harnessing carbon dioxide (CO2) as an abundant and
renewable chemical feedstock for the synthesis of value-added
organic compounds is an area of significant interest,[10] and it was
shown that a-CF3 benzyl bromides could undergo
electrochemical carboxylation to a-CF3 carboxylic acids (path
c).[11] However, several synthetic procedures are needed to
access the fluorinated starting material, which limits the synthetic
utility of this process.
we investigated and found
a simple and straightforward
procedure to prepare a-CF3 carboxylic acids via multi-component
fluorocarboxylation reactions between gem-difluoroalkenes,
cesium fluoride, and CO2.[14]
We began our investigations by examining the
fluorocarboxylation of gem-difluorostyrene derivative 1a with
cesium fluoride and CO2 (Table 1). It was found that when
relatively non-polar solvents were utilized, the nucleophilic
fluorination of 1a with CsF hardly proceeded (entry 1-2). On the
other hand, most polar aprotic solvents enabled the formation of
the anticipated a-CF3 carbanion, but the carboxylation of this
intermediate hardly proceeded and the protonated substrate 2a
was the major product (entries 3-7). Fortunately, when DMSO
was employed as a solvent, the fluorocarboxylation proceeded
well to afford 3a as the major product (entry 8). In order to promote
the carboxylation process further, it was found that by conducting
the multi-component reaction under pressurized CO2 conditions
further improved the yield of 3a and completely suppressed the
formation of the protonated product 2a (entry 9).
With the optimized conditions in hand, the substrate scope of
the fluorocarboxylation reaction of 1-aryl-2,2-difluoroalkenes 1a-
u with cesium fluoride and CO2 was examined (Scheme 2). It
should be noted that during the course of isolating 3a, it was found
that 3a was unstable and was prone to decarboxylation. Therefore,
the crude carboxylic acid 3a was converted to the corresponding
methyl ester 4a with trimethylsilyldiazomethane prior to
[a]
Dr. W.-J. Yoo, Prof. Dr. S. Kobayashi
Green & Sustainable Chemistry Cooperation Laboratory
Graduate School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: wyoo@chem.s.u-tokyo.ac.jp; shu_kobayashi@chem.s.u-
tokyo.ac.jp
[b]
J. Kondo, J. A. Rodríguez-Santamaría, Dr. T. V. Q. Nguyen, Prof.
Dr. S. Kobayashi
Department of Chemistry, School of Science, The University of
Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201902779
Angewandte Chemie International Edition
COMMUNICATION
CO2R2
CF3
Table 1. Optimization studies for the fluorocarboxylation of activated gem-
difluorostyrene 1a.[a]
F
R1
R1
CsF (3 equiv), CO2 (20 atm)
F
R
DMSO
F
R2 = H, 3h-n, 3q-u
R2 = Me, 4a-g, 4o-p
1a-t
CF3
F
CsF (3 equiv), CO2 (1 atm)
solvent, 30 °C, 18 h
MeO2C
MeO2C
CO2Me
CF3
CO2Me
CF3
1a
R = H (2a), CO2H (3a)
CO2Me
CF3
Entry
Solvent
MePh
THF
Conv. [%][b]
Yield 2a [%][b]
Yield 3a [%][b]
MeO
Et2N
NC
O
O
1
8
<5
<5
25
20
32
47
52
16
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
7
4a, 79%
4b, 86%
4c, 72%
(30 °C, 1 h)
(30 °C, 18 h)
(30 °C, 18 h)
2
10
25
20
48
58
60
93
91
CO2Me
CO2Me
CO2Me
3
MeCN
acetone
HMPA
DMA
CF3
CF3
CF3
F3C
TsO
tBu
4
Cl
Br
4d, 78%
(30 °C, 18 h)
4e, 86%
4f, 87%
(30 °C, 18 h)
5
(30 °C, 18 h)
CO2Me
CF3
CO2H
CO2H
6
CF3
CF3
7
DMF
7
Me
4g, 93%
(30 °C, 18 h)
3h, 87%
3i, 74%
(60 °C, 18 h)
8
DMSO
DMSO
72
(30 °C, 18 h)
9[c]
84
CO2H
CF3
CO2H
CF3
CO2H
MeO
CF3
[a] Reaction conditions: difluorostyrene 1a (0.25 mmol) and CsF (0.75 mmol)
in solvent (1 mL) under a balloon of CO2 at 30 °C for 18 h. [b] Yields of 2a and
3a were determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as
an internal standard. [c] Under 20 atm of CO2.
MeO
3j, 70%
3k, 59%
(60 °C, 18 h)
3l, 97%
(30 °C, 18 h)
(60 °C, 18 h)
CO2Me
CF3
CO2H
CF3
OMe CO2H
CF3
MeO
MeO
N
Ac
purification. Activated difluoroalkenes 1b-g were subjected to the
optimized conditions, and good to excellent yields of the desired
methyl esters 4b-g were obtained. In case of the nitrile substituted
alkene 1c, the reaction was conducted for only 1 h due to the
formation of undesired side products. Although the generation
and applications of a-CF3 anions, derived from unactivated gem-
difluoroalkenes and CsF, for nucleophilic substitution and addition
reactions was not reported,[12c] it was found that by increasing the
reaction temperature to 60 °C, 1-aryl-2,2-alkenes 1i-k and 1m-n
underwent fluorocarboxylation smoothly to afford a-CF3
carboxylic acids 3i-k and 3m-n in moderate to good yields. In
these cases, the carboxylic acids did not readily suffer from
decarboxylation, presumably due to the fact that the unactivated
aryl substituents would destabilize the carbanion intermediates.
As for meta-methoxybenzyl substituted difluoroalkene 1l, the
reaction could be conducted at 30 °C since the alkene was slightly
activated by the ether substituent to afford carboxylic acid 3l in an
excellent yield. Heteroaromatic gem-difluoroalkenes 1o-p, could
also undergo fluorocarboxylation to generate a-CF3 methyl esters
4o-p in moderate yields. Since the incorporation of fluorine atoms
into active pharmaceutical agents can alter its biological
properties, the concise syntheses of CF3-varients of nonsteroidal
anti-inflammatory drugs (NSAIDs), such as ibuprofen 3q,
fenoprofen 3r, ketoprofen 3s, flurbiprofen 3t, and naproxen 3u,
were achieved in good to excellent yields through this multi-
component carboxylation reaction. Furthermore, to demonstrate
the synthetic utility of this process, gram-scale fluorocarboxylation
of gem-difluoroalkene 1r (1.03 g) led to 3r in 97% yield. Finally,
non-aryl difluoroalkenes were investigated, and while alkenyl
3m, 73%
(60 °C, 18 h)
3n, 75%
(60 °C, 18 h)
4o, 63%
(30 °C, 18 h)
CO2H
CF3
CO2H
CO2Me
PhO
CF3
S
CF3
4p, 73%
(30 °C, 18 h)
3q, 73%
(60 °C, 18 h)
3r, 95%
(30 °C, 18 h)
CO2H
CF3
CO2H
CF3
O
CO2H
CF3
F
Ph
Ph
MeO
3s, 99%
(30 °C, 18 h)
3t, 91%
(30 °C, 18 h)
3u, 94%
(30 °C, 18 h)
Scheme 2. Substrate scope for the fluorocarboxylation of gem-difluoroalkenes
1a-u. Reaction conditions: gem-difluoroalkenes 1a-u (0.50 mmol) and CsF (1.5
mmol) in DMSO (2 mL) in an autoclave pressurized with CO2 (20 atm) at the
indicated times and temperature. Esterification was conducted with crude
carboxylic acids 3a-g and 3o-p with TMSCH2N2 (0.6 mmol) in MePh (4.5 mL)
and MeOH (1.5 mL) for 1 h.
substituted olefin 1v could undergo selective 1,2-
fluorocarboxylation to provide 4v in a moderate yield, alkyl
substituted alkene 1w could not, due to the difficulty of generating
the key a-CF3 carbanion intermediate (Scheme 3). In addition, the
application of the fluorocarboxylation conditions to alkynyl
substituted fluoroalkene 1x led to a complex reaction mixture,
presumably due to the instability of the carbanion intermediate.
In conclusion, we developed a facile multi-component
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10.1002/anie.201902779
Angewandte Chemie International Edition
COMMUNICATION
CO2Me
CF3
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F
CsF (3 equiv)
CO2 (20 atm)
DMSO, 30 °C, 18 h
TMSCH2N2 (1.2 equiv)
MePh:MeOH, rt, 1 h
Ph
F
Ph
1v (alkene)
1w (alkane)
1x (alkyne)
4v, 59%
4w, N.D.
4x, N.D.
Scheme 3. Fluorocarboxylation of non-aryl-substituted gem-difluoroalkenes.
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to access a wide variety of a-CF3 carboxylic acids and esters in
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decarboxylation and required conversion to a more stable ester
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through the synthesis of CF3-derivatives of well-known NSAIDs.
It should be noted that the above described synthetic procedures
are quite simple and CO2 could be directly utilized as a convenient
C1 carbon feedstock.
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This work was partially supported by Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), Global COE Program, The University of Tokyo, MEXT,
Japan, the Japan Science and Technology Agency (JST), and
Japan Agency for Medical Research and Development (AMED).
Keywords: carbon dioxide • cesium fluoride • gem-
difluoroalkenes • carboxylic acids • fluorination
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Layout 2:
COMMUNICATION
CO2R2
W.-J. Yoo,* J. Kondo, J. A. Rodríguez-
Santamaría, T. V. Q. Nguyen, S.
Kobayashi*
acid-base extraction
or
F
F
R1
R1
CsF (3 equiv)
CO2 (20 atm)
DMSO
TMSCH2N2 (1.2 equiv)
MePh:MeOH, rt, 1 h
F
F
F
R1 = EDG, R2 = H
R1 = EWG, R2 = Me
•
•
22 examples, 59% to 99%.
used to prepare CF3-varients of NSAIDs.
Page No. – Page No.
Efficient Synthesis of -
a
Trifluoromethyl Carboxylic Acids and
Esters via Fluorocarboxylation of
gem-Difluoroalkenes
Three-component coupling reactions of gem-difluoroalkenes with cesium fluoride
and carbon dioxide affords a-trifluoromethyl carboxylic acids and esters in
moderate to excellent yields. The synthetic utility of this methodology was
demonstrated through the preparation of trifluoromethylated versions of popular
nonsteroidal anti-inflammatory drugs (NSAIDs).
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