Catalyst-Free Decarboxylative Fluorination of Tertiary β-Keto Carboxylic Acids

Article abstract of DOI:10.1055/s-0037-1611019

Decarboxylative fluorination of tertiary β-keto carboxylic acids was performed using an electrophilic fluorinating reagent. The reaction proceeded in the absence of a catalyst or base to yield the corresponding α-fluoroketones with tertiary fluorocarbons in good to high yields. Considering that the α-fluorination of asymmetrical ketones often causes problems with the regioselectivity between the α- and α′-positions, this method could be a good alternative to the α-fluorination of simple ketones for the synthesis of tertiary fluoroketones.

Full text of DOI:10.1055/s-0037-1611019

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
M. Katada et al.
Letter
Synlett
Catalyst-Free Decarboxylative Fluorination of Tertiary β-Keto
Carboxylic Acids
Misaki Katada
O
O
Cl
N
Kazumasa Kitahara
Seiji Iwasa
CO2H
R2 R3
1 = alkyl, aryl
F
+
R1
R1
+
N
– CO2
+
R2 R3
–
F
2BF4
Kazutaka Shibatomi*
0
0
0
0-
0
0
0
1-6
3
6
8-4
8
2
3
R
14 examples
56–93% yield
R2, R3 = alkyl, allyl, benzyl
Department of Environmental and Life Sciences, Toyohashi
University of Technology, 1-1 Hibarigaoka, Tempaku-cho,
Toyohashi 441-8580, Japan
easily accessible to various tertiary fluorides
catalyst-free reaction
shiba@ens.tut.ac.jp
Received: 21.08.2018
a) Electrophilic fluorination of simple ketones
Accepted after revision: 17.09.2018
Published online: 16.10.2018
DOI: 10.1055/s-0037-1611019; Art ID: st-2018-u0537-l
O
O
O
[F+]
R2
R3
R1
R2
R1
R2
R1
+
R3
Involving a difficulty in regioselection
F
R3
F
Abstract Decarboxylative fluorination of tertiary β-keto carboxylic
acids was performed using an electrophilic fluorinating reagent. The re-
action proceeded in the absence of a catalyst or base to yield the corre-
sponding α-fluoroketones with tertiary fluorocarbons in good to high
yields. Considering that the α-fluorination of asymmetrical ketones
often causes problems with the regioselectivity between the α- and α′-
positions, this method could be a good alternative to the α-fluorination
of simple ketones for the synthesis of tertiary fluoroketones.
b) Decarboxylative fluorination of β-keto carboxylic acids
O
O
[F+]
R2
R3
R1
CO2H
R2 R3
R1
– CO2
F
Easily accessible to α-fluoroketones with a tertiary fluorocarbon
Key words fluorination, decarboxylation, α-fluoroketones, noncata-
Scheme 1 Synthetic methods to α-fluoroketones
lytic reaction, tertiary fluorides
Fluorinated organic compounds have attracted a great
deal of attention in the field of medicinal chemistry.1 There-
fore, the development of an efficient method to synthesize
organofluorides, especially tertiary fluorides, is highly re-
quired.2 Generally, electrophilic fluorination of α-branched
carbonyl compounds has proved to be a useful method for
the synthesis of tertiary fluorides.3 However, the regioselec-
tivity between two different α-carbons remains an inher-
ent problem in the fluorination of asymmetrical ketones,
except in the case of 1,3-dicarbonyl compounds (Scheme 1,
a).
β-Oxocarboxylic acids are known to easily undergo de-
carboxylation.4 The application of this property to decar-
boxylative functionalizations, including fluorination reac-
tions, has been intensively studied in recent years.5–8 For
example, in 2015, Deng and coworkers reported the base-
mediated decarboxylative fluorination of β-keto carboxylic
acids to form α-fluoroketones using Selectfluor as a fluori-
nating reagent.6a Later, they successfully performed a decar-
boxylative difluorination of β-keto carboxylic acids to yield
α,α-difluoroketones in the absence of catalyst.6b Additional-
ly, Hu and coworkers reported the decarboxylative fluorina-
tion of β-keto carboxylic acids with N-fluorobenzenesul-
fonimide (NFSI).7 Nevertheless, in most of these studies,
primary and secondary carboxylic acids have been em-
ployed, no successful example with tertiary carboxylic acids
has been reported. Therefore, we were interested in the re-
activity of tertiary β-keto acids in decarboxylative fluorina-
tion.
Recently, our research group demonstrated the first
enantioselective decarboxylative chlorination of β-keto
carboxylic acids using a BINOL-derived chiral primary
amine catalyst.8,9 Notably, the reaction was applicable to
tertiary carboxylic acids, which yielded the corresponding
tertiary α-chloroketones with high enantioselectivity. Addi-
tionally, in our continuous study on the method, we discov-
ered that the decarboxylative fluorination of tertiary β-keto
carboxylic acids proceeds smoothly even in the absence of
any catalyst or base. Hence, this procedure allows for the
formation of a variety of tertiary fluorides from easily avail-
able β-keto carboxylic acids, while simultaneously avoiding
the problem of regioselectivity (Scheme 1, b).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
M. Katada et al.
Letter
Synlett
Based on our previous results, in this study we used
tetralone-derived tertiary β-keto carboxylic acid (1a) as a
model substrate and treated it with 3.0 equiv NFSI in the
presence of 30 mol% quinuclidine, which was employed as a
base catalyst. The reaction proceeded slowly to give the de-
sired product (2a) in poor yield, along with protonated
product 3a (Table 1, entry 1). The screening of several base
reagents, including both organic and inorganic bases, did
not improve the yield of 2a significantly (Table 1, entries 2–
6). However, the reaction proceeded even in the absence of
a base to give products 2a and 3a (Table 1, entries 7 and 8).
Therefore, we tested different reaction solvents that would
potentially improve the chemoselectivity of the noncatalyt-
ic reaction (Table 1, entries 9–14). As a result, we found that
the use of DMF as a solvent allowed for the formation of
fluorinated product 2a in good yield, while suppressing the
generation of 3a (Table 1, entry 14). In addition, Selectfluor
showed a slightly better reactivity than NFSI, whereas the
use of N-fluoro-2,6-dichloropyridium salt F1 gave only
trace amount of fluorinated product (Table 1, entries 15 and
16). Moreover, the chemoselectivity of the reaction did not
diminish even when the amount of Selectfluor was reduced
to 1.5 equiv (Table 1, entry 17).
After obtaining the optimized reaction conditions, we
examined the substrate scope of the decarboxylative fluori-
nation.10 As summarized in Table 2, aromatic β-keto car-
boxylic acids 1a–h were successfully converted into the
corresponding α-fluoroketones 2a–h in good to high
yields.11 Furthermore, aliphatic β-keto carboxylic acids 1i–
n, which have acidic hydrogen atoms at the α′-position, also
afforded the desired tertiary fluorides 2i–n in good yields.
The reaction proceeded smoothly with both cyclic and acy-
clic substrates. In order to suppress the generation of pro-
tonated products 3, 3.0 equiv of Selectfluor was employed
Table 1 Optimization of the Reaction Conditionsa
O
O
O
CO2H
H
F
[F+] (3 equiv)
Me
Me
Me
+
r.t.
– CO2
1a
2a
3a
[F+] : electrophilic fluorination reagent
–
Cl
O
O O O
BF4
Cl
N
S
S
+
Ph
N
F
Ph
N
Cl
N+
+
–
2BF4
F
F
Selectfluor
NFSI
F1
Entry
[F+]
NFSI
Base (mol%)
Solvent
Time (h)
Yield of 2a (%)b
Yield of 3a (%)b
1
2
quinuclidine (30)
i-Pr2NEt (30)
2,6-lutidine (30)
PhCH2NH2 (30)
DMAP (30)
Cs2CO3 (300)
none
toluene
toluene
toluene
toluene
toluene
DMF
5
5
15
29
26
21
22
54
19
27
39
39
47
17
6
23
20
21
27
12
34
27
62
6
NFSI
3
NFSI
5
4
NFSI
5
5
NFSI
5
6
NFSI
24
5
7
NFSI
toluene
toluene
CH3CN
MeOH
CH2Cl2
THF
8
NFSI
none
24
24
24
24
24
24
24
24
24
24
9
NFSI
none
10
11
12
13
14
15
16
17c
NFSI
none
25
27
8
NFSI
none
NFSI
none
NFSI
none
DMSO
DMF
85
<1
90
2
NFSI
none
82
<1
88
86
F1
none
DMF
Selectfluor
Selectfluor
none
DMF
none
DMF
4
a Reactions were carried out at room temperature using 1a and 3.0 equiv of the fluorinating reagent.
b Isolated yield.
c 1.5 equiv of Selectfluor was applied.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
M. Katada et al.
Letter
Synlett
in some reactions. As mentioned above, the synthesis of
tertiary α-fluoroketones (2i–n) from simple ketones often
causes inherent problems with the regioselectivity
(Scheme 1, a). Therefore, we believe that our method would
be an efficient alternative for the synthesis of highly substi-
tuted α-fluoroketones.
acids suggests that the reaction proceeded via an electro-
philic fluorination of the enol intermediate, which was gen-
erated from the decarboxylation of 2 (Scheme 2, b).
a) Reaction with secondary carboxylic acids
O
O
O
O
[F+]
CO2H
F
–
R1
R1
O
R1
base
– CO2
R2
F
Table 2 Substrate Scopea
R2
R2
O
O
b) Reaction with tertiary carboxylic acids
OH
Selectfluor (1.5 equiv)
CO2H
R2 R3
F
R1
R1
O
O
DMF, r.t.
– CO2
R2 R3
[F+]
CO2H
R2 R3
R3
F
R1
R1
R1
1
2
– CO2
R2 R3
R2
Entry
Product
Time (h) Yield (%)b
Scheme 2 Reaction pathways
O
F
1c
2
2b R = allyl
2c R = benzyl
48
24
81
72
R
In conclusion, herein we demonstrated that the decar-
boxylative fluorination of tertiary β-keto carboxylic acids
with Selectfluor proceeded in the absence of a catalyst or
additive. The reaction yielded the corresponding α-fluoro-
ketones with tertiary fluorocarbons in good to high yields.
Considering the fact that it has hitherto been a challenge to
introduce a fluorine atom to the α-position of asymmetric
ketones with high regioselectivity, we believe that this
method would be useful in the synthesis of tertiary fluoro-
ketones.
O
3
2d X = H
2e X = OMe
2f X = Br
24
19
48
80
85
72
F
4
5c
Me
X
O
F
Me
6
2g
32
93
O
R
7
2h R = Ph
2i R = Me
2j R = Et
24
24
42
92
81
86
Funding Information
F
8
9c
Bn Bn
This study was supported by the Grants-in-Aid for Scientific Research
(B) (18H01974), the Grant-in-Aid for Research Fellow of JSPS (No.
18J12369), and the Tatematsu Foundation.()
O
F
10c
11c
2k
2l
24
51
56
89
Et
Supporting Information
O
Supporting information for this article is available online at
F
https://doi.org/10.1055/s-0037-1611019.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
Bn Bn
References and Notes
O
F
12c
13c
2m n = 1
2n n = 2
24
24
75
82
(1) (a) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biol-
ogy; Wiley-Blackwell: Chichester, 2009. (b) Müller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (c) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(d) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (e) Wang, J.;
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Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2013, 114, 2432.
(2) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok,
V. A.; Coelho, J. A. S.; Toste, F. D. Chem. Rev. 2018, 118, 3887.
(3) (a) Baudoux, J.; Cahard, D. Org. React. 2007, 69, 347. (b) Ma, J.-A.;
Cahard, D. Chem. Rev. 2008, 108, PR1. (c) Furuya, T.; Kuttruff, C.
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115, 826.
Ph
n
a Reactions were carried out using 1.5 equiv of Selectfluor at room
temperature in DMF, unless otherwise noted.
b Isolated yield.
c 3.0 equiv of Selectfluor were employed.
Previous studies on the decarboxylative fluorination of
primary and secondary β-keto carboxylic acids propose
that the reaction proceeds via the α-fluorination of β-keto
carboxylic acids and the subsequent decarboxylative pro-
tonation of the resulting α-fluoro-β-keto carboxylates
(Scheme 2, a).6a,7 However, the fact that the method pre-
sented herein was successful also using tertiary carboxylic
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
M. Katada et al.
Letter
Synlett
(4) (a) Pedersen, K. J. J. Am. Chem. Soc. 1929, 51, 2098. (b) Pedersen,
K. J. J. Phys. Chem. 1933, 38, 559. (c) Pedersen, K. J. J. Am. Chem.
Soc. 1938, 60, 595. (d) Westheimer, F. H.; Jones, W. A. J. Am.
Chem. Soc. 1941, 63, 3283. (e) Swain, C. G.; Bader, R. F. W.;
Esteve, R. M. Jr.; Griffin, R. N. J. Am. Chem. Soc. 1961, 83, 1951.
(f) Brower, K. P.; Gay, B.; Konkol, T. L. J. Am. Chem. Soc. 1966, 88,
1681. (g) Straub, T. S.; Bender, M. L. J. Am. Chem. Soc. 1972, 94,
8881. (h) Logue, M. W.; Pollack, R. M.; Vitullo, V. P. J. Am. Chem.
Soc. 1975, 97, 6868.
(9) Shibatomi, K.; Kitahara, K.; Okimi, T.; Abe, Y.; Iwasa, S. Chem.
Sci. 2016, 7, 1388.
(10) Typical Procedure of Decarboxylative Fluorination of 1
A dried flask was charged with 1a (0.5 mmol), Selectfluor (0.75
mmol), and DMF (2.5 mL) under argon atmosphere. The
mixture was stirred at ambient temperature for 24 h. The
mixture was subjected to silica gel column chromatography
purification (hexane/EtOAc = 20:1) to give 86% yield of 2a as a
colorless liquid.
(5) For reviews, see: (a) Pan, Y.; Tan, C.-H. Synthesis 2011, 2044.
(b) Bernardi, L.; Fochi, M.; Franchini, M. C.; Ricci, A. Org. Biomol.
Chem. 2012, 2911. (c) Wang, Z.-L. Adv. Synth. Catal. 2013, 355,
2745. (d) Nakamura, S. Org. Biomol. Chem. 2014, 12, 394. (e) Bae,
H. Y. Synlett 2015, 26, 705.
(6) (a) Li, J.; Li, Y.-L.; Jin, N.; Ma, A.-L.; Huang, Y.-N.; Deng, J. Adv.
Synth. Catal. 2015, 357, 2474. (b) Li, Y.-L.; Li, J.; Deng, J. Adv.
Synth. Catal. 2017, 359, 1407.
(11) Characterization Data of 2a
1H NMR (500 MHz, CDCl3): δ = 8.07 (d, J = 7.6 Hz, 1 H), 7.52 (dt,
J = 7.5, 1.5 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 1
H), 3.18 (dt, J = 17.2, 5.4 Hz, 1 H), 3.01 (ddd, J = 17.2, 9.6, 5.2 Hz,
1 H), 2.53–2.46 (m, 1 H), 2.33–2.24 (m, 1 H), 1.60 (d, J = 22.2 Hz,
3 H). 13C NMR (126 MHz, CDCl3): δ = 194.3 (J = 19.2 Hz), 142.7,
134.0, 130.7, 128.7, 128.3, 127.1, 93.8 (J = 179.9 Hz), 35.0 (J =
22.8 Hz), 26.2 (J = 9.6 Hz), 20.9 (J = 25.2 Hz). 19F NMR (470 MHz,
CDCl3): δ = –153.1. HRMS (DART): m/z [M + NH4]+ calcd for
(7) Zhang, R.; Ni, C.; He, Z.; Hu, J. J. Fluorine Chem. 2017, 203, 166.
(8) Shibatomi, K.; Kitahara, K.; Sasaki, N.; Kawasaki, Y.; Fujisawa, I.;
Iwasa, S. Nat. Commun. 2017, 8, 15600.
C
11H15F1N1O1+1: 196.1138; found: 196.1138.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D