Decarboxylative fluorination of β-Ketoacids with N-fluorobenzenesulfonimide (NFSI) for the synthesis of α-fluoroketones: Substrate scope and mechanistic investigation

Article abstract of DOI:10.1016/j.jfluchem.2017.08.010

Cesium carbonate (Cs₂CO₃)-mediated decarboxylative fluorination of β-ketoacids using NFSI in the MeCN/H₂O mixed solvent system affords α-fluoroketones with a broad scope. Both electron-rich and electron-deficient α-non-substituted β-ketoacids are amenable to this protocol. The mechanistic study indicates that the reaction proceeds through electrophilic fluorination followed by decarboxylation, which is different from the decarboxylative fluorination of normal carboxylic acids.

Full text of DOI:10.1016/j.jfluchem.2017.08.010

JournalofFluorineChemistry203(2017)166–172
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Decarboxylative fluorination of β-Ketoacids with N-
fluorobenzenesulfonimide (NFSI) for the synthesis of α-fluoroketones:
Substrate scope and mechanistic investigation
Rui Zhang, Chuanfa Ni, Zhengbiao He, Jinbo Hu⁎
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-
Ling Road, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Dedicated to Prof. Dr. Antonio Togni on the
occasion of his receipt of the ACS Award for
Creative Work in Fluorine Chemistry 2017
Cesium carbonate (Cs2CO3)-mediated decarboxylative fluorination of β-ketoacids using NFSI in the MeCN/H2O
mixed solvent system affords α-fluoroketones with a broad scope. Both electron-rich and electron-deficient α-
non-substituted β-ketoacids are amenable to this protocol. The mechanistic study indicates that the reaction
proceeds through electrophilic fluorination followed by decarboxylation, which is different from the dec-
arboxylative fluorination of normal carboxylic acids.
Keywords:
Decarboxylative fluorination
NFSI
β-ketoacids
α-fluoroketones
1. Introduction
Considering that the enol form of β-ketoacids are a special type of
α,β-unsaturated carboxylic acids (Scheme 1b), we envisioned that β-
Organofluorine compounds are widely applied in pharmaceutical
and agrochemical research owing to the unique effect of the fluorine in
enhancing the bioactivity of organic molecules [1–4]. Carbon − fluorine
bond formation has attracted increasing attention as an effective strategy
for selective introduction of fluorine atoms [5–10]. Among many
methods developed for this purpose, fluorinations via functional group
transformation, such as deoxyfluorination [8], Balz-Schiemann fluor-
ination [9] and halex fluorination [10], are among the most reliable ones
due to their predictable site-selectivity. However, the extension of site-
selective fluorination to other common functional groups, such as car-
boxylic acids, would provide new opportunities to access desired
fluorinated compounds.
ketoacids can undergo similar reactions as we previously reported. In-
deed, β-ketoacids have been widely used as promising precursors for
the generation of ketone enolate equivalents under very mild reaction
conditions [23]. In 2015, Deng and coworkers reported the decarbox-
ylative fluorination of β-ketoacids for the synthesis of α-fluoro ketones
by using Selectfluor under phase-transfer conditions; however, the
method is limited to electron-neutral and electron-rich substrates [24].
Herein, we report an improved method for the synthesis of α-fluoro
ketones via transition-metal-free, fluorination-initiated decarboxylation
of β-ketoacids with N-fluorobenzenesulfonimide (NFSI) (Scheme 1c).
2. Results and discussion
Carboxylic acids, which are ubiquitous organic compounds, have
been frequently used as attractive synthetic precursors for site-specific
decarboxylative functionalization reactions [11–13]. Recently, dec-
arboxylative fluorination of aliphatic carboxylic acids has been well
established to be efficient for the synthesis of alkyl fluorides under mild
conditions [6,14–17]. Mechanistically, these reactions proceed through
decarboxylation followed by radical fluorination [18]. During our in-
vestigation of the decarboxylative fluoroalkylation of α,β- and β,γ-un-
saturated carboxylic acids (Scheme 1a) [19–22], we demonstrated that
these reactions occur in a different manner, that is, via fluoroalkylation
followed by decarboxylation.
At the onset of our investigation, we chose β-ketoacid 1a as a model
substrate to survey the reaction conditions (Table 1). We screened the
reaction conditions using different combinations of electrophilic fluor-
ination reagent, solvent and base. When Selectfluor was used as the
reagent, the reaction of 1a in MeCN at room temperature for 12 h re-
sulted in the complete conversion of 1a and produced α-fluoro acet-
ophenone (2a) in only trace amount (∼2% yield) (Table 1, entry 1);
however, α,α-difluoro acetophenone was formed in 31% yield, which
probably arose from further fluorination of the monofluorinated β-ke-
toacid followed by decarboxylation [25]. In light of the amount of
⁎
Corresponding author.
E-mail address: jinbohu@sioc.ac.cn (J. Hu).
http://dx.doi.org/10.1016/j.jfluchem.2017.08.010
Received 18 July 2017; Received in revised form 18 August 2017; Accepted 20 August 2017
Availableonline12September2017
0022-1139/©2017ElsevierB.V.Allrightsreserved.

R. Zhang et al.
JournalofFluorineChemistry203(2017)166–172
Scheme 1. Decarboxylative fluoroalkylation and
fluorination of unsaturated carboxylic acids.
Table 1
Optimization of reaction conditions for decarboxylative fluorination of 1aa.
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JournalofFluorineChemistry203(2017)166–172
Selectfluor used (only 1 equivalent), the over-fluorination indicates that
Selectfluor is of high electrophilicity. To alleviate the reactivity of Se-
lectfluor, we tried to add a tertiary amine as an additive to form a re-
latively weak “N-F” fluorinating reagent [26]. Thus, when Selectfluor
was mixed with the same equivalent of quinine in advance, the fluor-
ination of 1a proceeded smoothly to give 2a in good yield (77%)
(Table 1, entry 2). Encouraged by the above preliminary results, we
turned our attention to the use of NFSI, which contains a neutral
fluorinated nitrogen atom and thus is expected to be a milder fluor-
inating reagent. The reaction conducted in the absence of a base,
however, failed to give any fluorination product (Table 1, entry 3). The
addition of K2CO3 promoted the reaction smoothly at room tempera-
ture, affording 2a in 72% yield (Table 1, entry 4). A survey on the
influence of solvent revealed that MeCN was the most suitable solvent
(Table 1, entries 4–9). In terms of the base, Cs2CO3 was established to
be slightly superior to K2CO3 (Table 1, entries 10–15). The molar ratio
1a/NFSI/Cs2CO3 was further optimized to 1.0:1.0:3.0, and 2a was ob-
tained in 81% yield as the only fluorinated ketone product (Table 1,
entries 16–20). An additional investigation showed that the reaction
time could be shortened to 1 h without significant loss of the yield
(Table 1, entries 21).
sensitive to the solubility of 1 in MeCN and a relatively low solubility
usually led to decreased yield. We found that adding water to improve
the solubility is beneficial for the desired fluorination. Therefore, we
modified the optimized conditions as listed under entry 21 (Table 1) by
using water as a co-solvent and the scope of aryl substituted β-ketoacids
are shown in Table 2. Various substituents on the aryl ring at the β-
position, both electron-donating (1a-1f) and electron-withdrawing (1g-
1j), are compatible with the reaction conditions, and the mono-
fluorination products were obtained in good yields. Moreover, fully
aliphatic substrates also worked well after a slight modification of re-
action conditions, which is exemplified by the reaction of 1k to give 2k
in moderate yield. Compared with the recently reported method using
Selectfluor in aqueous media [24], our method is more suitable for the
decarboxylative monofluorination of β-ketoacids bearing an electron-
deficient β-aryl substituent such as F, Cl, Br, and CF3. However, the
current protocol is not compatible with α-substituted β-ketoacids such
as 2-methyl-3-oxo-3-phenylpropanoic acid (1l) and 2,2-dimethyl-3-oxo-
3-phenylpropanoic acid (1r). The reaction of 1 l afforded the desired
monofluorination product 2 l in only 24% yield, whereas the reaction of
1r failed to afford any fluorination products. As a complementary, we
achieved the decarboxylative monofluorination of α-monosubstituted
β-ketoacids 1l-1p by using Selectfluor instead of NFSI (Table 3). In all
cases, no difluorination products were detected.
Then we continued to examine the substrate scope of the reaction
between β-ketoacids 1 and NFSI. Initially, we applied the optimized
reaction conditions (as described in Table 1, entry 21) to other β-ke-
toacids such as 1b; however, we quickly realized that the reaction is
To gain insight into the reaction mechanism, we monitored the
progress of the reaction of β-ketoacid 1a and NFSI by variable-
Table 2
Decarboxylative fluorination of various β-ketoacids with NFSIa.
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JournalofFluorineChemistry203(2017)166–172
Table 3
Decarboxylative fluorination of α-monosubstituted β-ketoacids with Selectfluora.
temperature (VT) 19F NMR spectroscopy (Fig. 1). When 1a, NFSI and
Cs2CO3 were mixed in a 1.0:1.0:3.0 ratio in MeCN/H2O (20:1, v/v) at
0 °C, a fast consumption of NFSI [δ −39.4 ppm (s)] led to the genera-
intermediate 3a, and (2) the further fluorination of α-fluoro-β-keto-
carboxylate salt 3a is much slower than the fluorination of the car-
boxylate salt of 1a, probably due to the steric hindrance of a fluorine
substitution, which is in line with the aforementioned sluggish fluor-
ination of β-ketoacid 1 l with NFSI.
Based on the above experimental results, we proposed that the
decarboxylative fluorination of α-nonsubstituted β-ketoacids with NFSI
might proceed via the mechanism as depicted in Scheme 2. Initially, β-
ketoacid 1, which was in equilibrium with its enol form, was depro-
tonated by Cs2CO3 to give a dianion intermediate 4. Subsequently,
2
tion of α-fluoro-β-ketocarboxylate salt 3a [δ −179.7 ppm (d, JH-
F = 56 Hz)] as the major intermediate product (Fig. 1a-1b). The dec-
2
arboxylation of 3a to form 2a [δ −233.4 ppm (t, JH-F = 47 Hz)] was
slow at 0 °C (Fig. 1c-1d); however, an increase in the temperature sig-
nificantly accelerated the formation of 2a (Fig. 1e-1f). This experiment
indicated that: (1) the monofluorination of β-ketoacid 1a is much faster
than the decarboxylation of both 1a itself and the fluorinated
Fig. 1. Monitoring of the reaction of 1a, NFSI and Cs2CO3 in MeCN/H2O by VT 19F NMR spectroscopy. PhOCF3 was used as an internal standard. a–c) Reaction was performed at 0 °C for
3, 15 and 55 min, respectively; d–e) Reaction was performed at 0 °C for 1 h, then at r.t. for 5 and 15 min, respectively.
169

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JournalofFluorineChemistry203(2017)166–172
Scheme 2. Proposed mechanism.
intermediate 4 underwent a fast electrophilic fluorination with NFSI to
afford α-fluoro-β-ketocarboxylate salt 3. Finally, the slow decarbox-
ylation of intermediate 3 resulted in the final product α-fluoroketone 2.
The compatibility of this protocol with electron-deficient β-ketoacids
can be attributed to the moderate reactivity of NFSI in the mixed sol-
vent system of MeCN/H2O, which can readily fluorinate various α-
nonsubstituted β-ketoacids with high selectivity.
4.1.1. 2-Fluoro-1-phenylethanone (2a)[29,30]
51.1 mg, 74% yield, colorless oil. 1H NMR (400 MHz, CDCl3): δ
7.89–7.87 (m, 2H), 7.62–7.59 (m, 1H), 7.50–7.46 (m, 2H), 5.51 (d,
J = 47.0 Hz, 2H); 19F NMR (376 MHz, CDCl3):
δ −230.8 (t,
3. Conclusion
J = 46.9 Hz, 1F); MS (EI, m/z, %): 138 (M+, 10.05), 105 (100.00). The
1H and 19F NMR data are consistent with previous reports [29,30].
In summary, we have described a new protocol for the synthesis of
α-fluoroketones, that is, Cs2CO3-mediated decarboxylative fluorination
of β-ketoacids using NFSI in the mixed solvent system MeCN/H2O. Both
electron-rich and electron-deficient α-nonsubstituted β-ketoacids could
be converted into the corresponding α-fluoroketones in good yields.
The mechanistic study by variable temperature 19F NMR shows that the
reaction proceeded through electrophilic fluorination (C-F bond for-
mation) followed by decarboxylation, which is different from the dec-
arboxylative fluorination of normal carboxylic acids.
4.1.2. 2-Fluoro-1-(p-tolyl)ethanone (2b) [29]
64.0 mg, 84% yield, white solid. 1H NMR (400 MHz, CDCl3): δ 7.79
(d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.51 (d, J = 47.0 Hz,
2H), 2.43 (s, 3H); 19F NMR (376 MHz, CDCl3):
δ −229.8 (t,
4. Experimental
J = 47.1 Hz); MS (EI, m/z, %): 152 (M+, 21.50), 119 (100.00). The 1
H
and 19F NMR data are consistent with previous report [29].
Unless otherwise mentioned, solvents and reagents were purchased
from commercial sources and used as received. The solvents MeCN and
DMF were distilled over CaH2. The solvents THF and toluene were
distilled over sodium. All the β-ketoacids were prepared according to
reported procedures [27,28]. 1H, 19F and 13C NMR spectra were re-
corded on a Bruker AM-300 NMR, VarianMercury-300, or Agilent MR-
400 NMR spectrometer. 1H NMR chemical shifts were determined re-
lative to internal (CH3)4Si (TMS) at δ 0.0 or to the signal of a residual
protonated solvent CDCl3 at δ 7.26. 19F NMR chemical shifts were de-
termined relative to CFCl3 at δ 0.0. 13C NMR chemical shifts were de-
termined relative to internal (CH3)4Si (TMS) at δ 0.0. MS (EI-MS) were
obtained on an Agilent 5975C gas chromatography and HP5989A mass
spectrometer. MS (ESI) were obtained on an AGILENT1100 mass
spectrometer. HRMS(EI) were recorded on a Waters Micromass GCT
Premier mass spectrometer.
4.1.3. 1-([1,1′-Biphenyl]-4-yl)-2-fluoroethanone (2c) [30]
90.9 mg, 85% yield, white solid. 1H NMR (400 MHz, CDCl3): δ
7.98–7.96 (m, 2H), 7.71–7.69 (m, 2H), 7.63–7.60 (m, 2H), 7.49–7.45
(m, 2H), 7.43–7.39 (m, 1H), 5.54 (d, J = 46.9 Hz, 2H); 19F NMR
(376 MHz, CDCl3): δ −230.35 (t, J = 47.0 Hz, 1F); MS (EI, m/z, %):
214 (M+, 29.64), 181 (100.00). The 1H and 19F NMR data are con-
sistent with previous report [30].
4.1.4. 2-Fluoro-1-(4-methoxyphenyl)ethanone (2d) [29,30]
4.1. Typical procedures for decarboxylation fluorination of α-
nonsubstituted β-ketoacids with NFSI
Into a 20-mL Schlenk flask equipped with a stirring bar were added
β-ketoacid 1a (82.0 mg, 0.5 mmol), N-fluorobenzenesulfonimide (NFSI)
(167.7 mg, 0.5 mmol), Cs2CO3 (188.7 mg, 1.5 mmol), MeCN (10 mL),
and H2O (0.5 mL). The mixture was stirred for 1 h at room temperature
and then filtered through Celite layer. The filtrate was concentrated in
vacuo and purified using flash column chromatography (silica gel;
petroleum ether/diethyl ether, 5:1, v/v) to give 2a (51.1 mg, 74%
yield) as colorless oil.
65.5 mg, 78% yield, white solid. 1H NMR (400 MHz, CDCl3): δ 7.88
(d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.46 (d, J = 47.1 Hz,
2H), 3.87 (s, 3H); 19F NMR (376 MHz, CDCl3):
δ −229.86 (t,
J = 47.0 Hz, 1F); MS (EI, m/z, %): 168 (M+, 13.28), 135 (100.00). The
1H and 19F NMR data are consistent with previous reports [29,30].
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JournalofFluorineChemistry203(2017)166–172
4.1.5. 2-Fluoro-1-(4-(methylthio)phenyl)ethanone (2e)
4.2. -Fluoro-1-(4-(trifluoromethyl)phenyl)ethenone (2j) [31]
66.3 mg, 72% yield, white solid. 1H NMR (400 MHz, CDCl3): δ 7.81
(d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 5.48 (d, J = 47.0 Hz,
78.4 mg, 76% yield, white solid. 1H NMR (400 MHz, CDCl3) δ 8.01
(d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 5.52 (d, J = 46.8 Hz,
2H); 19F NMR (376 MHz, CDCl3) δ −63.82 (s, 3F), −230.30 (t,
J = 46.8 Hz, 1F); MS (ESI, m/z, %): 205.0 (M+-H, 100.00). The 1H and
19F NMR data are consistent with previous report [31].
2H), 2.53 (s, 3H); 19F NMR (376 MHz, CDCl3):
δ −230.15 (t,
J = 47.0 Hz, 1F); 13C NMR (101 MHz, CDCl3) δ 192.4 (d, J = 15.6 Hz),
147.5, 129.8 (s), 128.2 (d, J = 2.8 Hz), 125.1, 83.5 (d, J = 182.3 Hz),
14.6; MS (EI, m/z, %): 184 (M+, 34.74), 151 (100.00); HRMS (EI):
Calcd. For C9H9OFS: 184.0358; Found: 184.0359.
4.3. Typical procedures for decarboxylation fluorination of α-
monosubstituted β-ketoacids with selectfluor
4.1.6. 2-Fluoro-1-(5-methylfuran-2-yl)ethanone (2f)
Into a 20-mL Schlenk flask equipped with a stirring bar were
added β-ketoacid 11 (89.0 mg, 0.5 mmol), 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)
(Selectfluor)
(177.3 mg, 0.5 mmol), K2CO3 (207.3 mg, 1.5 mmol), and MeCN
(10 mL), and H2O (1 mL). The mixture was stirred at room temperature
for 12 h and then filtered through Celite layer. The filtrate was con-
centrated in vacuo and purified using flash column chromatography
(silica gel; petroleum ether/diethyl ether, 5:1, v/v) to give 2 l (53.9 mg,
78% yield).
54.6 mg, 77% yield, white solid. 1H NMR (400 MHz, CDCl3): δ
7.31–7.30 (m, 1H), 6.22–6.21 (m, 1H), 5.26 (d, J = 47.1 Hz, 2H), 2.41
(s, 3H); 19F NMR (282 MHz, CDCl3): δ −234.25 (t, J = 47.2 Hz, 1F);
13C NMR (101 MHz, CDCl3) δ 181.9 (d, J = 17.8 Hz), 159.0, 148.6,
121.6 (d, J = 7.0 Hz), 109.4 (d, J = 1.3 Hz), 83.1 (d, J = 183.0 Hz),
14.0; MS (EI, m/z, %): 142 (M+, 26.19), 109 (100.00). HRMS (EI):
Calcd. For C7H7O2F: 142.0430; Found: 142.0424.
4.3.1. 2-Fluoro-1-phenylpropan-1-one (2l)[32]
4.1.7. 2-Fluoro-1-(4-fluorophenyl)ethanone (2g) [30]
45.8 mg, 60% yield, colorless oil. 1H NMR (400 MHz, CDCl3) δ
7.99–7.96 (m, 2H), 7.63–7.44 (m, 3H), 5.71 (dq, J = 48.6, 6.8 Hz, 1H),
1.67 (dd, J = 24.0, 6.8 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −181.50
59.1 mg, 76% yield, white solid. 1H NMR (400 MHz, CDCl3): δ
7.98–7.94 (m, 2H), 7.74–7.16 (m, 2H), 5.48 (d, J = 47.0 Hz, 2H); 19F
NMR (282 MHz, CDCl3): δ −102.76 (s, 1F), −229.23 (t, J = 46.9 Hz,
1F); MS (EI, m/z, %): 156 (M+, 6.01), 123 (100.00). The 1H and 19F
NMR data are consistent with previous report [30].
(dq, J = 48.2, 24.0 Hz, 1F); Ms (ESI, m/z, %): 175.05 (M + Na+
,
100.00). The 1H and 19F NMR data are consistent with previous reports
[32].
4.3.2. -Fluoro-1-phenylbutan-1-one (2m) [33]
4.1.8. 1-(4-Chlorophenyl)-2-fluoroethanone (2 h) [30]
47.1 mg, 57% yield, colorless oil. 1H NMR (400 MHz, CDCl3) δ
8.00–7.97 (m, 2H), 7.65–7.46 (m, 3H), 5.54 (ddd, J = 49.3, 7.7,
4.5 Hz, 1H), 2.17–1.92 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H); 19F NMR
(376 MHz, CDCl3) δ −191.0 (m, 1F); Ms (ESI, m/z, %): 189.10 (M
+ Na+, 100.00). The 1H and 19F NMR data are consistent with previous
report [33].
65.7 mg, 76% yield, white solid. 1H NMR (400 MHz, CDCl3): δ 7.86
(d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 5.48 (d, J = 46.9 Hz,
2H); 19F NMR (376 MHz, CDCl3): δ −229.69 (t, J = 46.9 Hz, 1F); MS
(EI, m/z): 172 (M+, 9.22), 139 (100.00). The 1H and 19F NMR data are
consistent with previous report [30].
4.3.3. 2-Fluoro-3,4-dihydronaphthalen-1(2H)-one (2n) [30]
4.1.9. 1-(4-Bromophenyl)-2-fluoroethanone (2i) [30]
65.6 mg, 80% yield, white solid. 1H NMR (400 MHz, CDCl3) δ 8.06
(d, J = 7.9 Hz, 1H), 7.53 (td, J = 7.6, 1.3 Hz, 1H), 7.36 (t, J = 7.6 Hz,
1H), 7.31–7.24 (m, 1H), 5.15 (ddd, J = 47.9, 12.8, 5.2 Hz, 1H), 3.14
(dd, J = 9.2, 4.0 Hz, 2H), 2.60–2.55 (m, 1H), 2.41–2.31 (m, 1H); 19F
NMR (376 MHz, CDCl3) δ −190.8 (m, 1F); Ms (ESI, m/z, %): 187.10
(M + Na+, 100.00). The 1H and 19F NMR data are consistent with
previous report [30].
81.8 mg, 76% yield, white solid. 1H NMR (400 MHz, CDCl3) δ 7.77
(d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 5.47 (d, J = 46.9 Hz,
2H); 19F NMR (376 MHz, CDCl3) δ −229.79 (t, J = 46.2 Hz, 1F); MS
(ESI, m/z, %): 214.90 (M-H−, 100.00). The 1H and 19F NMR data are
consistent with previous report [30].
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4.3.4. 2-Fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (2o) [34]
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Acknowledgements
Support of our work by the National Basic Research Program of
China (2015CB931900), the National Key Research and Development
Program of China (2016YFB0101204), the National Natural Science
Foundation of China (21632009, 21472221, 21421002, 21402227, and
21372246), the Key Programs of the Chinese Academy of Sciences
(KGZD-EW-T08), the Key Research Program of Frontier Sciences of CAS
(QYZDJ-SSW-SLH049), Shanghai Academic Research Leader Program
(15XD1504400), and the Youth Innovation Promotion Association CAS
(2014231) is gratefully acknowledged.
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172