One-Pot Synthesis of α-Fluoroketones and 3-Fluoro-2,4-diaryl-furans from Trifluoromethyl β-Diketones via Decarboxylation

Article abstract of DOI:10.1055/s-0034-1380441

A facile and mild one-pot protocol via decarboxylation of trifluoromethyl β-diketones has been developed for the construction of α-fluoroketones and 3-fluoro-2,4-diarylfurans which are important units in many biologically active compounds and useful precursors in a variety of functional-group transformations.

Full text of DOI:10.1055/s-0034-1380441

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1835–1840
letter
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Letter
Synlett
One-Pot Synthesis of α-Fluoroketones and 3-Fluoro-2,4-diaryl-
furans from Trifluoromethyl β-Diketones via Decarboxylation
Tongle Shaoa
O
Xiang Fang*a,b
Xueyan Yang*a
SelectfluorTM (1.2 equiv)
Na2CO3 (3 equiv)
Ar
F
a Laboratory for Advanced Material and Institute of Fine Chemicals, School of
Chemistry and Molecular Engineering, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
b Department of Chemistry, University of Toronto, 80 St. George St., Toronto,
Ontario, M5S 3H6, Canada
O
O
NaOH
(4 equiv)
Ar
CF3
Ar
F
NaOH (4 equiv)
SelectfluorTM (1.2 equiv)
Ar
O
Received: 17.04.2015
Accepted after revision: 17.05.2015
Published online: 09.07.2015
α-Fluoroketones are extremely valuable building blocks
in medicinal and biological chemistry and can be easily
transformed into chiral α-fluoroethylamines,3 α-fluoroeth-
ylhydroxys,4 and a large number of interesting molecules.5
In general, there are mainly two synthetic approaches to α-
fluoroketones.6 One is the introduction of fluorine atom
into nonfluorinated substrates with electrophilic fluorinat-
ing agents,7 and the other is the nucleophilic substitution of
α-haloketones with fluoride (Scheme 1).8 However, most of
the methods suffer from limitations such as reagent toxici-
ty, low atom economy, and complicated procedures. There-
fore, an effective and especially environmentally friendly
method is still required.
The furan structure is an ubiquitous unit in a variety of
natural products, active pharmaceuticals, agricultural com-
pounds, fragrances, and synthetic precursors.9 Although
two classic methodologies, the Paal–Knorr synthesis10 and
the Feist–Benary synthesis,11 have proven to be a very use-
ful approach to multisubstituted furans, there exit some
limitations, such as difficulty to obtain furans with sensi-
tive functional groups. Also the low reactivity of the furan
DOI: 10.1055/s-0034-1380441; Art ID: st-2015-w0268-l
Abstract A facile and mild one-pot protocol via decarboxylation of tri-
fluoromethyl β-diketones has been developed for the construction of α-
fluoroketones and 3-fluoro-2,4-diarylfurans which are important units
in many biologically active compounds and useful precursors in a vari-
ety of functional-group transformations.
Key words fluorine, α-fluoroketones, 3-fluorofurans, one-pot, decar-
boxylation
It is well recognized that organofluorine compounds
have been extensively used as pharmaceuticals, agrochemi-
cals, fine chemicals, and in material science.1 In particular,
5–15% of the total number of drugs launched worldwide
over the past 50 years bear fluorinated substituents.2 As a
consequence, the development of new and efficient meth-
ods to synthesize organic fluorides has become a hot topic
in organic synthesis.
O
CH2X
CH3
nucleophilic
O
O
O
O
O
fluorinating agents
this work
CF3
O
F
Selectfluor
electrophilic
fluorinating agents
O
F
Ph
F
H+
this work
Ph
CF3
Ph
Selectfluor
Ph
O
O
Scheme 1 Strategies for synthesis of α-fluoroketone and 3-fluoro-2,4-diphenylfuran
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1835–1840

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Table 1 Base Screening for the Reactiona
O
O
OH
CF3
Selectfluor (1.2 equiv)
base
Ph
F
F
+
MeCN–H2O (5:2)
6 h
Ph
O
2a
3a
1a
Entry
Base (equiv)
Temp (°C)
Yield of 2a (%)b
Yield of 3a (%)b
1
2
3
4
5
6
7
DBU (3.0)
30
30
30
30
50
50
50
–
–
Na2CO3 (3.0)
NaOAc (3.0)
NaOH (3.0)
Na2CO3 (3.0)
NaOAc (3.0)
NaOH (3.0)
66
59
55
63
58
50
–
–
31
–
–
40
a Reaction conditions: 1a (0.5 mmol), Selectfluor (0.6 mmol), base (1.5 mmol), MeCN–H2O (5:2, 0.7 mL), 6 h.
b Isolated yields.
C3-position makes the introduction of functional groups,
such as fluorine atom, into this position difficult.12 In 1965,
the first 3-fluoro-2,4-diphenylfuran sample was synthe-
sized from 2-fluoro-1,3-diphenylbutan-1-one (Scheme 1).13
Recently, Hammond reported the iodocyclization of gem-
difluorohomopropargyl alcohols with ICl to produce fluori-
nated 4-iodofurans and continue to prepare multisubstitut-
ed 3-fluorofurans using Suzuki cross-coupling reaction.14
Our group has reported the decarboxylation of trifluo-
romethyl α-fluorinated gem-diols by cleavage of carbon–
carbon bonds through a mild release of the trifluoroacetate
unit.15 Herein we wish to report a one-pot approach for
synthesis of α-fluoroketones from trifluoromethyl β-dike-
tones through decarboxylation process. This protocol also
provides a facile and mild synthetic approach to 3-fluoro-
2,4-diarylfurans.
(3a) are extremely valuable building blocks, we wished to
optimize the reaction conditions to afford 2a and 3a using
Na2CO3 or NaOH as base, respectively.
Subsequently, we found that the ratio of mixed solvents
impacts the yield of the model reaction with Na2CO3 as base
(Table 2). When EtOH–H2O and MeOH–H2O were used,
moderate yields of 2a (60% and 62%) were obtained (Table
2, entries 1 and 2). Good yield (73%) was obtained when
MeCN–H2O (5:2) was used as solvent (Table 2, entry 3). To
our delight, the yield of 2a increased significantly with in-
Table 2 Optimization of Solvent for the Synthesis of 2-Fluoro-1-
phenylethanonea
O
O
OH
CF3
F
Selectfluor (1.2 equiv)
The starting material trifluoromethyl β-diketones exist
exclusively in the enol form.16 Our initial study started with
the reaction of 4,4,4-trifluoro-3-hydroxy-1-phenylbut-2-
en-1-one (1a), and the results of the base screening are
shown in Table 1. With acetonitrile and water as solvent
and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]oc-
tane bis(tetrafluoroborate) (SelectfluorTM) as electrophilic
fluorinating agent, the DBU did not work at all (Table 1, en-
try 1), and weak inorganic bases, such as Na2CO3 and
NaOAc, gave 2-fluoro-1-phenylethanone (2a) in 66% and
59% yields, respectively (Table 1, entries 2 and 3). Relatively
low yields of 2a were obtained at 50 °C (Table 1, entries 5
and 6, 63% and 58%). Surprisingly, using NaOH as base pro-
vided 2a in 55% yield along with 3-fluoro-2,4-diphenylfu-
ran (3a) in 31% yield (Table 1, entry 4), and 3a was isolated
in a slightly higher yield of 40% at 50 °C (Table 1, entry 7).
Both α-fluoroketone 2a and 3-fluoro-2,4-diphenylfuran
Na2CO3
solvent, 0 °C
2a
Time (h) Yield (%)c
1a
Entry Base (equiv)
Solvent (ratio)b
1
2
3
4
5
6
7
8
Na2CO3 (3.0)
EtOH–H2O (5:2)
MeOH–H2O (5:2)
MeCN–H2O (5:2)
MeCN–H2O (5:3)
MeCN–H2O (5:4)
MeCN–H2O (3:2)
MeCN–H2O (3:2)
MeCN–H2O (3:2)
8
8
60
62
73
80
90
93
81
92
Na2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (3.0)
Na2CO3 (4.0)
Na2CO3 (3.0)
8
8
8
8
8
10
a Reaction conditions: 1a (0.5 mmol), Selectfluor (0.6 mmol), Na2CO3, sol-
vent (1.0 mL), 0 °C.
b The ratio of mixed solvent was calculated in volume.
c Isolated yields.
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creasing proportion of H2O in the mixed solvent (Table 2,
entries 4 and 5). But the yield reduced to 81% when the
quantity of Na2CO3 was elevated to 4.0 equivalents (Table 2,
entry 7). This is probably due to the fact that the addition of
H2O is conducive to the solvability of Na2CO3 and Selectflu-
or in the reaction mixture. Screening of different ratios of
MeCN–H2O revealed that 3:2 gave the best result (Table 2,
entry 6, 93%). The yield did not increase any further with
prolonged reaction time, giving 2a in 92% yield (Table 2, en-
try 8).
With the optimized conditions in hand, the scope of
making α-fluoroketones 2 was investigated (Scheme 2).17
The protocol was found to tolerate a wide range of func-
tionalities (e.g., methyl, methoxy, phenyl, benzyloxy, fluoro,
chloro, and bromo) on the phenyl ring of aryl-substituted
trifluoromethyl β-diketones, and good to excellent yields
were achieved (2b–i). Sterically hindered groups, such as
phenyl and benzyloxy, at the para-position of phenyl ring
were also well tolerated, generating the desired products
2d,e in 60% and 74% yield, respectively. And excellent yield
of 1-(4-ethoxy-3-fluorophenyl)-2-fluoroethanone (2l) was
generated when sterically hindered substrate 1-(4-ethoxy-
3-fluorophenyl)-4,4,4-trifluoro-3-hydroxybut-2-en-1-one
(1l) was tested (97%). But the substrate bearing 2-methyl on
the phenyl ring showed relatively low reactivity, affording
2i in a lower yield of 55%. Heterocyclic substituted trifluo-
romethyl β-diketones were also found to be effective in this
protocol, giving the corresponding products 2j and 2k in
good yields of 65% and 63%, respectively.
Next, the reaction conditions for the synthesis of 3-fluo-
ro-2,4-diphenylfuran (3a) were optimized, and the results
are summarized in Table 3. Increasing the amount of NaOH
to 4.0 equivalents gave the best result, generating 3a in 67%
yield (Table 3, entry 2). And continuing to add 5.0 equiva-
lents NaOH only got a worse result (Table 3 entry 3, 41%).
Then we changed the ratio of the mixed solvent (MeCN–
H2O), but lower yields were obtained (Table 3, entries 4–6).
With 4.0 equivalents of NaOH used, various solvents includ-
ing EtOH, MeOH, (CH2OH)2, acetone, DMSO, DMF, and
EtOH–MeCN–H2O were screened, unfortunately no good re-
sults were obtained (Table 3, entries 7–14). Also, extended
reaction time did not lead to an improvement in overall ef-
ficiency (Table 3, entry 15). Totally, optimization of the re-
action conditions demonstrated that MeCN–H2O (5:2) to be
an optimal solvent in terms of yield (Table 3, entry 2).
Table 3 Optimization of Solvent for the Synthesis of 3-Fluoro-2,4-di-
phenylfurana
Selectfluor (1.2 equiv)
O
O
OH
O
OH
CF3
2
3
Ph
F
F
Selectfluor (1.2 equiv)
Ar
MeCN–H2O (3:2)
0 °C, 8 h
Ar
CF3
2
1
2
NaOH, solvent
0 °C for 3 h, then 50 °C for 6 h
Ph
O
3a
1a
Entry NaOH (equiv)
O
O
O
F
F
Solvent (ratio)b
Time (h) Yield (%)c
F
1
2
NaOH (3.0)
NaOH (4.0)
NaOH (5.0)
NaOH (5.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
NaOH (4.0)
MeCN–H2O (5:2)
MeCN–H2O (5:2)
MeCN–H2O (5:2)
MeCN–H2O (5:3)
MeCN–H2O (5:3)
MeCN–H2O (5:1)
EtOH–H2O (5:2)
9
9
40
67
41
25
35
37
24
–
MeO
2a: 93%
2b: 73%
2c: 75%
3
9
O
O
O
4
9
F
F
F
5
9
F
6
9
BnO
7
9
2d: 60%a
2e: 74%
2f: 81%a
8
MeOH–H2O (5:2)
(CH2OH)2–H2O (5:2)
acetone–H2O (5:2)
DMSO–H2O (5:2)
DMF–H2O (5:2)
9
O
O
O
9
9
–
F
F
F
10
11
12
13
14
15d
9
–
9
–
Br
Cl
2g: 69%
2h: 61%
2i: 55%
9
–
O
EtOH–MeCN–H2O (3:2:2)
EtOH–MeCN–H2O (2:3:2)
MeCN–H2O (5:2)
9
51
60
66
O
O
F
F
9
O
S
12
F
F
EtO
a Reaction conditions: 1a (0.5 mmol), Selectfluor (0.6 mmol), NaOH, solvent
(0.7 mL), 0 °C for 3 h, then 50 °C for 6 h.
2j: 65%
2k: 63%
2l: 97%
Scheme 2 Scope for the synthesis of α-fluoroketones. Reagents and
b The ratio of mixed solvent was calculated in volume.
c Isolated yield.
conditions: 1 (0.5 mmol), Selectfluor (0.6 mmol), Na2CO3 (1.5 mmol),
MeCN–H2O (3:2; 1 mL), 0 °C, 8 h. a The reaction was carried out using
MeCN–H2O (7:5; 1.2 mL).
d The reaction was carried out at 0 °C for 3 h, then at 50 °C for 9 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1835–1840

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The scope of synthesizing 3-fluoro-2,4-diarylfurans is
Selectfluor (1.2 equiv)
NaOH (4 equiv)
Ar
F
shown in Scheme 3.18 Aryl substrates with electron-donat-
ing or electron-withdrawing groups at the homopropargyl
position gave the corresponding 3-fluoro-2,4-diarylfurans
3b,c,f–h in acceptable to good yields. Sterically hindered
substrate 1-(4-ethoxy-3-fluorophenyl)-4,4,4-trifluoro-3-
hydroxybut-2-en-1-one was tested, and an acceptable yield
of product 3l was achieved (30%). Lastly, heteroaromatic tri-
fluoromethyl ketones were also suitable substrates in this
protocol, delivering the desired furan derivatives 3j,k in rel-
atively low yields, which were attributed to the loss of
product during isolation because of their low boiling points
(Scheme 3, 22% and 36%).
O
OH
2
Ar
MeCN–H2O (5:2)
Ar
CF3
O
0 °C for 3 h, then 50 °C for 6 h
3
1
F
F
O
O
CH3
3b: 63%
3a: 67%
To further investigate the plausible mechanism of the
reaction, the 2-fluoro-1-phenylethanone (2a) was put into
NaOH solution (4 equiv) of EtOH–H2O (5:2; 0.7 mL) at 30 °C
for five hours. And 3-fluoro-2,4-diphenylfuran (3a) was iso-
lated in 76% yield as expected (Scheme 4).
MeO
F
F
F
O
O
Ph
F
O
F
NaOH (4 equiv)
OMe
F
2
3c: 52%
3f: 45%
Ph
EtOH–H2O (5:2)
30 °C, 5 h
O
2a
3a 76%
Cl
Br
Scheme 4 The reaction of 2a to 3a with NaOH as base
F
F
According to our previous reports and experimental ob-
servations, a possible mechanism for this transformation is
proposed in Scheme 5. First, 4,4,4-trifluoro-3-hydroxy-1-
phenylbut-2-en-1-one (1a) transfers to 2,4,4,4-tetrafluoro-
3,3-dihydroxy-1-phenylbutan-1-one with Selectfluor in
MeCN–H2O solution, releasing the trifluoroacetate group to
generate the α-fluoroketone product of 2a. Then the inter-
molecular condensation reaction occurred to afford the 3-
fluoro-2,4-diphenylfuran (3a) in strong base.
In conclusion, a one-pot synthesis of α-fluoroketones
and 3-fluoro-2,4-diarylfurans through mild release of tri-
fluoroacetate moiety has been developed. This method pro-
vides a practical, simple, and mild synthetic approach to α-
fluoroketones and 3-fluoro-2,4-diarylfurans, which are im-
portant units in biologically active molecules. Further stud-
ies to extend the synthetic applications for fluorinated
compound are ongoing in our laboratory.
O
O
Cl
Br
3g: 35%
3h: 32%
S
F
F
O
S
O
S
O
3j: 22%
3k: 36%
CF3
EtO
F
O
F
F
O
Acknowledgment
CF3
O
OEt
O
We thank the National Natural Science Foundation of China (Nos.
21172148, 21202044) and China Scholarship Council (Nos.
201306745008).
F
3m: 20%a
3l: 30%a
Scheme 3 Scope for the synthesis of 3-fluoro-2,4-diarylfurans. Re-
agents and conditions: 1 (0.5 mmol), selectfluor (0.6 mmol), NaOH (2.0
mmol), MeCN–H2O (5:2; 0.7 mL), 0 °C for 3 h, then 50 °C for 6 h. a The
reaction was carried out at 0 °C for 3 h, then 50 °C for 9 h.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380441.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1835–1840

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O
O
OH
CF3
O
HO OH
CF3
–
– CF3CO2
Selectfluor
CH2F
F
2a
1a
O
H
H
OH–
O
H
O
F
HO CH2F
O–
O
CHF
FH2C
H
F
F
OH–
F
O– HC
F
F
O
3a
Scheme 5 Proposed mechanism
References and Notes
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(17) Typical Experimental Procedure for the Synthesis of 2 from 1
To a mixture of 1d (146 mg, 0.5 mmol) and Na2CO3 (159 mg, 1.5
mmol) in MeCN (0.3 mL) and H2O (0.1 mL), a solution of Select-
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Synlett
fluor (212 mg, 0.6 mmol) in MeCN (0.3 mL) and H2O (0.3 mL)
was added over 30 min at 0 °C. The reaction mixture was then
stirred for 8 h at 0 °C. When the reaction was complete (moni-
tored by TLC), sat. aq NH4Cl (4 mL) was added to quench the
reaction. After extraction with CH2Cl2 and drying with Na2SO4,
the organic layer was concentrated under reduced pressure, and
the residue was purified by column chromatography on silica
gel using hexane–EtOAc (20:1) as eluent to afford the desired
products 2d (64 mg, 60%).
fluor (212 mg, 0.6 mmol) in MeCN (0.3 mL) and H2O (0.1 mL)
was added slowly at 0 °C. The reaction mixture was stirred for 3
h at 0 °C. It was then heated for 6 h at 50 °C. When the reaction
was complete (monitored by TLC), sat. aq NH4Cl (6 mL) was
added to quench the reaction. After extraction with EtOAc and
drying with Na2SO4, the organic layer was concentrated under
reduced pressure, and the residue was purified by column chro-
matography on silica gel using hexane–EtOAc (60:1 to 30:1) as
eluent to afford the desired products 3a (40 mg, 67%).
1-[(1,1′-Biphenyl)-4-yl]-2-fluoroethanone (2d)
3-Fluoro-2,4-diphenylfuran (3a)
White solid; mp 131.5–132.4 °C. 1H NMR (400 MHz, CDCl3): δ =
7.98 (d, J = 8.0 Hz, 2 H), 7.73–7.71 (m, 2 H), 7.64–7.62 (m, 2 H),
7.51–7.47 (m, 2 H), 7.44–7.40 (m, 1 H), 5.56 (d, J = 48.0 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 193.0 (d, J = 15.2 Hz), 146.8,
139.5, 132.3, 129.0, 128.5, 128.4 (d, J = 2.0 Hz), 127.4, 127.2,
83.7 (d, J = 183.8 Hz). 19F NMR (376 MHz, CDCl3): δ = –230.28 (t,
J = 48.8 Hz, 1 F). IR (KBr): ν = 3380, 2929, 2851, 1700, 1602,
1407, 1241, 1207, 1091, 975, 766, 691 cm–1. MS (EI): m/z = 214,
182, 181 (100), 152, 76, 51. HRMS: m/z calcd for [C14H11FO]+:
214.0794; found: 214.0795.
White solid; mp 78.4–79.0 °C. 1H NMR (400 MHz, CDCl3) δ =
7.75 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 4.0
Hz, 1 H), 7.46–7.41 (m, 4 H), 7.36–7.29 (m, 2 H). 13C NMR (101
MHz, CDCl3): δ = 147.5 (d, J = 256.5 Hz), 137.7 (d, J = 21.2 Hz),
136.3 (d, J = 7.1 Hz), 129.3 (d, J = 3.0 Hz), 128.9 (d, J = 3.0 Hz),
128.8, 128.7, 127.7, 127.3, 126.5 (d, J = 3.0 Hz), 123.5 (d, J = 6.0 Hz),
119.4 (d, J = 14.1 Hz). 19F NMR (376 MHz, CDCl3): δ = –166.91 (d,
J = 3.7 Hz, 1 F). IR (KBr): ν = 3422, 3151, 2923, 2852, 1948, 1879,
1634, 1496, 1443, 1410, 1066, 908, 759, 747, 690 cm–1. MS (EI):
m/z = 238 (100), 209, 133, 105, 91, 77, 44. HRMS: m/z calcd for
[C16H11FO]+: 238.0794; found: 238.0795.
(18) Typical Experimental Procedure for the Synthesis of 3 from 1
To a mixture of 1a (108 mg, 0.5 mmol) and NaOH (80 mg, 2.0
mmol) in MeCN (0.2 mL) and H2O (0.1 mL), a solution of Select-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1835–1840