Synthesis of α-fluoroketones and α-fluoroenones in aqueous media

Article abstract of DOI:10.1016/j.jfluchem.2013.08.006

An efficient synthesis of α-fluoroketones via the nucleophilic fluorination of α-bromoketones in water with TBAF·3H₂O as the fluorinating agent was developed in this paper. In addition, a simple and efficient synthesis of α-fluoroenones through the condensation of α-fluoroketones with aldehydes promoted by sodium hydroxide in water was also discovered.

Full text of DOI:10.1016/j.jfluchem.2013.08.006

Journal of Fluorine Chemistry 156 (2013) 9–14
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of
a-fluoroketones and a-fluoroenones in aqueous media
Yan He a,b, Xinying Zhang b, Nana Shen b, Xuesen Fan a,b,
*
a School of Environment, Key Laboratory for Yellow River and Huai River Water Environment and Pollution Control, Ministry of Education,
Henan Normal University, Xinxiang, Henan 453007, PR China
b School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient synthesis of
a-fluoroketones via the nucleophilic fluorination of a-bromoketones in water
Received 13 June 2013
with TBAFꢀ3H2O as the fluorinating agent was developed in this paper. In addition, a simple and efficient
Received in revised form 23 July 2013
Accepted 12 August 2013
Available online 30 August 2013
synthesis of
a
-fluoroenones through the condensation of
a-fluoroketones with aldehydes promoted by
sodium hydroxide in water was also discovered.
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
a
a
-Fluoroketones
-Fluoroenones
TBAFꢀ3H2O
Aqueous media
1. Introduction
are highly efficient, they are expensive for large-scale preparation
and/or difficult to be prepared due to the involvement of the
In our recent study on functionalized allenes, we found that
dangerous F2. The second approach toward
a-fluoroketone is the
TBAFꢀ3H2O in water could be used as a mild base to abstract the
proton of 1,2-allenic ketone to generate an allenyl anion species,
which then reacted with -bromoketone to afford the desired
1,3,40-triketone derivatives [1]. During that study, we observed
that in addition to the corresponding 1,3,40-triketones,
fluoroketones could also be obtained as minor products in some
cases (Scheme 1). We deduced that the -fluoroketones must be
-bromoketones with
a
-
nucleophilic substitution of -bromoketones with fluoride, which
a
could be provided by KF [5], KF/Ph3SnF [6], KF/18-crown-6 [7,8],
KF/PEG-1000 [8], KF/[bmim][BF4] [9], KF/PEG-400 or TBAFꢀ3H2O/
ZnF2/KF [10]. These nucleophilic fluorination processes are
generally convenient to handle and more economical for large-
scale fluorinations. It is also noted that these nucleophilic
fluorinations were usually carried out in polar aprotic organic
solvents, polyethylene glycol (PEG) or ionic liquids. To the best of
a
a
-
a
formed via the nucleophilic fluorination of
a
TBAFꢀ3H2O as a fluorinating agent.
our knowledge, efficient nucleophilic fluorination of
tones carried out in water has yet to be developed. Based on the
above facts, we were interested in a detailed study on the reaction
a-bromoke-
It is well known that
a
-fluoroketones are frequently found in
bioactive molecules or building blocks toward other organo-
fluorine derivatives. It has been well recognized that the electron-
withdrawing effect of fluorine atom(s) can increase the suscepti-
bility of carbonyl to hydration and this property has been exploited
in the design of inhibitors of hydrolytic enzyme [2]. Due to their
of
develop it into a practical and general protocol for the preparation
of -fluoroketones.
a
-bromoketone with TBAFꢀ3H2O in water with the aim to
a
importance, efficient and practical synthetic strategies toward
fluoroketones have long been pursued. In general, there are mainly
two synthetic approaches to -fluoroketones [3]. The first strategy
involves the introduction of fluorine atom(s) into nonfluorinated
substrates with electrophilic fluorinating agents [4], such as N-
fluorosulfonimides, NFSI, or Selectfluor. While these N-F reagents
a-
2. Results and discussion
a
Initially, the reaction was optimized by using 2-bromoaceto-
phenone (1a) as a model substrate (Table 1). After some trials, we
were pleased to find that when 1a was treated with TBAFꢀ3H2O
(3 equiv.) in water at 100 8C for 20 min, the expected 2-
fluoroacetophenone (2a) could be obtained in a yield of 82%
(Table 1, entry 7). The reactions were also conducted in several
organic solvents including CH2Cl2, Et2O, CH3CN, EtOH, and CH3OH.
Compared with water, the reactions carried out in organic solvents
gave 2a in lower yields (Table 1, entries 8–12). When 3 equiv. of KF
was tried instead of TBAFꢀ3H2O, however, only trace amount of 2a
*
Corresponding author at: School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang, Henan 453007, PR China. Tel.: +86 3733329261;
fax: +86 3733326336.
E-mail addresses: xuesen.fan@htu.cn, xuesen.fan@yahoo.com (X. Fan).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.08.006

10
Y. He et al. / Journal of Fluorine Chemistry 156 (2013) 9–14
Scheme 1. Formation of
a-fluoroketone from TBAFꢀ3H2O promoted reaction of 1,2-allenic ketone with
a-bromoketone.
Table 1
Table 2
Optimization study for the fluorination of 1a.a
Scope of the preparation of a
-fluoroketones.a
Entry
Fꢁ source (equiv.)
T (8C)
Solvent
t (min)
Yield (%)b
Entry
R1
R2
Products
Yield (%)b
1
2
TBAFꢀ3H2O (2)
TBAFꢀ3H2O (2)
TBAFꢀ3H2O (2)
TBAFꢀ3H2O (2)
TBAFꢀ3H2O (2)
TBAFꢀ3H2O (2)
TBAFꢀ3H2O (3)
TBAFꢀ3H2O (3)
TBAFꢀ3H2O (3)
TBAFꢀ3H2O (3)
TBAFꢀ3H2O (3)
TBAFꢀ3H2O (3)
KF (3)
r.t.
H2O
120
120
60
Trace
Trace
31
1
2
Ph
H
2a
2b
2c
2d
2e
2f
82
81
83
80
75
71
83
81
53
75
40
H2O
o-Cl-C6H4
o-Br-C6H4
m-Cl-C6H4
p-CH3-C6H4
H
3
60
H2O
3
H
4
80
H2O
60
70
4
H
5
100
H2O
60
73
5
H
6
100
H2O
20
72
6
p-CH3O-C6H4
p-F-C6H4
p-Cl-C6H4
p-NO2-C6H4
Ph
H
7
100
H2O
20
82
7
H
2g
2h
2i
8
Reflux
Reflux
Reflux
Reflux
Reflux
100
CH2Cl2
Et2O
CH3CN
EtOH
CH3OH
H2O
20
55
8
H
9
20
78
9
H
10
11
12
13
14
20
58
10
CH3
2j
20
50
20
30
11
–
2k
74
120
20
Trace
20
TBAFꢀ3H2O (0.5)
KF (1)
100
H2O
15
16
17
18
a
TBAFꢀ3H2O (1)
KF (1)
100
100
100
100
H2O
H2O
H2O
H2O
20
20
20
60
40
55
58
81
TBAFꢀ3H2O (1)
KF (2)
c
12
–
–
TBAFꢀ3H2O (1)
KF (3)
TBAFꢀ3H2O (2)
KF (1)
Reaction conditions: 1a (0.5 mmol), solvent (1.5 mL).
a
Conditions: 1 (1 mmol), TBAFꢀ3H2O (3 mmol), H2O (3 mL).
Isolated yield.
b
Isolated yield.
b
c
Complicated mixture was formed.
was formed (Table 1, entry 13). Interestingly, a combination of
2 equiv. of TBAFꢀ3H2O with 1 equiv. of KF could give similar yield of
2a as that using 3 equiv. of TBAFꢀ3H2O, albeit the reaction period
was longer (Table 1, entry 18).
The optimized reaction conditions were then applied to a
series of -bromoketones and the results are summarized
in Table 2. It is observed that nucleophilic fluorination of
-bromoketones with TBAFꢀ3H2O in water allows efficient
a
a
Table 3
Scope of the reaction toward
a
-fluoroenones.a
Entry
R1
R2
Products
Yield (%)b
1
2
4-CH3-C6H4
4-CH3-C6H4
4-F-C6H4
4-F-C6H4
3-Cl-C6H4
3-Cl-C6H4
Ph
4-CH3-C6H4
4-Cl-C6H4
6a
6b
6c
6d
6e
6f
78
81
75
82
80
86
82
88
83
72
73
3
4-CH3-C6H4
4-Cl-C6H4
4
5
4-CH3-C6H4
4-Cl-C6H4
6
7
3-Cl-C6H4
6g
6h
6i
8
Ph
4-F-C6H4
9
Ph
4-Br-C6H4
4-CH3O-C6H4
4-CH3O-C6H4
10
11
Ph
6j
4-Cl-C6H4
6k
a
Conditions: 1 mmol of 2, 1 mmol of 5, 0.7 mL of NaOH aqueous solution (10%), 0.5 mL of EtOH, r.t.
b
Isolated yield.

Y. He et al. / Journal of Fluorine Chemistry 156 (2013) 9–14
11
Scheme 2. Attempted fluorination of benzyl bromide with TBAFꢀ3H2O.
Scheme 3. Reactions of
a-fluoroketone and a-bromoketone with aldehyde.
preparation of
including the electron-donating methoxy group and the electron-
withdrawing nitro group on the phenyl ring of the -bromoketone
substrates (Table 2, entries 1–9). With substrates containing
hydrogen(s), such as 2-bromo-1-phenylpropan-1-one and 2-
bromo-2,3-dihydro-1H-inden-1-one, the likely -elimination
was not observed at all and the desired -fluoroketones were
isolated in good yields (Table 2, entries 10–11). On the other hand,
we observed that 2-bromocyclohexanone failed to give the
desired product (Table 2, entry 12).
a
-fluoroketones with various functional groups,
carbonyl group should be crucial for a successful fluorination in
this case.
a
With a batch of
focused on their utility as potential synthetic intermediates. In
studying the reaction of -fluoroketone (2) toward aldehyde, we
serendipitously discovered a new approach toward -fluoroenone
a-fluoroketone (2) in hands, our study was then
b
-
a
b
a
a
(6). To be specific, treatment of 2-fluoro-1-p-tolylethanone (2e)
with 4-methylbenzaldehyde (5a) in an aqueous solution of sodium
hydroxide afforded (Z)-2-fluoro-1,3-dip-tolylprop-2-en-1-one
(6a) in a yield of 78% (Scheme 3). Under similar conditions, on
the other hand, 2-bromo-1-p-tolylethanone (1e) gave p-tolyl(3-p-
tolyloxiran-2-yl)methanone (7) as a main product.
Having established an efficient fluorination of a-bromoketones
with TBAFꢀ3H2O in water, we were interested in trying this reagent
to fluorinate simple alkyl bromide. Thus, 2-bromobenzylbromide
(3) was treated with TBAFꢀ3H2O in water at 100 8C for 20 min
(Scheme 2). Unfortunately, it afforded (2-bromophenyl)methanol
(4), rather than the envisioned 1-bromo-2-(fluoromethyl)benzene.
Considering the fact that 1c could be fluorinated smoothly with
TBAFꢀ3H2O in water, we suggested that the presence of an adjacent
The formation of 6a from easily obtainable a-fluoroketone and
commercially available aldehyde without using any expensive
metal catalyst and carried out in aqueous media under mild
conditions is promising due to the following two reasons. Firstly,
a
-fluoroenones are versatile intermediates in organic synthesis
and have been frequently used as precursors toward dipeptide
Scheme 4. Some literature procedures toward
a-fluoroenones.

12
Y. He et al. / Journal of Fluorine Chemistry 156 (2013) 9–14
mimics [11]. Secondly, while several valuable methods for the
preparation of -fluoroenones have already been developed
196.3 (d, JC-F = 17.0 Hz). 19F NMR (376 MHz, CDCl3)
d
: ꢁ224.42 (d,
a
JH-F = 46.8 Hz). MS: m/z 173 [MH]+. HRMS calcd for C8H7ClFO:
(Scheme 4) [12], more practical synthetic protocols toward
fluoroenones are still desirable.
a
-
173.0169 [M+H], found: 173.0161.
To develop the reaction of 2e with 5a into a new method for the
synthesis of -fluoroenone (6), various substrates were tested. To
our delight, all the -fluoroketones and aldehydes screened
participated in this reaction smoothly to afford the corresponding
-fluoroenones in good yields (Table 3). It is also worth to be noted
that all the -fluoroenones were formed stereo-selectively and
only the Z-isomers were obtained from the reactions. The
confirmation of the Z/E configuration was based on the J value
of F/H coupling with ca. 35 Hz for Z-isomers and 25 Hz for E-
isomers [12].
4.2.3. 1-(2-Bromophenyl)-2-fluoroethanone (2c)
a
1H NMR (400 MHz, CDCl3)
d
: 5.28 (d, JH-F = 47.6 Hz, 2H), 7.26–
7.33 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3) : 84.1 (d, JC-F = 185.0 Hz), 119.2, 127.6,
129.4 (d, JC-F = 1.0 Hz), 132.8, 133.8, 137.2, 197.5 (d, JC-F = 18.0 Hz).
a
d
a
a
19F NMR (376 MHz, CDCl3)
d
: ꢁ224.47(d, JH-F = 47.6 Hz). MS: m/z
217 [MH]+. HRMS calcd for C8H7BrFO: 216.9664 [M+H], found:
216.9652.
4.2.4. 1-(3-Chlorophenyl)-2-fluoroethanone (2d)
1H NMR (400 MHz, CDCl3)
d
: 5.50 (d, JH-F = 46.8 Hz, 2H), 7.44 (t,
J = 8.0 Hz, 1H), 7.58–7.60 (m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.87 (s,
1H). 13C NMR (100 MHz, CDCl3)
: 83.5 (d, JC-F = 182.0 Hz), 126.0 (d,
JC-F = 2.0 Hz), 128.0 (d, JC-F = 3.0 Hz), 130.3, 134.1, 135.1, 135.3,
3. Conclusion
d
In summary, a facile and efficient synthetic method for the
preparation of
tion of
a
-fluoroketones through nucleophilic substitu-
192.4 (d, J C-F = 16.0 Hz). 19F NMR (376 MHz, CDCl3)
JH-F = 46.8 Hz). MS: m/z 173 [MH]+. HRMS calcd for C8H7ClFO:
d
: ꢁ230.45 (d,
a
-bromoketones with TBAFꢀ3H2O as the fluorinating
agent in water has been developed. This new strategy has notable
features such as high efficiency, and environmental benigncy.
173.0169 [M+H], found: 173.0168.
Moreover, in exploring the synthetic applications of
oketones, an efficient, stereoselective and easy-to-perform
synthetic protocol to synthesize -fluoroenones through con-
densation of -fluoroketones with aldehydes in aqueous media
a
-fluor-
4.2.5. 2-Fluoro-1-p-tolylethanone (2e)
1H NMR (400 MHz, CDCl3)
d
: 2.40 (s, 3H), 5.49 (d, JH-F = 46.8 Hz,
2H), 7.26 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3) : 21.8, 83.4 (d, JC-F = 180.0 Hz), 127.8 (d, JC-
F = 2.0 Hz), 129.6, 131.0, 145.2, 193.0 (d, JC-F = 15.0 Hz). 19F NMR
a
a
d
was also discovered.
(376 MHz, CDCl3)
d
: ꢁ231.17 (d, JH-F = 46.8 Hz). MS: m/z 153
4. Experimental
[MH]+. HRMS calcd for C9H10FO: 153.0715 [M+H], found:
153.0701.
4.1. General information
4.2.6. 2-Fluoro-1-(4-methoxyphenyl)ethanone (2f) [4d,13]
All reagents were purchased from commercial sources and
used without further purification. 1H, 13C and 19F NMR spectra
were recorded on a Bruker AC 400 spectrometer as CDCl3
solutions. Chemical shifts were expressed in parts per million
1H NMR (400 MHz, CDCl3)
d
: 3.82 (s, 3H), 5.48 (d, JH-F = 46.8 Hz,
2H), 6.90 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3) : 55.5, 83.4 (d, JC-F = 180.0 Hz), 114.1, 126.5,
d
130.1 (d, JC-F = 2.0 Hz), 164.2, 191.8 (d, JC-F = 15.0 Hz). MS: m/z 169
[MH]+.
(
d
) downfield from the internal standard tetramethylsilane and
were reported as s (singlet), d (doublet), t (triplet), m (multiplet)
and coupling constants J were given in Hz. High-resolution mass
spectra (HRMS) were measured on a Bruker MicroTOF mass
spectrometer.
4.2.7. 2-Fluoro-1-(4-fluorophenyl)ethanone (2g) [4d]
1H NMR (400 MHz, CDCl3)
d
: 5.49 (d, JH-F = 46.8 Hz, 2H), 7.16 (t,
J = 8.4 Hz, 2H), 7.91–7.95 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
:
83.5 (d, JC-F = 182.0 Hz), 116.2 (d, JC-F = 22.0 Hz), 130.1, 130.7 (dd,
J1C-F = 9.5 Hz, J2C-F = 2.5 Hz,), 166.2 (d, JC-F = 255.0 Hz), 192.0 (d, JC-
F = 16.0 Hz). MS: m/z 157 [MH]+.
4.2. Typical procedure for the preparation of 2-fluoro-1-
phenylethanone (2a)
To a flask containing water (3 mL) and TBAFꢀ3H2O (3 mmol)
was added 2-bromo-1-phenyl ethanone (1a, 1 mmol). The mixture
was stirred at 100 8C for 20 min. It was then cooled to room
temperature and extracted with diethyl ether (5 mL 3ꢂ). The
combined organic phases were dried, filtered and concentrated
under vacuum. The residue was purified by column chromatogra-
phy on silica gel eluting with ethyl acetate/hexane (5%) to give 2-
fluoro-1-phenyl ethanone (2a). 2b–2k were obtained in a similar
manner.
4.2.8. 1-(4-Chlorophenyl)-2-fluoroethanone (2h)
1H NMR (400 MHz, CDCl3)
d
: 5.49 (d, JH-F = 46.8 Hz, 2H), 7.47 (d,
J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
83.5 (d, JC-F = 182.0 Hz), 129.29, 129.4 (d, JC-F = 3.0 Hz), 131.9,
d
:
140.7, 192.5 (d, JC-F = 16.0 Hz). 19F NMR (376 MHz, CDCl3)
d:
ꢁ230.41 (d, JH-F = 46.8 Hz). MS: m/z 173 [MH]+. HRMS calcd for
C8H7ClFO: 173.0169 [M+H], found: 173.0153.
4.2.9. 2-Fluoro-1-(4-nitrophenyl)ethanone (2i) [4d,13]
1H NMR (400 MHz, CDCl3)
d
: 5.54 (d, JH-F = 46.8 Hz, 2H), 8.10 (d,
4.2.1. 2-Fluoro-1-phenylethanone (2a) [4d,13,14]
J = 8.8 Hz, 2H), 8.36 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d:
1H NMR (400 MHz, CDCl3)
d
: 5.52 (d, JH-F = 46.8 Hz, 2H), 7.49 (t,
J = 8.0 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H). 13C
NMR (100 MHz, CDCl3) : 83.5 (d, JC-F = 181.0 Hz), 127.8 (d, JC-
83.8 (d, JC-F = 184.0 Hz), 124.1, 129.3 (d, JC-F = 3.0 Hz), 138.1, 150.8,
192.2 (d, JC-F = 15.0 Hz). MS: m/z 184 [MH]+.
d
F = 2.0 Hz), 128.9, 133.6, 134.2, 193.4 (d, JC-F = 15.0 Hz). MS: m/z
139 [MH]+.
4.2.10. 2-Fluoro-1-phenylpropan-1-one (2j) [14,15]
1H NMR (400 MHz, CDCl3)
d: 1.66 (dd JH-F = 24.2 Hz, JH-
H = 6.6 Hz, 3H), 5.71 (dq, JH-F = 48.6 Hz, JH-H = 6.6 Hz, 1H), 7.48 (t,
J = 7.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 2H). 13C
NMR (100 MHz, CDCl3) d: 18.3 (d, JC-F = 23.0 Hz), 90.2 (d, JC-
F = 179.0 Hz), 128.7, 128.9 (d, JC-F = 3.0 Hz), 133.7, 134.0, 196.9 (d,
JC-F = 19.0 Hz). MS: m/z 153 [MH]+ [15].
4.2.2. 1-(2-Chlorophenyl)-2-fluoroethanone (2b)
1H NMR (400 MHz, CDCl3)
d
: 5.39 (d, JH-F = 46.8 Hz, 2H), 7.34–
7.45 (m, 3H), 7.61 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
84.8 (d, JC-F = 184.0 Hz), 127.2, 130.6, 130.8, 131.8, 133.2, 135.0,
d
:

Y. He et al. / Journal of Fluorine Chemistry 156 (2013) 9–14
13
4.2.11. 2-Fluoro-2,3-dihydro-1H-inden-1-one (2k) [14]
1H NMR (400 MHz, CDCl3)
: 3.16–3.26 (m, 1H), 3.59–3.65 (m,
1H), 5.18–5.33 (m, 1H), 7.42–7.46 (m, 2H), 7.64–7.68 (m, 1H),
7.77–7.79 (m, 1H). 13C NMR (100 MHz, CDCl3)
: 33.4 (d, JC-
F = 29.0 Hz). 19F NMR (376 MHz, CDCl3)
d
: ꢁ104.33, ꢁ118.20 (d,
d
JH-F = 36.0 Hz). MS: m/z 279 [MH]+. HRMS calcd for C15H10ClF2O:
279.0388 [M+H], found: 279.0371.
d
F = 21.0 Hz), 90.4 (d, JC-F = 189.0 Hz), 124.7, 126.8, 128.4, 133.9,
136.3, 149.6 (d, JC-F = 5.0 Hz), 199.9 (d, JC-F = 16.0 Hz). MS: m/z 151
[MH]+.
4.3.5. (Z)-1-(3-chlorophenyl)-2-fluoro-3-p-tolylprop-2-en-1-one
(6e)
1H NMR (400 MHz, CDCl3)
d: 2.40 (s, 3H), 6.87 (d, JH-F = 36.0 Hz,
1H), 7.24 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.56–7.62 (m,
3H), 7.77 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H). 13C NMR (100 MHz, CDCl3)
4.3. Typical procedure for the preparation of (Z)-2-fluoro-1,3-di-p-
tolylprop-2-en-1-one (6a)
d: 21.6, 120.7 (d, JC-F = 6.0 Hz), 127.4 (d, JC-F = 4.0 Hz), 128.4 (d, JC-
F = 4.0 Hz), 129.3 (d, JC-F = 4.0 Hz), 129.7 (d, JC-F = 4.0 Hz), 130.76,
130.84, 132.7, 134.7, 137.9, 140.9, 153.8 (d, JC-F = 269.0 Hz), 186.4
To a flask containing an aqueous solution of sodium hydroxide
(0.7 mL, 10%) and EtOH (0.5 mL) were added 2-fluoro-1-p-
tolylethanone (2e, 1 mmol) and 4-methylbenzaldehyde (5a,
1 mmol). The mixture was stirred at room temperature. Upon
completion as monitored by TLC, the reaction was quenched with
aqueous NH4Cl. Then, the mixture was filtered on diatomite and
the filtrate was extracted with ethyl acetate (5 mL 3ꢂ). The
combined organic phases were dried, filtered and concentrated
under vacuum. The residue was purified by column chromatogra-
phy on silica gel eluting with ethyl acetate/hexanes (2%) to give (Z)-
2-fluoro-1,3-di-p-tolylprop-2-en-1-one (6a). 6b–6k were obtained
in a similar manner.
(d, JC-F = 29.0 Hz). 19F NMR (376 MHz, CDCl3)
d
: ꢁ121.10 (d, JH-
F = 36.0 Hz). MS: m/z 275 [MH]+. HRMS calcd for C16H13ClFO:
275.0639 [M+H], found: 275.0636.
4.3.6. (Z)-1-(3-chlorophenyl)-3-(4-chlorophenyl)-2-fluoroprop-2-
en-1-one (6f)
1H NMR (400 MHz, CDCl3)
d
: 6.85 (d, JH-F = 36.0 Hz, 1H), 7.39–
7.46 (m, 3H), 7.57–7.65 (m, 3H), 7.78 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H).
13C NMR (100 MHz, CDCl3)
: 118.8 (d, JC-F = 6.0 Hz), 127.4 (d, JC-
d
F = 5.0 Hz), 129.3, 129.4 (d, JC-F = 5.0 Hz), 129.6 (d, JC-F = 4.0 Hz),
129.8, 131.9 (d, JC-F = 8.0 Hz), 133.0, 134.8, 136.3, 137.5, 154.4 (d,
JC-F = 272.0 Hz), 186.0 (d, JC-F = 29.0 Hz). 19F NMR (376 MHz, CDCl3)
4.3.1. (Z)-2-fluoro-1,3-di-p-tolylprop-2-en-1-one (6a)
d
C
: ꢁ119.07 (d, JH-F = 36.0 Hz). MS: m/z 295 [MH]+. HRMS calcd for
1H NMR (400 MHz, CDCl3)
d
: 2.38 (s, 3H), 2.43 (s, 3H), 6.85 (d, JH-
15H10Cl2FO: 295.0092 [M+H], found: 295.0074.
F = 36.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.60
(d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz,
4.3.7. (Z)-3-(3-chlorophenyl)-2-fluoro-1-phenylprop-2-en-1-one
CDCl3)
d
: 21.5, 21.6, 119.8, 128.7 (d, JC-F = 4.0 Hz), 129.1, 129.5 (d,
(6g)
JC-F = 5.0 Hz), 129.6, 130.6 (d, JC-F = 9.0 Hz), 133.7, 140.3, 143.7,
154.4 (d, JC-F = 270.0 Hz), 187.4 (d, JC-F = 28.0 Hz). 19F NMR
1H NMR (400 MHz, CDCl3)
d
: 6.80 (d, JH-F = 35.2 Hz, 1H), 7.35 (t,
J = 3.2 Hz, 2H), 7.48–7.62 (m, 4H), 7.70 (s, 1H), 7.89 (d, J = 8.4 Hz,
2H). 13C NMR (100 MHz, CDCl3)
: 118.3, 128.6 (d, JC-F = 6.4 Hz),
128.7, 129.4 (d, JC-F = 4.4 Hz), 129.9 (d, JC-F = 2.7 Hz), 130.2 (d, JC-
F = 10.8 Hz), 130.3, 133.0 (d, JC-F = 3.7 Hz), 133.2, 134.8, 135.9,
155.0 (d, JC-F = 273.4 Hz), 187.5 (d, JC-F = 28.9 Hz). 19F NMR
(376 MHz, CDCl3)
d
: ꢁ119.98 (d, JH-F = 36.4 Hz). MS: m/z 255
d
[MH]+. HRMS calcd for C17H16FO: 255.1185 [M+H], found:
255.1166.
4.3.2. (Z)-3-(4-chlorophenyl)-2-fluoro-1-p-tolylprop-2-en-1-one
(376 MHz, CDCl3)
d
: ꢁ116.98 (d, JH-F = 35.2 Hz). MS: m/z 261
(6b)
[MH]+. HRMS calcd for C15H11ClFO: 261.0482 [M+H], found:
261.0483.
1H NMR (400 MHz, CDCl3)
d
: 2.43 (s, 3H), 6.80 (d, JH-F = 36.0 Hz,
1H), 7.29 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 7.6 Hz,
2H), 7.81 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
: 21.7, 118.0
d
4.3.8. (Z)-2-fluoro-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one
(d, JC-F = 6.0 Hz), 129.2 (d, JC-F = 7.0 Hz), 129.6 (d, JC-F = 4.0 Hz), 130.0
(d, JC-F = 4.0 Hz), 131.6, 131.8, 133.3, 135.8 (d, JC-F = 4.0 Hz), 144.1,
154.9 (d, JC-F = 274.0 Hz), 187.1(d, JC-F = 28.0 Hz). 19F NMR (376 MHz,
(6h)
1H NMR (400 MHz, CDCl3)
d
: 6.84 (d, JH-F = 36.0 Hz, 1H), 7.11 (t,
J = 8.4 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.58–7.62 (m, 1H), 7.68–7.71
(m, 2H), 7.88 (d, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3)
: 116.1
CDCl3)
d
: ꢁ117.89 (d, JH-F = 36.0 Hz). MS: m/z 275 [MH]+. HRMS calcd
d
for C16H13ClFO: 275.0639 [M+H], found: 275.0635.
(d, JC-F = 21.9 Hz), 119.0, 127.6 (t, JC-F = 3.6 Hz), 128.5, 129.4 (d, JC-
F = 3.4 Hz), 132.6 (d, JC-F = 9.0 Hz), 132.9 (d, JC-F = 22.6 Hz), 136.1,
154.2 (d, JC-F = 267.9 Hz), 163.4 (dd, J1 C-F = 250.5 Hz, J2C-F = 4.0 Hz),
4.3.3. (Z)-2-fluoro-1-(4-fluorophenyl)-3-p-tolylprop-2-en-1-one
(6c)
187.8 (d, JC-F = 29.8 Hz). 19F NMR (376 MHz, CDCl3)
d
: ꢁ108.91,
1H NMR (400 MHz, CDCl3)
d
: 2.39 (s, 3H), 6.87 (d, JH-F = 36.0 Hz,
1H), 7.14–7.18 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz,
2H), 7.94–7.97 (m, 2H). 13C NMR (100 MHz, CDCl3)
: 21.5, 115.7
ꢁ120.47 (d, JH-F = 36.0 Hz). MS: m/z 245 [MH]+. HRMS calcd for
C15H11F2O: 245.0778 [M+H], found: 245.0782.
d
(d, JC-F = 22.0 Hz), 119.9 (d, JC-F = 6.0 Hz), 128.5 (d, JC-F = 4.0 Hz),
129.6, 130.7 (d, JC-F = 9.0 Hz), 132.1 (dd, J1C-F = 9.0 Hz, J2C-
F = 5.0 Hz), 132.5, 140.6, 154.2 (d, JC-F = 270.0 Hz), 165.6 (d, JC-
4.3.9. (Z)-3-(4-bromophenyl)-2-fluoro-1-phenylprop-2-en-1-one
(6i)
1H NMR (400 MHz, CDCl3)
d
: 6.80 (d, JH-F = 36.0 Hz, 1H), 7.47–
F = 253.0 Hz), 186.1 (d, JC-F = 29.0 Hz). 19F NMR (376 MHz, CDCl3)
d
:
7.62 (m, 7H), 7.88 (d, J = 6.8 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d:
ꢁ104.96, ꢁ120.23 (d, JH-F = 36.0 Hz). MS: m/z 259 [MH]+. HRMS
118.7 (d, JC-F = 5.6 Hz), 124.4 (d, JC-F = 4.9 Hz), 128.6, 129.4 (d, JC-
F = 4.0 Hz), 130.3 (d, JC-F = 4.4 Hz), 132.0 (d, JC-F = 8.2 Hz), 132.2,
133.1, 136.0, 154.7 (d, JC-F = 273.5 Hz), 187.6 (d, JC-F = 29.2 Hz). 19
calcd for C16H13F2O: 259.0934 [M+H], found: 259.0918.
F
4.3.4. (Z)-3-(4-chlorophenyl)-2-fluoro-1-(4-fluorophenyl)prop-2-
NMR (376 MHz, CDCl3)
d
: ꢁ118.01 (d, JH-F = 36.0 Hz). MS: m/z 305
en-1-one (6d)
[MH]+. HRMS calcd for C15H11BrFO: 304.9977 [M+H], found:
304.9989.
1H NMR (400 MHz, CDCl3)
d
: 6.85 (d, JH-F = 36.0 Hz, 1H), 7.15–
7.19 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.94–
7.97 (m, 2H). 13C NMR (100 MHz, CDCl3)
: 115.8 (d, JC-F = 22.0 Hz),
d
4.3.10. (Z)-2-fluoro-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one
118.1 (d, JC-F = 6.0 Hz), 129.2, 129.8 (d, JC-F = 4.0 Hz), 131.7, 131.8,
132.2 (dd, J1C-F = 9.5 Hz, J2C-F = 5.5 Hz), 136.0 (d, JC-F = 4.0 Hz), 154.7
(d, JC-F = 273.0 Hz), 165.7 (d, JC-F = 254.0 Hz), 185.7 (d, JC-
(6j)
1H NMR (400 MHz, CDCl3)
d
: 3.84 (s, 3H), 6.82 (d, JH-F = 36.8 Hz,
1H), 6.93 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H), 7.57–7.59 (m,

14
Y. He et al. / Journal of Fluorine Chemistry 156 (2013) 9–14
1H), 7.66 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 7.6 Hz, 2H). 13C NMR
(100 MHz, CDCl3) : 55.4, 114.4, 120.8 (d, JC-F = 6.1 Hz), 124.0 (d, JC-
For a review, see:
d
[3] T. Furuya, C.A. Kuttruff, T. Ritter, Curr. Opin. Drug Discov. Devel. 11 (2008) 803–
819.
F = 4.8 Hz), 128.5, 129.3 (d, JC-F = 4.5 Hz), 132.5 (d, JC-F = 8.7 Hz),
136.6, 153.5 (d, JC-F = 267.2 Hz), 161.1 (d, JC-F = 3.3 Hz), 188.1 (d, JC-
F = 27.6 Hz). 19F NMR (376 MHz, CDCl3)
d
:
ꢁ121.22 (d, JH-
For the preparation of a-fluoroketone with electrophilic
fluorinating agents, see:
F = 36.8 Hz). MS: m/z 257 [MH]+. HRMS calcd for C16H14FO2:
257.0978 [M+H], found: 257.0980.
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4.3.11. (Z)-1-(4-chlorophenyl)-2-fluoro-3-(4-methoxyphenyl)prop-
2-en-1-one (6k)
´
(c) N. Ahlsten, A. Bartoszewicz, S. Agrawal, B. Martın-Matute, Synthesis (2011)
1H NMR (400 MHz, CDCl3)
d
: 3.85 (s, 3H), 6.84 (d, JH-F = 37.2 Hz,
1H), 6.94 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.66 (d,
J = 8.4 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
2600–2608;
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9556;
d
:
55.4, 114.5, 120.5 (d, JC-F = 5.3 Hz), 123.9 (d, JC-F = 3.8 Hz), 128.8,
130.8 (d, JC-F = 4.8 Hz), 132.6 (d, JC-F = 8.1 Hz), 134.8, 139.2, 153.4
(d, JC-F = 267.2 Hz), 161.2 (d, JC-F = 3.8 Hz), 186.5 (d, JC-F = 28.9 Hz).
(h) G. Stavber, M. Zupan, S. Stavber, Synlett (2009) 589–594;
(i) J. Liu, J. Chan, C.M. Bryant, P.A. Duspara, E.E. Lee, D. Powell, H. Yang, Z. Liu, C.
Walpole, E. Roberts, R.A. Batey, Tetrahedron Lett. 53 (2012) 2971–2975;
(j) W.-B. Yi, X. Huang, C. Cai, W. Zhang, Green Chem. 14 (2012) 3185–3189.
[5] P.J. Wagner, M.J. Thomas, A.E. Puchalski, J. Am. Chem. Soc. 108 (1986) 7739–7742.
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(b) L. Fitjer, Synthesis 3 (1977) 189–191.
19F NMR (376 MHz, CDCl3)
d
: ꢁ123.10 (d, JH-F = 37.2 Hz). MS: m/z
291 [MH]+. HRMS calcd for C16H13ClFO2: 291.0588 [M+H], found:
291.0582.
Acknowledgments
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[11] G. Dutheuil, S. Couve-Bonnaire, X. Pannecoucke, Angew. Chem. Int. Ed. 46 (2007)
1290–1292.
We are grateful to the National Natural Science Foundation of
China (21272058, 21172057), RFDP (20114104110005), and
PCSIRT (IRT 1061).
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