Synthesis of β-fluoroenones and their reductive rearrangement in aqueous media

Article abstract of DOI:10.1016/j.tet.2013.07.065

In this paper, a simple and efficient preparation of β-fluoroenones, as a mixture of E/Z isomers with the E-isomer as the main product, from 1,2-allenic ketones by using TBAF·3H₂O in water as a nucleophilic fluorination agent has been developed. Moreover, in exploring the synthetic applications of β-fluoroenones, an unprecedented reductive defluorination rearrangement of β-fluoroenones toward enones under mild conditions in aqueous media was also discovered.

Full text of DOI:10.1016/j.tet.2013.07.065

Tetrahedron xxx (2013) 1e6
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of
b
-fluoroenones and their reductive rearrangement in
aqueous media
,
,
b
,
b
Yan He a b, Nana Shen b, Xuesen Fan a , Xinying Zhang
*
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:
In this paper, a simple and efficient preparation of b-fluoroenones, as a mixture of E/Z isomers with the E-
Received 22 May 2013
Received in revised form 11 July 2013
Accepted 18 July 2013
Available online xxx
isomer as the main product, from 1,2-allenic ketones by using TBAF$3H2O in water as a nucleophilic
fluorination agent has been developed. Moreover, in exploring the synthetic applications of -fluo-
-fluoroenones toward enones
b
roenones, an unprecedented reductive defluorination rearrangement of
b
under mild conditions in aqueous media was also discovered.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
b
-Fluoroenones
TBAF$3H2O
Aqueous media
Rearrangement
1. Introduction
or Clꢀ on 1,2-allenic ketones in HOAc or HOAc/CF3CO2H at ambient
temperature.13 From these reactions, a series of
b-halo-b,g-un-
Fluorine-containing organic compounds are attracting much
attention of scientists from different disciplines because of their
wide applications in medicinal, material, chemical and other
fields.1,2 Among them, fluoroenones and their derivatives, endowed
with unique property and diverse reactivity, have been frequently
used in organic synthesis and drug discovery.3e5 Due to their im-
saturated ketones were obtained with high efficiency (Scheme 1).
portance, several methods to prepare
b-fluoroenones, such as
hydrofluorination of alkynyl ketones,6 alkylation of difluor-
oenones,7 elimination of HF from difluoroalkyl ketones,3 alkylation
Scheme 1. Nucleophilic halogenations of 1,2-allenic ketones by Ma, et al.
of b-fluoro-a,b b-
-unsaturated acid chloride,8 deoxy-fluorination of
diketones,9 or cyclization of difluorovinyl ketones,3a,10 have been
developed. While these methods are generally efficient and reli-
able, new protocols using readily available precursors and realized
in a more environmentally sustainable manner are still highly
desirable.
Notwithstanding the success achieved with Iꢀ, Brꢀ, and Clꢀ, to
our knowledge, nucleophilic addition of Fꢀ on 1,2-allenic ketone, to
the best of our knowledge, has not been studied.14 Based on the
above facts and as a continuation of our recent research with regard
to the synthesis and application of functionalized allenes,15 we
were interested in exploring the nucleophilic fluorination of 1,2-
allenic ketones.
Initially, the elegant strategy for the chlorination, bromination
and iodination of allenic ketones as shown in Scheme 1 was tried to
see if it is also suitable for the fluorination of allenic ketones. For this
purpose, 1-phenylbuta-2,3-dien-1-one (1a) as a model substrate
was treated with KF in HOAc. After the mixture was stirred at 25 ꢁC
for 7 h, 1a was completely consumed. However, the desired fluori-
As an excellent nucleophilic addition acceptor,1,2-allenic ketone
is remarkably powerful in forming carbonecarbon and carbon-
eheteroatom bonds and this property has been extensively
exploited in the synthesis of various organic compounds.11,12 In this
regard, Ma’s group has studied the nucleophilic addition of Iꢀ, Brꢀ,
* Corresponding author. Tel.: þ86 373 332 9261; fax: þ86 373 332 6336; e-mail
addresses: xuesen.fan@henannu.edu.cn, xuesen.fan@yahoo.com, xuesen.fan@
htu.cn (X. Fan).
nation product(s) was not isolated from the mixture. Instead,
b-
acetoxy- -unsaturated ketone (I) and -acetoxy- -unsaturated
b
,g
b
a,b
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.065
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2
Y. He et al. / Tetrahedron xxx (2013) 1e6
ketone (II) resulting from the conjugate addition of acetic acid across
the allene moiety of 1a were obtained (Scheme 2). Furthermore,
when the reactionwas run in a mixed solvent of HOAc/THF (v:v/1:1),
similar results were observed. Then, another frequently used Fꢀ
source, TBAF$3H2O, was used to replace KF. Nevertheless, treatment
of 1a with TBAF$3H2O in HOAc or in HOAc/THF still gave I and II as
the dominating products.
The observations described above showed that the optimal condi-
tions for the preparation of 2a involve 1a (1 equiv) and TBAF$3H2O
(3 equiv) in water at 100 ꢁC for 20 min. Under such conditions, 2a
could be obtained in a yield of 81% as shown in entry 6.
It was soon noted that in Ma’s hydrohalogenation of 1,2-
allenic ketones with MX in HOAc,
oketones were obtained as dominating products while
saturated
b
,
g
-unsaturated
b
a,b
-hal-
-un-
b
-haloketones were isolated only in trace amount
(Scheme 1). In this work, on the other hand, we observed that the
fluorination of 1,2-allenic ketones with TBAF$3H2O in water gave
b
-fluoro-a,b-unsaturated ketones exclusively. A plausible mech-
anism accounting for this reversed regioselectivity is shown in
Scheme 3. Firstly, conjugate addition of Fꢀ on 1,2-allenyl ketones
at the central carbon of the allenyl moiety gives two resonance
contributors, A and B. Protonation of B affords enol C, from which
Scheme 2. Attempted fluorination of allenic ketone in HOAc.
b
-fluoro-
a
,
b
-unsaturated ketone (2a) is formed as the final
-fluoro- -unsaturated ketone (D) may
product. Meanwhile,
b
b,g
also be formed via protonation of anion A. However, under the
basic and refluxing temperature conditions, D would readily
2. Results and discussion
isomerize to the thermodynamically much more stable
b-fluoro-
The results shown in Scheme 2 clearly indicate that under the
reaction conditions HOAc is actually a better nucleophile than
fluoride toward allenic ketone. Under this circumstance, solvents
other than HOAc were screened as possible media for the envi-
sioned fluorination. After some trials, we were pleased to find that
when 1a was treated with TBAF$3H2O (2 equiv) in water at 100 ꢁC
a,b
-unsaturated ketone (2a). On the other hand, in Ma’s hydro-
halogenation, the mild acidic reaction conditions used therein is
believed to be crucial to suppress the possible isomerization of
the initially formed
a,b
b,g-unsaturated ketones to the more stable
-unsaturated ketones.13
for 20 min, 3-fluoro-1-phenylbut-2-en-1-one (2a), a b-fluoro-a,b-
unsaturated ketone, could be obtained as a mixture of E/Z isomers
in a total yield of 71% (Table 1, entry 5). Increasing the amount of
TBAF$3H2O from 2 to 3 equiv could improve the yield to 81% (entry
6). Surprisingly, we observed that the reactions run in several
refluxing organic solvents, such as CH2Cl2, Et2O, CH3CN, or THF,
gave complicated mixtures (entries 7e10). These results reveal that
besides possible economic and environmental benefits, water as
a medium can remarkably facilitate this nucleophilic fluorination
process.16 Furthermore, KF was also tried as a possible Fꢀ source for
the fluorination of 1a in water. However, with 3 equiv of KF, the
formation of 2a was not observed even over prolonged reaction
period (entry 11). Combination of 1 equiv of TBAF$3H2O with dif-
ferent amounts of KF did not give fruitful results (entries 12e13).
Scheme 3. Plausible mechanism for the formation of 2a.
The scope of the above reaction was then studied. While all the
aryl substituted substrates under screening underwent the fluori-
nation process smoothly (Table 2, entries 1e11), substrates with
electron-withdrawing group (EWG) gave lower yields of
b-fluo-
roenones (entries 2, 4, and 7e9) than those bearing electron-
donating group (EDG) (entries 5e6 and 10e11). From substrates
with EWG, 1,3-diketones, formed through hydration of the allene
Table 1
Optimization for the nucleophilic fluorination of 1aa
unit, were usually isolated along with b-fluoroenones. This is pre-
sumably attributed to the fact that the enhanced electrophilicity of
substrates with EWG makes them less selective toward Fꢀ over
H2O, thus resulting in the formation of 1,3-diketones and de-
creasing yields of fluoroenones. As a further aspect, benzyl and
phenylethyl substituted substrates could afford the corresponding
Entry
Fꢀ source (equiv)
Solvent
T (ꢁC)
t (min)
Yield (%)b
1
2
3
4
5
6
7
8
TBAF$3H2O (2)
TBAF$3H2O (2)
TBAF$3H2O (2)
TBAF$3H2O (2)
TBAF$3H2O (2)
TBAF$3H2O (3)
TBAF$3H2O (3)
TBAF$3H2O (3)
TBAF$3H2O (3)
TBAF$3H2O (3)
KF (3)
H2O
H2O
H2O
H2O
rt
40
60
80
100
100
Reflux
Reflux
Reflux
Reflux
100
100
60
60
60
20
20
20
20
20
20
20
120
120
Trace
15
51
66
71
b-fluoroenones in good yields (entries 12 and 13). Notably, re-
actions of substrates bearing a methyl group on the internal or
terminal position of the allenyl moiety need longer period to
complete, indicating that steric hindrance plays a role for this
conjugate addition process (entries 14e18). Under the reaction
conditions, an unsaturated ester moiety is well tolerated (entry 19).
Promisingly, by using the synthetic strategy developed above,
a fluorovinyl substituted pyrimidine nucleoside with potential bi-
ological activity was prepared in moderate yield (entry 20). It is also
noted that simple alkyl substituted substrate only give the desired
product in trace amount (entry 21).
H2O
H2O
CH2Cl2
Et2O
CH3CN
THF
81
dc
dc
dc
dc
d
9
10
11
12
H2O
H2O
TBAF$3H2O (1)
KF (1)
TBAF$3H2O (1)
KF (2)
Trace
13
H2O
100
120
Trace
With a batch of
b-fluoroenones (2) in hands, our study was
The use of bold font indicates the optimum reaction conditions for the preparation
then focused on their utility as potential synthetic intermediates.
During this process, an unprecedented and mechanistically at-
tractive transformation was serendipitously discovered. To be
specific, treating 2a with KBH4 in aqueous methanol did not
of 2a.
a
Reaction conditions: 1a (0.5 mmol), solvent (1.5 mL).
Isolated yield (as a mixture of E/Z isomers).
Complicated mixture was obtained.
b
c
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Y. He et al. / Tetrahedron xxx (2013) 1e6
3
cation H0 and H. Capture of the Fꢀ stabilized cation H by water af-
fords a gem-fluorohydrin (I). Subsequent expulsion of HF from I
affords 3a as the final product (Scheme 5).
Table 2
Scope of the fluorination of 1,2-allenic ketonesa
Entry
R1
R2
R3
Product
Yield (%)b
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
81 (4:1)c
58 (5:1)c
72 (7:1)c
60 (5:1)c
85 (4:1)c
86 (4:1)c
57 (8:1)c
60 (5:1)c
65 (6:1)c
88 (4:1)c
87 (4:1)c
80 (4:1)c
70 (5:1)c
51 (4:1)c
55 (7:1)c
65 (5:1)c
63 (8:1)c
64 (7:1)c
o-CleC6H4
m-CH3eC6H4
m-FeC6H4
p-CH3eC6H4
p-CH3OeC6H4
p-FeC6H4
p-CleC6H4
p-BreC6H4
m, p-di-CH3OeC6H3
2-Naphthyl
PhCH2
PhCH2CH2
p-CH3eC6H4
p-CleC6H4
Ph
p-CH3eC6H4
p-CleC6H4
Scheme 5. Another plausible pathway for the formation of 3a from 2a.
To clarify the mechanism, the reaction of 2a was then tried in
the presence of H128O (Scheme 6). It turned out the reaction still
gave 3a rather than the isotopically labelled product [18O]-3a. This
result may eliminate the possibility of the formation of cation H as
shown in Scheme 5 since if such a cation intermediate had formed,
it should have been captured by H128O to afford [18O]-3a.
9
10
11
12
13
14
15
16
17
18
H
CH3
CH3
H
H
H
CH3
CH3
CH3
Scheme 6. Reductive defluorination rearrangement of 2a in H128O.
19
20
H
H
H
H
H
H
2s
2t
66 (6:1)c
52 (8:1)c
Trace
The generality of the above described reductive defluorination
rearrangement of
b-fluoroenone was further confirmed with
a range of substrates, from which various enones with diverse
substituents could be formed with high efficiency (Table 3), thus
resulting an alternative synthetic method toward enones.
Table 3
Scope of the reductive defluorination rearrangement of b
-fluoroenonea
21
n-Pr
2u
a
Reaction conditions: 1 (1 mmol), TBAF$3H2O (3 mmol), H2O (3 mL), 100 ꢁC,
20 min or 2 h for entries 14e18.
b
Isolated yield (as a mixture of E/Z isomer).
c
Ratio of E/Z isomer determined by 19F NMR of the crude product.
Entry
R1
R2
Products
Yield (%)b
afford the expected fluoroalcohol.17,18 On the other hand, an
enone, (E)-4-phenylbut-3-en-2-one (3a), was obtained in a yield
of 78% (Scheme 4).
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
CH3
H
3a
3b
3c
3d
3e
3f
78
75
76
83
70
79
72
85
m-FeC6H4
m-CleC6H4
p-BreC6H4
m, p-di-CH3OeC6H3
Ph
o-CleC6H4
PhCH2CH2
3g
3h
H
a
Reaction conditions: 0.5 mmol of 2, 1.5 mmol of KBH4, 2.5 mL of H2O, 2.5 mL of
MeOH, rt, 4 h.
b
Isolated yield.
3. Conclusion
Scheme 4. Reductive defluorination rearrangement of b-fluoroenone and a plausible
reaction mechanism.
In summary, a facile and efficient synthetic method for the
preparation of b-fluoroenones through nucleophilic fluorination of
A plausible pathway for the formation of 3a is proposed in
Scheme 4. Initially, reduction of 2a with KBH4 may afford 3-fluoro-
1,2-allenic ketones with TBAF$3H2O in water has been developed.
This new strategy has notable features, such as high efficiency,
easily obtainable starting materials and reagents, and remarkably
enhanced reactivity by using water as the reaction medium.
1-phenylbut-2-en-1-ol (E) bearing a
b-hydroxyfluorovinyl unit,
which simultaneously undergoes an intramolecular nucleophilic
addition process to give intermediate F. Elimination of HF from F
gives an oxetene intermediate (G). Subsequent ring opening of G
affords enone 3a.19
Moreover, in exploring the synthetic applications of
b-fluo-
roenones, a novel reductive defluorination rearrangement of
b
-
fluoroenones realized in aqueous media was also discovered. It is
Another plausible reaction pathway toward 3a may involve the
initial solvolysis of alcohol E assisted by the vinyl fluoride to give
expected that the results reported in this paper may not only
provide a valuable alternative protocol for the preparation of b-
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4
Y. He et al. / Tetrahedron xxx (2013) 1e6
fluoroenones but also give a new example to showcase the diverse
reactivity of -fluoroenones.
JCeF¼22.0 Hz), 119.8 (d, JCeF¼22.0 Hz), 123.5 (d, JCeF¼3.0 Hz), 130.2
(d, JCeF¼4.0 Hz), 140.6, 162.9 (d, JCeF¼247.0 Hz), 175.4 (d,
JCeF¼276.0 Hz), 188.8 (d, JCeF¼20.0 Hz). MS: m/z 183 [MH]þ. HRMS
calcd for C10H9F2O: 183.0621 [MþH], found: 183.0638.
b
4. Experimental
4.1. General
4.2.5. (E)-3-Fluoro-1-p-tolylbut-2-en-1-one (2e). Oil; yield: 60%; 1H
NMR (400 MHz, CDCl3)
(d, JHeF¼20.4 Hz, 1H), 7.26 (d, J¼7.6 Hz, 2H), 7.81 (d, J¼7.6 Hz, 2H).
13C NMR (100 MHz, CDCl3)
d
: 2.41 (s, 3H), 2.46 (d, J¼19.6 Hz, 3H), 6.70
1,2-Allenic ketones were prepared based on literature pro-
cedures.20 Other reagents and solvents were purchased from
commercial suppliers and used without further purification. The 1H
and 13C NMR spectra were recorded at 400 MHz and 100 MHz,
respectively. Chemical shifts were reported in parts per million
from tetramethylsilane (TMS) as internal standard in CDCl3 solu-
tions. Multiplicity was indicated as follows: s (singlet); d (doublet);
t (triplet); m (multiplet); dd (doublet of doublets); td (triplet of
doublets); br s (broad singlet), etc. and coupling constants are given
in Hertz. The conversion of starting materials was monitored by
thin layer chromatography (TLC) using silica gel plates and com-
ponents were visualized by observation under UV light.
d: 17.2 (d, JCeF¼24.0 Hz), 21.6, 104.7 (d,
JCeF¼22.0 Hz), 128.0, 129.3, 136.0, 143.7, 174.4 (d, JCeF¼276.0 Hz),
189.6 (d, JCeF¼20.0 Hz). MS: m/z 179 [MH]þ. HRMS calcd for
C11H12FO: 179.0872 [MþH], found: 179.0887.
4.2.6. (E)-3-Fluoro-1-(4-methoxyphenyl)but-2-en-1-one (2f). White
solid, mp 26e28 ꢁC; yield: 66%; 1H NMR (400 MHz, CDCl3)
: 2.44
d
(d, J¼20.0 Hz, 3H), 3.86 (s, 3H), 6.68 (d, JHeF¼20.8 Hz, 1H), 6.94 (d,
J¼8.8 Hz, 2H), 7.89 (d, J¼8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d:
17.1 (d, JCeF¼24.0 Hz), 55.4, 104.6 (d, JCeF¼22.0 Hz), 113.8, 130.2,
131.4, 131.5, 163.4, 174.0 (d, JCeF¼275.0 Hz), 188.6 (d, JCeF¼19.0 Hz).
19F NMR (376 MHz, CDCl3)
calcd for C11H12FO2: 195.0821 [MþH], found: 195.0832.
d
: ꢀ65.53. MS: m/z 195 [MH]þ. HRMS
4.2. Typical procedure for the preparation of 3-fluoro-1-
phenylbut-2-en-1-one (2a)
4.2.7. (Z)-3-Fluoro-1-(4-methoxyphenyl)but-2-en-1-one
To a flask containing water (3 mL) and TBAF$3H2O (3 mmol) was
added 1-phenylbuta-2,3-dien-1-one (1a, 1 mmol). The mixture was
stirred at 100 ꢁC for 20 min. It was then cooled to room temperature
and extracted with diethyl ether (5 mLꢂ3). The organic phases
were dried, filtered and concentrated under vacuum. The residue
was purified by column chromatography on silica gel eluenting
with ethyl acetate/hexanes (5%) to give 3-fluoro-1-phenylbut-2-en-
1-one (2a) as a mixture of stereoisomers (E:Z¼4:1). 2bet were
obtained in a similar manner. Except for 2f, only the (E)-isomer of
(2f). Syrup; yield: 14%; 1H NMR (400 MHz, CDCl3)
d: 2.11 (d,
J¼16.8 Hz, 3H), 3.85 (s, 3H), 6.02 (d, JHeF¼33.6 Hz, 1H), 6.92 (d,
J¼8.8 Hz, 2H), 7.88 (d, J¼8.8 Hz, 2H).13C NMR (100 MHz, CDCl3)
d: 19.3
(d, JCeF¼26.2 Hz), 55.4,104.3 (d, JCeF¼6.6 Hz),113.7,130.6,131.0,163.4,
167.4 (d, JCeF¼281.1 Hz), 187.2. 19F NMR (376 MHz, CDCl3)
: ꢀ75.67.
d
4.2.8. (E)-3-Fluoro-1-(4-fluorophenyl)but-2-en-1-one (2g). Oil; yiel
d: 45%; 1H NMR (400 MHz, CDCl3)
d
: 2.45 (d, J¼19.6 Hz, 3H), 6.67 (d,
JHeF¼20.0 Hz, 1H), 7.13 (t, J¼8.8 Hz, 2H), 7.90e7.94 (m, 2H). 13C NMR
the
b
-fluoroenones was obtained as pure form by column chro-
(100 MHz, CDCl3)
d:17.2(d, JCeF¼24.0 Hz),104.4 (d, JCeF¼22.0 Hz),115.7
matography. The stereochemistry of the double bond was assigned
based on the coupling constant of the vinyl proton and fluorine. For
E-isomer, JHeF¼19.0e21.0 Hz; for (Z)-isomer, JHeF¼33.0e35.0 Hz.9
(d, JCeF¼22.0 Hz), 130.5 (d, JCeF¼10.0 Hz), 165.6 (d, JCeF¼252.0 Hz),
174.9 (d, JCeF¼276.0 Hz), 188.5 (d, JCeF¼20.0 Hz). MS: m/z 183 [MH]þ.
HRMS calcd for C10H9F2O: 183.0621 [MþH], found: 183.0629.
4.2.1. (E)-3-Fluoro-1-phenylbut-2-en-1-one (2a).9 Oil; yield: 58%;
4.2.9. (E)-1-(4-Chlorophenyl)-3-fluorobut-2-en-1-one (2h). White
1H NMR (400 MHz, CDCl3)
d
: 2.46 (d, J¼20.0 Hz, 3H), 6.72 (d,
solid, mp 38e40 ꢁC; yield: 42%; 1H NMR (400 MHz, CDCl3)
d: 2.45
JHeF¼20.0 Hz, 1H), 7.46 (t, J¼8.0 Hz, 2H), 7.55 (t, J¼8.0 Hz, 1H), 7.90
(d, J¼19.6 Hz, 3H), 6.65 (d, JHeF¼20.4 Hz, 1H), 7.42 (d, J¼8.4 Hz, 2H),
(d, J¼8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
:
17.2 (d,
7.83 (d, J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d: 17.3 (d,
JCeF¼24.0 Hz), 104.7 (d, JCeF¼22.0 Hz), 127.9, 128.6, 132.9, 138.47,
JCeF¼23.0 Hz), 104.4 (d, JCeF¼22.0 Hz), 128.9, 129.3, 136.75, 136.80,
138.52, 174.7 (d, JCeF¼275.0 Hz), 190.0 (d, JCeF¼20.0 Hz). 19F NMR
139.3, 175.2 (d, JCeF¼276.0 Hz), 188.7 (d, JCeF¼20.0 Hz). 19F NMR
(376 MHz, CDCl3)
d
: ꢀ64.56. MS: m/z 165 [MH]þ.
(376 MHz, CDCl3)
C10H9ClFO: 199.0326 [MþH], found: 199.0318.
d
: ꢀ62.72. MS: m/z 199 [MH]þ. HRMS calcd for
4.2.2. (E)-1-(2-Chlorophenyl)-3-fluorobut-2-en-1-one (2b). Oil; yiel
d: 42%; 1H NMR (400 MHz, CDCl3)
: 2.46 (d, J¼19.6 Hz, 3H), 6.43 (d,
d
4.2.10. (E)-1-(4-Bromophenyl)-3-fluorobut-2-en-1-one (2i). White
JHeF¼19.6 Hz, 1H), 7.32e7.35 (m, 1H), 7.38e7.40 (m, 2H), 7.47 (d,
solid, mp 56e58 ꢁC. yield: 52%; 1H NMR (400 MHz, CDCl3)
d: 2.46
J¼7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d
: 17.4 (d, JCeF¼23.0 Hz),
(d, J¼19.6 Hz, 3H), 6.66 (d, JHeF¼20.4 Hz, 1H), 7.60 (d, J¼8.4 Hz, 2H),
108.7 (d, JCeF¼23.0 Hz), 126.9, 129.3, 130.5, 131.1, 131.8, 140.0, 174.7
(d, JCeF¼314.0 Hz),191.7 (d, JCeF¼21.0 Hz). MS: m/z 199 [MH]þ. HRMS
calcd for C10H9ClFO: 199.0326 [MþH], found: 199.0338.
7.76 (d, J¼8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d: 17.3 (d,
JCeF¼24.0 Hz), 104.4 (d, JCeF¼23.0 Hz), 128.0, 129.4, 131.9, 137.2,
175.3 (d, JCeF¼276.0 Hz), 188.9 (d, JCeF¼21.0 Hz). 19F NMR (376 MHz,
CDCl3)
d
: ꢀ62.89. MS: m/z 243 [MH]þ. HRMS calcd for C10H9BrFO:
4.2.3. (E)-3-Fluoro-1-m-tolylbut-2-en-1-one (2c). Oil; yield: 57%;
242.9821 [MþH], found: 242.9806.
1H NMR (400 MHz, CDCl3)
d
: 2.40 (s, 3H), 2.45 (d, J¼20.0 Hz, 3H),
6.71 (d, JHeF¼20.0 Hz,1H), 7.34e7.35 (m, 2H), 7.68e7.71 (m, 2H). 13
C
4.2.11. (E)-1-(3,4-Dimethoxyphenyl)-3-fluorobut-2-en-1-one
(2j). White solid, mp 64e66 ꢁC; yield: 64%; 1H NMR (400 MHz,
NMR (100 MHz, CDCl3)
d: 17.2 (d, JCeF¼23.0 Hz), 21.3, 104.9 (d,
JCeF¼22.0 Hz), 125.1, 128.5, 133.6, 138.4, 138.5, 138.6, 173.5 (d,
JCeF¼275.0 Hz), 190.2 (d, JCeF¼20.0 Hz). MS: m/z 179 [MH]þ. HRMS
calcd for C11H12FO: 179.0872 [MþH], found: 179.0873.
CDCl3)
d
: 2.41 (d, J¼19.6 Hz, 3H), 3.90 (s, 6H), 6.66 (d, JHeF¼20.8 Hz,
1H), 6.84 (d, J¼8.4 Hz, 1H), 7.45e7.47 (m, 2H). 13C NMR (100 MHz,
CDCl3)
d
: 17.1 (d, JCeF¼24.0 Hz), 55.9, 56.0, 104.4 (d, JCeF¼22.0 Hz),
109.9, 110.0, 122.3, 131.5, 131.6, 149.0, 153.1, 174.0 (d, JCeF¼273.0 Hz),
4.2.4. (E)-3-Fluoro-1-(3-fluorophenyl)but-2-en-1-one (2d). Oil; yiel
188.5 (d, JCeF¼20.0 Hz). MS: m/z 225 [MH]þ. HRMS calcd for
d: 42%; 1H NMR (400 MHz, CDCl3)
d
: 2.47 (d, J¼20.0 Hz, 3H), 6.67 (d,
C12H14FO3: 225.0927 [MþH], found: 225.0931.
JHeF¼20.0 Hz, 1H), 7.26e7.29 (m, 1H), 7.42e7.46 (m, 1H), 7.59 (d,
J¼8.0 Hz, 1H), 7.67 (d, J¼8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d:
4.2.12. (E)-3-Fluoro-1-(naphthalen-2-yl)but-2-en-1-one (2k). Oil; yi
eld: 62%; 1H NMR (400 MHz, CDCl3)
: 2.52 (d, J¼20.0 Hz, 3H), 6.58
17.3 (d, JCeF¼23.0 Hz), 104.5 (d, JCeF¼22.0 Hz), 114.7 (d,
d
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Y. He et al. / Tetrahedron xxx (2013) 1e6
5
(d, JHeF¼19.6 Hz, 1H), 7.47e7.61 (m, 3H), 7.76 (d, J¼7.6 Hz, 1H), 7.88
JCeF¼30.0 Hz), 112.7, 112.8, 128.7, 130.4, 136.3, 139.1, 158.6 (d,
JCeF¼257.0 Hz), 195.1 (d, JCeF¼4.0 Hz). MS: m/z 213 [MH]þ. HRMS
calcd for C11H11ClFO: 213.0482 [MþH], found: 213.0486.
(d, J¼7.6 Hz, 1H), 7.97 (d, J¼8.0 Hz, 1H), 8.50 (d, J¼8.0 Hz, 1H). 13
C
NMR (100 MHz, CDCl3)
d
: 17.2 (d, JCeF¼24.0 Hz), 108.9 (d,
JCeF¼21.0 Hz), 124.5, 125.5, 126.4, 127.3, 127.6, 128.5, 130.0, 132.3,
133.9, 137.64, 137.69, 174.3 (d, JCeF¼275.0 Hz), 193.7 (d,
JCeF¼20.0 Hz). MS: m/z 215 [MH]þ. HRMS calcd for C14H12FO:
215.0872 [MþH], found: 215.0872.
4.2.20. (E)-Methyl
3-(2-((E)-3-fluorobut-2-enoyl)phenyl)acrylate
: 2.45 (d, J¼19.6 Hz, 3H),
(2s). Oil; yield: 51%; 1H NMR (400 MHz)
d
3.79 (s, 3H), 6.34 (d, J¼15.8 Hz, 1H), 6.44 (d, JHeF¼19.6 Hz, 1H),
7.44e7.49 (m, 2H), 7.58e7.62 (m, 2H), 8.03 (d, J¼15.2 Hz, 1H). 13
C
4.2.13. (E)-4-Fluoro-1-phenylpent-3-en-2-one (2l). Oil; yield: 55%;
NMR (100 MHz, CDCl3)
d: 17.3 (d, JCeF¼23.0 Hz), 51.8, 107.8 (d,
1H NMR (400 MHz, CDCl3)
d
: 2.34 (d, J¼20.0 Hz, 3H), 3.71 (s, 2H),
JCeF¼22.0 Hz), 120.4, 128.0, 128.4, 129.6, 131.6, 134.2, 140.2 (d,
JCeF¼4.0 Hz), 143.3, 167.0, 175.2 (d, JCeF¼277.0 Hz), 192.8. MS: m/z
249 [MH]þ. HRMS calcd for C14H14FO3: 249.0927 [MþH], found:
249.0922.
6.00 (d, JHeF¼20.0 Hz, 1H), 7.20 (d, J¼7.2 Hz, 2H), 7.25e7.29 (m, 1H),
7.34 (t, J¼7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d: 16.9 (d,
JCeF¼24.0 Hz), 51.6, 51.7, 106.8 (d, JCeF¼20.0 Hz), 127.1, 128.8, 129.5,
134.1, 174.0 (d, JCeF¼277.0 Hz), 197.0 (d, JCeF¼19.0 Hz). MS: m/z 179
[MH]þ. HRMS calcd for C11H12FO: 179.0872 [MþH], found:
179.0866.
4.2.21. ((2R,3S,5R)-3-Acetoxy-5-(5-((E)-3-fluorobut-2-enoyl)-4-
(methylthio)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl
acetate (2t). Yellow solid, mp 159e161 ꢁC; yield: 38%; 1H NMR
4.2.14. (E)-5-Fluoro-1-phenylhex-4-en-3-one (2m). Oil; yield: 51%;
(400 MHz, CDCl3)
d
: 2.00e2.09 (s, 7H), 2.39 (d, J¼20.0 Hz, 3H), 2.47
1H NMR (400 MHz, CDCl3)
d
: 2.37 (d, J¼19.6 Hz, 3H), 2.78 (t,
J¼7.6 Hz, 2H), 2.93 (t, J¼7.6 Hz, 2H), 5.98 (d, JHeF¼20.0 Hz, 1H),
7.19e7.22 (m, 3H), 7.27e7.31 (m, 2H). 13C NMR (100 MHz, CDCl3)
(s, 3H), 2.86e2.91 (m, 1H), 4.35e4.42 (m, 3H), 5.18 (d, J¼6.0 Hz, 1H),
6.16 (t, J¼6.8 Hz, 1H), 6.39 (d, JHeF¼20.0 Hz, 1H), 8.41 (s, 1H). 13C
d:
NMR (100 MHz, CDCl3)
d: 14.3, 17.3 (d, JCeF¼23.0 Hz), 20.6, 20.8,
16.9 (d, JCeF¼24.0 Hz), 29.8, 46.2 (d, JCeF¼4.0 Hz), 107.3 (d,
JCeF¼20.0 Hz), 126.1, 128.4 (d, JCeF¼19.0 Hz), 140.9, 171.8 (d,
JCeF¼275.0 Hz), 198.7 (d, JCeF¼19.0 Hz). 19F NMR (376 MHz, CDCl3)
39.2, 63.5, 74.0, 83.7, 87.8, 103.9 (d, JCeF¼24.0 Hz),115.8, 143.5,151.3,
170.2, 170.3, 177.9 (d, JCeF¼223.0 Hz), 184.8 (d, JCeF¼20.0 Hz). MS:
m/z 429 [MH]þ. HRMS calcd for C18H22FN2O7S: 429.1131 [MþH],
found: 429.1132.
d
: ꢀ66.86. MS: m/z 193 [MH]þ. HRMS calcd for C12H14FO: 193.1028
[MþH], found: 193.1012.
4.3. Typical procedure for the preparation of (E)-4-phenyl
4.2.15. (E)-3-Fluoro-1-p-tolylpent-2-en-1-one (2n). Oil; yield: 35%;
but-3-en-2-one (3a)
1H NMR (400 MHz, CDCl3)
d: 1.20e1.25 (m, 3H), 2.42 (s, 3H),
2.84e2.92 (m, 2H), 6.65 (d, JHeF¼20.8 Hz,1H), 7.27 (d, J¼8.0 Hz, 2H),
To a flask containing 3-fluoro-1-phenylbut-2-en-1-one (2a,
0.5 mmol) were added methanol (2.5 mL), water (2.5 mL) and KBH4
(1.5 mmol). The mixture was stirred at room temperature for 4 h.
Then, the reaction was quenched with water and extracted with
ethyl acetate (5 mLꢂ3). The combined organic phases were dried,
filtered and concentrated under vacuum. The residue was purified
by column chromatography on silica gel eluenting with ethyl ace-
tate/hexanes (5%) to give (E)-4-phenylbut-3-en-2-one (3a). 3beh
were obtained in a similar manner.
7.81 (d, J¼8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d: 10.3, 21.6, 23.9
(d, JCeF¼23.0 Hz), 103.9 (d, JCeF¼22.0 Hz), 128.1, 129.3, 136.0, 143.7,
178.5 (d, JCeF¼278.0 Hz), 189.6 (d, JCeF¼20.0 Hz). MS: m/z 193
[MH]þ. HRMS calcd for C12H14FO: 193.1028 [MþH], found:
193.1042.
4.2.16. (E)-1-(4-Chlorophenyl)-3-fluoropent-2-en-1-one (2o). Oil;
yield: 43%; 1H NMR (400 MHz, CDCl3)
d
: 1.22 (t, J¼7.6 Hz, 3H),
2.81e2.95 (m, 2H), 6.61 (d, JHeF¼20.0 Hz,1H), 7.44 (d, J¼8.4 Hz, 2H),
7.84 (d, J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
: 10.3, 24.0 (d,
4.3.1. (E)-4-Phenylbut-3-en-2-one (3a).21 Oil; 1H NMR (400 MHz,
JCeF¼23.0 Hz), 103.6 (d, JCeF¼23.0 Hz), 128.9, 129.4, 136.8, 139.3,
179.0 (d, JCeF¼280.0 Hz), 188.7 (d, JCeF¼21.0 Hz). MS: m/z 213
[MH]þ. HRMS calcd for C11H11ClFO: 213.0482 [MþH], found:
213.0486.
CDCl3)
d
: 2.38 (s, 3H), 6.71 (d, J¼16.0 Hz, 1H), 7.38e7.40 (m, 3H),
7.49e7.55 (m, 3H). 13C NMR (100 MHz, CDCl3)
d: 27.5, 127.1, 128.2,
129.0, 130.5, 134.4, 143.5, 198.5. MS: m/z 147 [MH]þ.
4.3.2. (E)-4-(3-Fluorophenyl)but-3-en-2-one (3b). Oil; 1H NMR
4.2.17. (E)-3-Fluoro-2-methyl-1-phenylbut-2-en-1-one (2p).9 Oil; yi
(400 MHz, CDCl3)
d
: 2.39 (s, 3H), 6.70 (d, J¼16.0 Hz, 1H), 7.07e7.11
eld: 49%; 1H NMR (400 MHz, CDCl3)
d: 1.89 (s, 3H), 2.06 (d,
(m, 1H), 7.22e7.38 (m, 3H), 7.46 (d, J¼16.0 Hz, 1H). 13C NMR
J¼17.6 Hz, 3H), 7.43 (t, J¼7.2 Hz, 2H), 7.51 (t, J¼7.2 Hz, 1H), 7.83 (d,
(100 MHz, CDCl3) d: 27.8, 114.3, 114.6, 117.3, 117.5, 124.29, 124.32,
J¼7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
: 14.2 (d, JCeF¼5.3 Hz),
128.12, 130.51, 130.60, 136.64, 136.72, 141.9, 161.8, 164.2, 198.2. MS:
m/z 165 [MH]þ. HRMS calcd for C10H10FO: 165.0715 [MþH], found:
165.0730.
15.5 (d, JCeF¼30.6 Hz), 113.0 (d, JCeF¼14.8 Hz), 128.4, 129.1, 132.9,
137.8, 158.1 (d, JCeF¼256.2 Hz), 196.5 (d, JCeF¼3.6 Hz). MS: m/z 179
[MH]þ. HRMS calcd for C11H12FO: 179.0872 [MþH], found:
179.0877.
4.3.3. (E)-4-(3-Chlorophenyl)but-3-en-2-one (3c). Oil; 1H NMR
(400 MHz, CDCl3)
(m, 5H). 13C NMR (100 MHz, CDCl3)
130.4, 134.9, 136.2, 141.7, 198.1. MS: m/z 181 [MH]þ. HRMS calcd for
10H10ClO: 181.0420 [MþH], found: 181.0422.
d
: 2.35 (s, 3H), 6.66 (d, J¼16.0 Hz, 1H), 7.29e7.48
4.2.18. (E)-3-Fluoro-2-methyl-1-p-tolylbut-2-en-1-one (2q). Oil; yie
d
: 27.8, 126.4, 128.0, 128.1, 130.2,
ld: 51%; 1H NMR (400 MHz, CDCl3)
d
: 1.89 (s, 3H), 2.08 (d, J¼18.4 Hz,
3H), 2.41 (s, 3H), 7.25 (d, J¼8.0 Hz, 2H), 7.76 (d, J¼8.0 Hz, 2H). 13
C
C
NMR (100 MHz, CDCl3)
d
:
14.2 (d, JCeF¼5.0 Hz), 15.3 (d,
JCeF¼30.0 Hz), 21.7, 113.0, 113.1, 129.1, 129.2, 135.1, 143.8, 157.2 (d,
JCeF¼254.0 Hz), 196.1 (d, JCeF¼4.0 Hz). MS: m/z 193 [MH]þ. HRMS
calcd for C12H14FO: 193.1028 [MþH], found: 193.1019.
4.3.4. (E)-4-(4-Bromophenyl)but-3-en-2-one (3d).21 Oil; 1H NMR
(400 MHz, CDCl3)
d
: 2.36 (s, 3H), 6.68 (d, J¼16.0 Hz, 1H), 7.37e7.44
(m, 3H), 7.50 (d, J¼8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d: 27.8,
124.8, 127.5, 129.6, 132.2, 133.3, 142.0, 198.2. MS: m/z 225 [MH]þ.
4.2.19. (E)-1-(4-Chlorophenyl)-3-fluoro-2-methylbut-2-en-1-one
(2r). Oil; yield: 48%; 1H NMR (400 MHz, CDCl3)
d: 1.88 (s, 3H), 2.09
4.3.5. (E)-4-(3,4-Dimethoxyphenyl)but-3-en-2-one (3e). White soli
(d, J¼17.6 Hz, 3H), 7.41 (d, J¼8.0 Hz, 2H), 7.76 (d, J¼8.0 Hz, 2H). 13
C
d, mp 73e75 ꢁC; 1H NMR (400 MHz, CDCl3)
d: 2.33 (s, 3H), 3.88 (s,
NMR (100 MHz, CDCl3)
d:
14.1 (d, JCeF¼5.0 Hz), 15.6 (d,
6H), 6.57 (d, J¼16.4 Hz, 1H), 6.84 (d, J¼8.4 Hz, 1H), 7.04 (d, J¼2.8 Hz,
Please cite this article in press as: He, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.07.065

6
Y. He et al. / Tetrahedron xxx (2013) 1e6
1H), 7.08e7.10 (m, 1H), 7.43 (d, J¼16.0 Hz, 1H). 13C NMR (100 MHz,
Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013; (g) Wei, H. C.; Lagow, R. J. Chem.
ꢀ
ꢀ
Commun. 2000, 2139; (h) Lee, Y.-S. J. Fluorine Chem. 2007, 128, 392; (i) Begue, J.-
P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992; (j) Isanbor, C.; O’Hagan,
D. J. Fluorine Chem. 2006, 127, 303.
CDCl3) d: 27.3, 55.8, 55.9, 109.6, 111.0, 123.0, 125.2, 127.3, 143.5,
149.2, 151.3, 198.3. MS: m/z 207 [MH]þ. HRMS calcd for C12H15O3:
207.1021 [MþH], found: 207.1032.
€
€
2. (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (b) Bohm, H.-J.;
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Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M.
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3. (a) Ichikawa, J.; Kaneko, M.; Yokota, M.; Itonaga, M.; Yokoyama, T. Org. Lett. 2006,
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Minami, T. Org. Lett. 2001, 3, 2345.
4.3.6. (E)-3-Methyl-4-phenylbut-3-en-2-one (3f).22 Oil; 1H NMR
(400 MHz, CDCl3)
7.52 (s, 1H). 13C NMR (100 MHz, CDCl3)
129.8, 135.9, 137.7, 139.8, 200.4. MS: m/z 161 [MH]þ. HRMS calcd for
11H13O: 161.0966 [MþH], found: 161.0972.
d
: 2.05 (s, 3H), 2.46 (s, 3H), 7.33e7.42 (m, 5H),
d: 13.0, 25.9, 128.5, 128.6,
C
4. (a) Shibatomi, K.; Futatsugi, K.; Kobayashi, F.; Iwasa, S.; Yamamoto, H. J. Am.
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Chem. Soc. 2010, 132, 5625; (b) Essers, M.; Muck-Lichtenfeld, C.; Haufe, G. J. Org.
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46, 1290.
4.3.7. (E)-4-(2-Chlorophenyl)but-3-en-2-one (3g). Oil; 1H NMR
(400 MHz, CDCl3)
d
: 2.42 (d, J¼2.4 Hz, 3H), 6.66 (dd, J1¼2.4 Hz,
6. Albert, P.; Cousseau, J. J. Chem. Soc., Chem. Commun. 1985, 961.
7. Ichikawa, J.; Yokota, N.; Kobayashi, M.; Minami, T. Synlett 1993, 186.
J2¼16.0 Hz,1H), 7.26e7.33 (m, 2H), 7.42e7.44 (m,1H), 7.62e7.64 (m,
1H), 7.93 (dd, J1¼2.0 Hz, J2¼16.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
^
8. Gillet, J. P.; Sauvetre, R.; Normant, J. F. Synthesis 1982, 297.
d
: 27.2, 127.2, 127.6, 129.6, 130.2, 131.3, 132.7, 135.1, 139.3, 198.5. MS:
9. Sano, K.; Fukuhara, T.; Hara, S. J. Fluorine Chem. 2009, 130, 708.
m/z 181 [MH]þ. HRMS calcd for C10H10ClO: 181.0420 [MþH], found:
10. Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J. Org. Chem. 1995, 60, 2320.
11. (a) Ma, S. Acc. Chem. Res. 2003, 36, 701; (b) Krause, N.; Hashmi, A. S. K. Modern
Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2, Chapter 10; (c)
Ma, S. Chem. Rev. 2005, 105, 2829; (d) Ma, S. Aldrichimica Acta 2007, 40, 91; (e)
181.0429.
4.3.8. (E)-6-Phenylhex-3-en-2-one (3h). Oil; 1H NMR (400 MHz,
€
Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43, 1196.
12. (a) Alcaide, B.; Almendros, P.; del Campo, T. M. Chem.dEur. J. 2010, 16, 5836; (b)
Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325; (c) Ma, S.; Yu, Z.
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CDCl3)
d
: 2.24 (s, 3H), 2.53e2.59 (m, 2H), 2.80 (t, J¼7.6 Hz, 2H), 6.10
(d, J¼15.6 Hz, 1H), 6.80e6.86 (m, 1H), 7.19e7.33 (m, 5H). 13C NMR
(100 MHz, CDCl3) d: 26.9, 34.1, 34.4, 126.1, 126.3, 128.36, 128.44,
128.6, 131.7, 140.7, 147.3, 198.7. MS: m/z 175 [MH]þ. HRMS calcd for
12H15O: 175.1123 [MþH], found: 175.1126.
C
14. For electrophilic fluorination of allenes with NeF reagents, see: (a) Pacheco, M. C.;
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Acknowledgements
We are grateful to the Natural Science Foundation of China
(21272058, 21172057), RFDP (20114104110005), and PCSIRT (IRT
1061).
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.07.065.
References and notes
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Please cite this article in press as: He, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.07.065