Regioselective synthesis of β-fluoro-α,β-unsaturated ketones by the reaction of β-diketones with DFMBA

Article abstract of DOI:10.1016/j.jfluchem.2009.05.009

The deoxyfluorination reaction of β-diketones with N,N-diethyl-α,α-difluoro-m-methylbenzylamine (DFMBA) gave β-fluoro-α,β-unsaturated ketones in good yields. The reaction proceeded regioselectively, and only one regioisomer was obtained from the unsymmetr

Full text of DOI:10.1016/j.jfluchem.2009.05.009

Journal of Fluorine Chemistry 130 (2009) 708–713
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Regioselective synthesis of
-diketones with DFMBA
b-fluoro-a,b-unsaturated ketones by the reaction of
b
*
Keisuke Sano, Tsuyoshi Fukuhara, Shoji Hara
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
The deoxyfluorination reaction of
b-diketones with N,N-diethyl-a,a-difluoro-m-methylbenzylamine
Received 13 April 2009
Received in revised form 10 May 2009
Accepted 12 May 2009
Available online 19 May 2009
(DFMBA) gave -fluoro- -unsaturated ketones in good yields. The reaction proceeded regioselec-
b
a,b
tively, and only one regioisomer was obtained from the unsymmetrical 1-aryl-1,3-diketones. The
reaction is applicable to diketones with a trifluoromethyl group, obtaining good yields of 3,4,4,4-
tetrafluorobutenones. We used the resulting
lithium dialkyl cuprates.
b
-fluoro-
a
,b
-unsaturated ketones for the reaction with
Keywords:
ß 2009 Elsevier B.V. All rights reserved.
b
b
-Fluoro-
a
,
b-unsaturated ketone
-Diketone
N,N-Diethyl-
a,
a-difluoro-m-
methylbenzylamine
Deoxyfluorination
Regioselective
1. Introduction
ketones 2 can be prepared from b-diketones 1 by the reaction with
DFMBA (Scheme 1).
b
-Fluoro-a,b-unsaturated ketones have been conveniently
used as a building-block for the synthesis of fluorinated cyclic
compounds via Diels–Alder reaction [1] and the synthesis of the
2. Result and discussion
heterocyclic compounds [2]. The
ketones were previously prepared by the hydrofluorination of
alkynyl ketones [3], the alkylation of -fluoro- -unsaturated
carboxylic acid chlorides [4], the alkylation of
unsaturated ketones [5], or the elimination of HF from
b
-fluoro-
a
,
b
-unsaturated
The reaction of undecane-5,7-dione 1a with DFMBA was
completed at 30 8C in 24 h and 7-fluoro-6-undecen-5-one 2a
was obtained in a 79% yield as a mixture of stereoisomers
(E:Z = 73:27) (entry 1 in Table 1). A two equivalent of DFMBA to 1a
is necessary, and with a smaller amount of DFMBA, the yield of 2a
decreased considerably. As for the solvent, 1,4-dioxane, DMF, and
CH2Cl2 are appropriate and hydrocarbon such as hexane is not
suitable for this reaction. When 1-phenylbutane-1,3-dione 1b was
used, the deoxyfluorination reaction occurred regioselectively at
the carbonyl group of C3 to give 3-fluoro-1-phenyl-2-buten-1-one
2b, but its regioisomer, 4-fluoro-4-phenyl-3-buten-2-one, did not
form (entry 2). Such regioselectivity was always observed in the
reaction with unsymmetrical 1-aryl-1,3-alkadiones (R1 = Ar,
R2 = H, R3 = alkyl) (entries 2, 4–9). In contrast, a poor stereo-
selectivity of the generated double bond in the products was
observed in most of the cases, and mixtures of the stereoisomers
were obtained (entries 1–3, and 5–9). When the diketone 1d with a
bulky substituent (R3 = tert-Bu) was used, the product (Z)-2d was
obtained stereo- and regioselectively (E:Z = 1:99) (entry 4). The
reactions of diketones 1c, 1d and 1i were sluggish and required
higher reaction temperatures for completion (entries 3, 4, and 9).
b
a,b
b
,b
-difluoro-
a
,
,
b
-
-
b
b
difluoroalkyl ketones [2a,b]. However, the starting materials,
alkynyl ketones, -fluoro- -unsaturated carboxylic acid chlor-
ides, -difluoro- -unsaturated ketones, and -difluoroalkyl
ketones are not easily available in those methods. The correspond-
b
a,b
b
,b
a
,b
b,b
ing chlorides,
prepared from
b
-chloro-
a,b-unsaturated ketones, can be easily
b
-diketones with chlorination reagents [6], but the
reaction of
deoxofluor gave poly-fluorinated products, so
unsaturated ketones could not be directly prepared from
b-diketones with fluorination reagents such as DAST or
b
-fluoro-
a
,b
-
-
b
diketones [7]. Recently, we reported the fluorination of alcohols
[8], epoxides [9], aldehydes [10], diols [11], and amino alcohols
[12]
using
N,N-diethyl-a,a-difluoro-m-methylbenzylamine
(DFMBA). During the course of our study of the fluorination
reaction using DFMBA, we found that
b-fluoro-a,b-unsaturated
In the reaction of the diketone 1j with an
a-substituent, we applied
* Corresponding author. Fax: +81 11 706 6556.
E-mail address: shara@eng.hokudai.ac.jp (S. Hara).
a microwave irradiation condition without solvent to optimize the
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.05.009

K. Sano et al. / Journal of Fluorine Chemistry 130 (2009) 708–713
709
Scheme 1.
result (entry 10). This reaction is applicable to the diketones 1e–h
with a trifluoromethyl group (R1 = Ar, R2 = H, R3 = CF3) and 1-aryl-
3,4,4,4-tetrafluoro-2-buten-1-ones 2e–h were obtained in good
yields (entries 5–8). 1-Phenyl-3,4,4,4-tetrafluoro-2-buten-1-one
2e was previously prepared from 1-phenyl-3,3,4,4,4-pentafluor-
obutan-1-one by elimination of HF, and used as a building-block
for the synthesis of various organofluorine compounds [2a,b].
However, the starting material of our reaction, 1-phenyl-4,4,4-
trifluorobutane-1,3-dione 1e, is commercially available and
more accessible than 1-phenyl-3,3,4,4,4-pentafluorobutan-1-one.
Therefore, our method is more useful for the synthesis of 1-aryl-
3,4,4,4-tetrafluoro-2-buten-1-ones than the previous method. In
the reaction of 4-tert-butyl-2-acetylcyclohexanone 1j, a double
bond was formed at exo-position selectively and 4-tert-butyl-2-(1-
fluoroethylidene)cyclohexanone 2j was obtained as a single isomer
[13].
Scheme 2.
The presumed reaction mechanism of the present deoxyfluor-
ination reaction is shown in Scheme 2. The b-diketones 1 exist as an
equilibrium mixture of keto and enol forms [14] and DFMBA reacted
with the enol form to give the intermediate 3. From 3, elimination of
deoxyfluorination reaction, only one regioisomer 2 was formed
from the unsymmetrical diketones (1b, 1d–1i). In the chlorination of
the fluoride, attack of the fluoride at the
elimination of an amide took place successively to give
b
-carbon, and the
-fluoro-
a,b-unsaturated ketones 2. In the reaction of unsymmetrical
the unsymmetrical b-diketones with Vielsmerer’s reagent, the
b
similar regioselectivity was observed and the selectivity was
explained by the difference in nucleophilicity of the hydroxy oxygen
(A > B: R1 = Ar, R3 = alkyl) [6]. Therefore, the enol form A is more
reactive towards DFMBA than B, and the reaction proceeded through
the intermediate 3 to give product 2 selectively.
diketones (R1 = Ar, R3 = alkyl or CF3), two kinds of enol forms (A
and B) exist, and they could give regioisomers 2 and 20 via the
reaction with DFMBA, respectively. However, in the present
Table 1
Reaction of
b
-diketones with DFMBAa.
Entry
Substrate
R1
R2
R3
Reac. cond.
Yield (%)b
1
1a
1b
1c
1d
1e
Bu
Ph
Ph
Ph
Ph
H
H
H
H
H
Bu
30 8C, 24 h
30 8C, 24 h
80 8C, 5 h
80 8C, 5 h
20 8C, 24 h
79 (73:27)
89 (62:38)
78 (56:44)
82 (1:99)
2
Me
Ph
tBu
CF3
3
4
5d
86 (16:84)
6d
7d
8d
1f
H
H
H
CF3
CF3
CF3
20 8C, 24 h
20 8C, 24 h
20 8C, 24 h
91e (21:79)
89e (29:71)
94 (19:81)
1g
1h
9c
1i
1j
Ph
Me
Me
Me
90 8C, 0.5 h
30 8C, 12 h
74 (86:14)
74
10d
a
If otherwise not mentioned, the reaction was carried out in 1,4-dioxane using 2 equiv. of DFMBA.
Isolation yield based on diketone used. In parentheses, E:Z ratio.
The reaction was carried out under microwave irradiation without solvent.
CH2Cl2 was used as solvent.
b
c
d
e
19F NMR yield.

710
K. Sano et al. / Journal of Fluorine Chemistry 130 (2009) 708–713
Table 2
The reaction of 2b with R2CuLia
.
Entry
1
Substrate
R2CuLi
Product
Yield (%)b
93
(E)-2b
Me2CuLi
2
(E)-2b
Bu2CuLi
Bu2CuLi
82 (24:76)
76 (30:70)
3
(Z)-2b
4b
a
The reaction was performed in THF using 2 equiv. of R2CuLi.
b
Isolation yield based on 2b. In parentheses, isomer ratio (E:Z).
Table 3
1-phenyl-3-methyl-3-buten-1-one 6a was obtained as a major
product. The unexpected product 6a must be formed by the
reduction of 5a with the copper reagent [17]. The result was not
dependent on the stereochemistry of the starting material 2e, and
from pure (Z)-2e, the same result was obtained. In the reaction of
2e with Bu2CuLi, 4,4-difluoro-1-phenyl-3-butyl-3-buten-1-one 6b
was also obtained in a 64% yield, whereas (E)-3-butyl-1-phenyl-
4,4,4-trifluoro-2-buten-1-one 5b was formed as a minor product
(8% yield).
The reaction of 2e with R2CuLia
.
R2CuLi
Product
Me2CuLi
3. Conclusion
We performed the reaction of DFMBA with various
including trifluoro diketones and obtained the
b
-diketones
b
-fluoro-
a,b-
Bu2CuLi
unsaturated ketones in good yields. The reaction proceeded
regioselectively and only one regioisomer was obtained from
the unsymmetrical diketones. The resulting
b-fluoro-a,b-unsatu-
rated ketones were used for the alkylation reactions with lithium
dialkyl cuprates.
a
The reaction was performed in THF using 2 equiv. of R2CuLi.
Isolation yield based on 2e.
19F NMR yield.
b
c
4. Experimental
4.1. General
b
-Halo- [15],
b
-alkylthio- [15b], and
b
-acetoxy-
a
,b
-unsatu-
rated ketones [16] have been used for the reaction with dialkyl
cuprates to introduce an alkyl group onto the double bond via the
The melting points were measured with a Yanagimoto micro-
melting-point apparatus. TheIRspectrawere recorded using a JASCO
FT/IR-410. The 1H NMR (400 MHz) spectra, 19F NMR (376 MHz)
spectra, and 13C NMR (100 MHz) were recorded in CDCl3 on a JEOL
substitution with the hetero atom.
ketones were also used for the reaction with dialkyl cuprates for
the synthesis of -dialkyl- -unsaturated ketones [5]. We also
b-Fluoro-a,b-unsaturated
b
,
b
a
,
b
JNM-A400II FT NMR and the chemical shift,
13C) and CFCl3 19F), respectively. The EI-high-resolution mass
d
, is referred to TMS (1H,
applied 2b and 2e to the reaction with dialkyl cuprates. The
reaction of (E)-2b with Me2CuLi proceeded at ꢀ78 8C and 3-
methyl-1-phenyl-2-buten-1-one 4a was obtained in high yield
(entry 1 in Table 2). However, when Bu2CuLi was used for the
reaction with (E)-2b, 3-methyl-1-phenyl-2-hepten-1-one 4b was
obtained as a mixture of stereoisomers (E:Z = 24:76) (entry 2). As
4b was also formed as a mixture of stereoisomers (E:Z = 30:70) in
the reaction with (Z)-2b (entry 3), the reaction of 2b with lithium
dialkyl cuprates proceeded non-stereoselectively as reported
previously [5] (Table 3).
(
spectra were measured on a JEOL JMS-700TZ. DFMBA was donated
from Mitsubishi Gas Chemical Company, Inc. Microwave irradiation
was carried out using an IDX microwave oven for organic synthesis
(0–300 W, IMCR-25003) with temperature control.
4.2. Reaction of
b-diketones with DFMBA
4.2.1. 7-Fluoro-6-undecen-5-one (2a)
A mixture of undecane-5,7-dione 1a (184 mg, 1 mmol), DFMBA
(426 mg, 2 mmol), and 1,4-dioxane (1 mL) in a reaction vessel
made of TeflonTM FEP with a tight screw cap was stirred at 30 8C for
24 h. The mixture was poured into water, neutralized with sat aq
NaHCO3, and extracted with ether (20 mL ꢁ 3). The combined
In the reaction of 1-phenyl-3,4,4,4-tetrafluoro-2-buten-1-one
2e (a mixture of E and Z isomers) with Me2CuLi, the expected
product, (E)-3-methyl-1-phenyl-4,4,4-trifluoro-2-buten-1-one 5a,
was obtained as a minor product, and the unexpected 4,4-difluoro-

K. Sano et al. / Journal of Fluorine Chemistry 130 (2009) 708–713
711
organic layer was dried over MgSO4 and concentrated under
1280, 1222 cmꢀ1. 1H NMR
d
7.89–7.86 (m, 2H), 7.58–7.43 (m, 3H),
reduced pressure. Purification by column chromatography (silica
gel/hexane-ether) gave 2a (147 mg) in 79% yield as a mixture of
stereoisomers (E:Z = 73:27, they are separable by column chro-
matography); (E)-2a; clear oil: IR (neat): 2960, 1672 cmꢀ1. 1H NMR
6.06 (d, J = 35.6 Hz, 1H, 55CH), 1.26 (s, 9H). 13C NMR
d 189.60,
177.15 (d, J = 289.3 Hz), 138.47, 132.65, 128.38 (2C), 128.27 (2C),
100.38 (d, J = 7.2 Hz), 36.02 (d, J = 21.7 Hz), 26.92 (d, J = 2.8 Hz, 3C).
19F NMR
d
ꢀ90.01 (d, J = 36.0 Hz, 1F). HRMS (EI): calcd for C13H15OF
d
5.94 (d, J = 20.5 Hz, 1H, 55CH), 2.78 (dt, J = 26.2, 7.3 Hz, 2H), 2.43
(t, J = 7.4 Hz, 2H), 1.63–1.50 (m, 4H), 1.44–1.26 (m, 4H), 0.95–0.88
(m, 6H) {lit. [18] 5.94 (d, J = 20.5 Hz, 1H, 55CH)}. 13C NMR
198.88
(M+): 206.1107, found: 206.1101.
d
4.2.5. 3,4,4,4-Tetrafluoro-1-phenyl-2-buten-1-one (2e)
(d, J = 19.5 Hz), 176.31 (d, J = 280.9 Hz), 107.03 (d, J = 20.1 Hz),
44.54 (d, J = 4.5 Hz), 29.90, 29.58, 28.01, 26.13, 22.22 (d, J = 2.2 Hz),
The reaction was carried out as described above using 1-
phenyl-4,4,4-trifluorobutane-1,3-dione 1e in CH2Cl2 at 20 8C for
24 h. Purification by column chromatography (silica gel/hexane-
ether) gave 2e in 86% yield as a mixture of stereoisomers
(E:Z = 16:84, only (Z)-isomer is isolable as pure form); (Z)-2e;
13.84, 13.70. 19F NMR
d
ꢀ76.40 (dt, J = 23.0, 23.0 Hz, 1F). HRMS
(EI): calcd for C11H19OF (M+): 186.1420, found: 186.1413. (Z)-2a;
clear oil: IR (neat): 2960, 1672 cmꢀ1. 1H NMR
5.32 (d, J = 39.0 Hz,
d
1H), 2.64 (dt, J = 2.3, 7.6 Hz, 2H), 2.29 (dt, J = 17.4, 7.2 Hz, 2H), 1.63–
1.50 (m, 4H), 1.45–1.26 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H), 0.91 (t,
clear oil: IR (neat): 3068, 1707, 1296, 1208, 1156 cmꢀ1. 1H NMR
7.94–7.91 (m, 2H), 7.68–7.50 (m, 3H), 6.72 (d, J = 31.3 Hz, 1H,
55CH). 13C NMR
186.46, 151.06 (dq, J = 283.9, 39.6 Hz), 136.18,
134.35, 128.96 (2C), 128.70 (2C), 117.78 (dq, J = 41.2, 273.1 Hz),
107.80–107.68 (m). 19F NMR
ꢀ73.78 (d, J = 9.7 Hz, 3F), ꢀ117.52
(dq, J = 31.1, 9.8 Hz, 1F) {lit. [2b]
ꢀ73.64 (d, J = 10 Hz, 3F), ꢀ117.5
(dt, J = 31, 10 Hz, 1F)}. HRMS (EI): calcd for C10H6OF4 (M+):
d
J = 7.3 Hz, 3H) {lit. [18] 5.32 (d, J = 38.8 Hz, 1H, 55CH)}. 13C NMR
d
d
199.86 (d, J = 2.3 Hz), 170.71 (d, J = 283.6 Hz), 108.46 (d, J = 7.8 Hz),
43.10 (d, J = 5.4 Hz), 32.61 (d, J = 25.1 Hz), 27.70 (d, J = 1.9 Hz),
d
26.05 (d, J = 1.6 Hz), 22.33, 21.93, 13.86, 13.62. 19F NMR
ꢀ80.28 (m, 1F).
d
ꢀ80.07 to
d
218.03546, found: 218.03524. (E)-2e; 1H NMR
d
6.72 (d, J = 18.9 Hz,
4.2.2. 3-Fluoro-1-phenyl-2-buten-1-one (2b)
1H, C55CH). 19F NMR
J = 18.2, 9.1 Hz, 1H).
d
ꢀ69.79 (d, J = 10.7 Hz, 3F), ꢀ119.58 (dq,
The reaction was carried out as described above using 1-
phenylbutane-1,3-dione 1b at 30 8C for 24 h. Purification by
column chromatography (silica gel/hexane-ether) gave 2b in 89%
yield as a mixture of stereoisomers (E:Z = 62:38, they are separable
by column chromatography); (E)-2b; clear oil: IR (neat): 3062,
4.2.6. 3,4,4,4-Tetrafluoro-1-(furan-2-yl)-2-buten-1-one (2f)
The reaction was carried out as described above using 1-(furan-
2-yl)-4,4,4-trifluorobutane-1,3-dione 1f in CH2Cl2 at 20 8C for 24 h.
19F NMR analysis using fluorobenzene as internal standard showed
that 2f was formed in 91% yield as a mixture of stereoisomers
(E:Z = 21:79, only (Z)-isomer is isolable as pure form by column
chromatography (silica gel/hexane-ether)); (Z)-2f; white solid:
1679, 1627, 1164 cmꢀ1. 1H NMR
3H), 6.72 (d, J = 21.1 Hz, 1H, 55CH), 2.47 (d, J = 19.7 Hz, 3H). 13C
NMR 190.02 (d, J = 20.1 Hz), 174.66 (d, J = 276.5 Hz), 138.48 (d,
J = 5.0 Hz), 132.84, 128.58 (2C), 127.88 (2C), 104.71 (d, J = 22.3 Hz),
d 7.93–7.89 (m, 2H), 7.60–7.44 (m,
d
17.19 (d, J = 24.2 Hz). 19F NMR
d
ꢀ64.50 (dq, J = 20.1, 20.1 Hz, 1F).
m.p. 30–31 8C: IR (KBr): 3137, 1712, 1646, 1317 cmꢀ1
7.67 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 30.0 Hz,
1H, 55CH), 6.64 (dd, J = 3.6, 1.8 Hz, 1H). 13C NMR
173.35, 152.55
(dq, J = 288.9, 39.8 Hz), 152.16, 147.71, 119.22, 117.62 (dq, J = 40.1,
273.7 Hz), 113.22, 105.96 (q, J = 2.9 Hz). 19F NMR
ꢀ74.07 (d,
J = 9.0 Hz, 3F), ꢀ115.66 (dq, J = 29.5, 8.9 Hz, 1F). HRMS (EI): calcd
for C8H4F4O2 (M+): 208.0147, found: 208.0151. (E)-2f; 1H NMR
. d
1H NMR
HRMS (EI): calcd for C10H9OF (M+): 164.0637, found: 164.0623. (Z)-
2b; white solid; m.p. 49–51 8C: IR (KBr): 3081, 1632, 1246 cmꢀ1. 1H
d
NMR
d
7.91–7.88 (m, 2H), 7.58–7.42 (m, 3H), 6.09 (d, J = 33.3 Hz,
188.49, 167.74 (d,
1H, 55CH), 2.14 (d, J = 16.7 Hz, 3H). 13C NMR
d
d
J = 284.9 Hz), 138.12, 132.75, 128.45 (2C), 128.25 (2C), 104.34 (d,
J = 5.0 Hz), 19.45 (d, J = 26.7 Hz). 19F NMR
16.5 Hz, 1F).
d
ꢀ74.35 (dq, J = 33.0,
d
7.68 (brs, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 19.0 Hz, 1H,
C55CH), 6.64–6.62 (m, 1H). 19F NMR
ꢀ115.9 (brs, 1F).
d
ꢀ69.51 (d, J = 8.5 Hz, 3F),
4.2.3. 3-Fluoro-1,3-diphenyl-2-propen-1-one (2c)
The reaction was carried out as described above using 1,3-
diphenylpropane-1,3-dione 1c at 80 8C for 5 h. Purification by
column chromatography (silica gel/hexane-ether) gave 2c in 78%
yield as a mixture of stereoisomers (E:Z = 56:44, they are separable
by column chromatography); (E)-2c; white solid; m.p. 36–38 8C: IR
4.2.7. 3,4,4,4-Tetrafluoro-1-(thien-2-yl)-2-buten-1-one (2g)
The reaction was carried out as described above using 1-(thien-
2-yl)-4,4,4-trifluorobutane-1,3-dione 1g in CH2Cl2 at 20 8C for
24 h. 19F NMR analysis using fluorobenzene as internal standard
showed that 2g was formed in 89% yield as a mixture of
stereoisomers (E:Z = 29:71, only (Z)-isomer is isolable as pure
form by column chromatography (silica gel/hexane-ether)); (Z)-
2g; white solid: m.p. 38–40 8C: IR (KBr): 3100, 1701, 1629,
(KBr): 3056, 1670, 1626, 1246 cmꢀ1. 1H NMR
7.71–7.68 (m, 2H), 7.58–7.35 (m, 6H), 6.77 (d, J = 21.8 Hz, 1H,
55CH). 13C NMR
189.77 (d, J = 17.9 Hz), 168.47 (d, J = 267.0 Hz),
d 7.96–7.93 (m, 2H),
d
137.98 (d, J = 4.2 Hz), 133.13, 131.32 (d, J = 1.7 Hz, 2C), 128.80,
128.71, 128.58 (2C), 128.49 (2C), 128.07 (2C), 106.07 (d,
1167 cmꢀ1
J = 3.8 Hz, 1H), 7.20 (dd, J = 4.9, 4.0 Hz, 1H), 6.65 (d, J = 30.1 Hz, 1H,
55CH). 13C NMR
178.00, 151.32 (dq, J = 286.9, 40.0 Hz), 143.62,
136.20, 133.68, 128.60, 117.67 (dq, J = 40.0, 273.7 Hz), 107.17–
107.07 (m). 19F NMR
ꢀ73.90 (d, J = 10.7 Hz, 3F), ꢀ116.80 (dq,
J = 30.4, 9.6 Hz, 1F). HRMS (EI): calcd for C8H4F4OS: 223.9919,
found: 223.9921. (E)-2g; 1H NMR
7.80 (dd, J = 4.8, 1.2 Hz, 1H),
. d 7.79 (dd, J = 4.9, 1.2 Hz, 1H), 7.74 (d,
1H NMR
J = 26.3 Hz). 19F NMR
d
ꢀ79.44 (d, J = 22.0 Hz, 1F). HRMS (EI):
calcd for C15H11OF (M+): 226.0794, found: 226.0799. (Z)-2c; white
solid; m.p. 59–60 8C (lit. [3b] 61 8C): IR (KBr): 3041, 1665, 1605,
d
1214 cmꢀ1. 1H NMR
d
7.99–7.96 (m, 2H), 7.78–7.74 (m, 2H), 7.62–
d
7.45 (m, 6H), 6.80 (d, J = 34.2 Hz, 1H, 55CH). 13C NMR
d
188.81,
165.21 (d, J = 278.1 Hz), 138.57, 132.85, 131.58 (2C), 128.89 (d,
J = 1.8 Hz), 128.53 (2C), 128.29 (d, J = 0.7 Hz, 2C), 125.85, 125.74
d
7.70 (dd, J = 3.7, 1.0 Hz, 1H), 7.20 (dd, J = 4.9, 4.0 Hz, 1H), 6.71 (d,
(2C), 101.70 (d, J = 6.8 Hz). 19F NMR
{lit. [3b] ꢀ98.7 (d, J = 35 Hz, 1F)}.
d
= ꢀ97.16 (d, J = 34.2 Hz, 1F)
J = 18.6 Hz, 1H, C55CH). 19F NMR
ꢀ118.71 (dq, J = 18.0, 8.9 Hz, 1F).
d
ꢀ69.54 (d, J = 9.0 Hz, 3F),
4.2.4. (Z)-3-Fluoro-1-phenyl-4,4-dimethyl-2-penten-1-one (2d)
The reaction was carried out as described above using 1-
phenyl-4,4-dimethylpentane-1,3-dione 1d at 80 8C for 5 h. Pur-
ification by column chromatography (silica gel/hexane-ether) gave
2d in 82% yield (Z:E = 99:1); clear oil: IR (neat): 2972, 1681, 1627,
4.2.8. 3,4,4,4-Tetrafluoro-1-(naphth-2-yl)-2-buten-1-one (2h)
The reaction was carried out as described above using 1-
(naphth-2-yl)-4,4,4-trifluorobutane-1,3-dione 1h in CH2Cl2 at
20 8C for 24 h. Purification by column chromatography (silica gel/
hexane-ether) gave 2h in 94% yield as a mixture of stereoisomers

712
K. Sano et al. / Journal of Fluorine Chemistry 130 (2009) 708–713
(E:Z = 19:81, only (Z)-isomer is isolable as pure form); (Z)-2h;
yellow solid: m.p. 62–63 8C: IR (KBr): 1702, 1650, 1213,
nyl-2-buten-1-one 4a (73 mg) in 93% yield; clear oil: IR (neat):
2912, 1660, 1614, 1248, 1011 cmꢀ1. 1H NMR
7.94–7.92 (m, 2H),
7.55–7.43 (m, 3H), 6.76–6.75 (m, 1H), 2.21 (d, J = 1.0 Hz, 3H, CH3),
2.02 (d, J = 1.1 Hz, 3H, CH3) {lit. [19] 2.23 (d, J = 1.14 Hz, 3H, CH3),
2.04 (d, J = 1.28 Hz, 3H, CH3)}. 13C NMR
d 191.46, 156.65, 139.18,
d
1139 cmꢀ1
.
1H NMR
d
8.40 (s, 1H), 8.02–7.90 (m, 4H), 7.69–
7.58 (m, 2H), 6.87 (d, J = 31.3 Hz, 1H, 55CH). 13C NMR
d
186.09,
150.99 (dq, J = 283.3, 39.3 Hz), 135.95, 133.45, 132.21, 131.09,
129.64, 129.21, 128.91, 127.79, 127.10, 123.36, 117.82 (dq,
132.21 (2C), 128.37 (2C), 128.12, 121.12, 27.93, 21.11.
J = 41.0, 273.7 Hz), 107.78–107.67 (m). 19F NMR
d
ꢀ73.70 (d,
J = 9.0 Hz, 3F), ꢀ117.70 (dq, J = 30.5, 10.2 Hz, 1F). HRMS (EI): calcd
4.3.2. Reaction of 2b with lithium dibutyl cuprate
for C14H8OF4 (M+): 268.05112, found: 268.05123. (E)-2h; 1H NMR
To a THF solution (5 mL) of CuBr Me2S (208 mg, 1.01 mmol) was
added at ꢀ45 8C, 1.6 M hexane solution of BuLi (1.25 mL, 2.0 mmol)
and the mixture was stirred for 45 min. Then, the mixture was
cooled to ꢀ78 8C and a THF solution of 2b (80.3 mg, 0.489 mmol)
was added. The mixture was stirred at the temperature for 3 h and
quenched by the successive addition of MeOH (5 mL) and sat aq
NH4Cl (10 mL). The mixture was extracted with ether (20 mL ꢁ 3)
and combined organic layer was washed with brine (20 mL). The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. Purification by column chromatography (silica
gel/hexane-ether) gave 3-methyl-1-phenyl-2-hepten-1-one 4b
(81.0 mg) in 82% yield as mixture of the stereoisomers
(E:Z = 24:76, they are separable by column chromatography).
d
6.85 (d, J = 18.7 Hz, 1H, C55CH). 19F NMR
d
ꢀ69.74 (d, J = 9.0 Hz,
3F), ꢀ119.62 (dq, J = 19.7, 8.9 Hz, 1F).
4.2.9. 3-Fluoro-2-methyl-1-phenyl-2-buten-1-one (2i)
To a TeflonTM PFA tube with a diameter of 10 mm sealed at one
end, 2-methyl-1-phenylbutane-1,3-dione 1i (176 mg, 1 mmol) and
DFMBA (426 mg, 2 mmol) were introduced. The open end of the
tube was connected to a reflux condenser. Then, the reaction
mixture was submitted for 30 min to microwave irradiation and
during the irradiation, the temperature was kept at 90 8C. After
cooling, the reaction mixture was poured into sat aq NaHCO3. The
product was extracted with ether (20 mL ꢁ 3) and the combined
ethereal layer was dried over MgSO4. Purification by column
chromatography (silica gel/hexane-ether) gave 2i (132 mg) in 74%
yield as a mixture of stereoisomers (E:Z = 86:14, they are separable
by column chromatography); (E)-2i; clear oil: IR (neat): 2926,
(Z)-4b; clear oil: IR (neat): 2958, 1661, 1611, 1254 cmꢀ1. 1H NMR
7.94–7.92 (m, 2H), 7.54–7.43 (m, 3H), 6.72 (s, 1H), 2.63 (t,
d
J = 7.8 Hz, 2H), 2.01 (d, J = 1.3 Hz, 3H), 1.56–1.35 (m, 4H), 0.93 (t,
J = 7.2 Hz, 3H). 13C NMR
d 191.23, 160.97, 139.30, 132.19, 128.37
1811, 1651, 1284 cmꢀ1. 1H NMR
3H), 2.09 (d, J = 18.4 Hz, 3H), 1.90 (brs, 3H). 13C NMR
d
7.86–7.82 (m, 2H), 7.58–7.41 (m,
196.42 (d,
(2C), 128.14 (2C), 121.10, 33.98, 30.40, 25.69, 22.92, 13.95. HRMS
d
(EI): calcd for C14H18O (M+): 202.1358, found: 202.1353. (E)-4b;
J = 2.2 Hz), 157.98 (d, J = 257.9 Hz), 137.84 (d, J = 1.6 Hz), 132.85,
128.95 (d, J = 1.6 Hz, 2C), 128.35 (2C), 113.01 (d, J = 14.2 Hz), 15.45
clear oil: IR (neat): 2930, 1661, 1611, 1239 cmꢀ1. 1H NMR
d 7.94–
7.92 (m, 2H), 7.55–7.43 (m, 3H), 6.73 (d, J = 1.3 Hz, 1H), 2.26 (t,
J = 7.4 Hz, 2H), 2.20 (d, J = 1.0 Hz, 3H, CH3), 1.59–1.51 (m, 2H),
1.43–1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H) {lit. [19] 2.20 (d, J = 1.0 Hz,
3H, CH3)}. 13C NMR
d 191.74, 160.61, 139.39, 132.22, 128.40 (2C),
(d, J = 29.8 Hz), 14.14 (d, J = 4.2 Hz). 19F NMR
d
ꢀ84.38 to ꢀ84.75
(m, 1F). HRMS (EI): calcd for C11H11FO (M+): 178.0794, found:
178.0792. (Z)-2i; clear oil: IR (neat): 2927, 1655, 1320 cmꢀ1 1H
NMR 7.82–7.79 (m, 2H), 7.59–7.45 (m, 3H), 1.95–1.85 (m, 6H).
13C NMR
197.69 (d, J = 12.6 Hz), 161.53 (d, J = 263.8 Hz), 137.64
.
d
128.15 (2C), 120.45, 41.24, 29.75, 22.39, 19.75, 13.92.
d
(d, J = 3.3 Hz), 132.98, 129.08 (2C), 128.64 (2C), 115.11 (d,
J = 16.5 Hz), 17.23 (d, J = 28.9 Hz), 12.62 (d, J = 7.4 Hz). 19F NMR
4.3.3. Reaction of 2e with lithium dimethyl cuprate
The reaction was carried out as in the case of Section 4.3.1 using
2e to give (E)-4,4,4-trifluoro-3-methyl-1-phenyl-2-buten-1-one
5a and 4,4-difluoro-3-methyl-1-phenyl-3-buten-1-one 6a. The
yield of 6a (53%) was determined by 19F NMR using fluorobenzene
as an internal standard, and the yield of 5a (23%) was obtained after
isolation by column chromatography (silica gel/hexane-ether);
d
ꢀ85.91 to ꢀ86.06 (m, 1F).
4.2.10. 4-tert-Butyl-2-(1-fluoroethylidene)cyclohexanone (2j)
The reaction was carried out as in the case of 2e using 4-tert-
butyl-2-acetylcyclohexanone 1j in CH2Cl2 at 30 8C for 12 h.
Purification by column chromatography (silica gel/hexane-ether)
gave 2j in 74% yield as a single isomer [13]; clear oil: IR (neat):
(E)-5a; clear oil: IR (neat): 1681, 1295, 1181, 1129 cmꢀ1. 1H NMR
7.95–7.93 (m, 2H), 7.64–7.60 (m, 1H), 7.53–7.49 (m, 2H), 7.24–7.23
(m, 1H), 2.16 (d, J = 1.4 Hz, 3H). 13C NMR
191.10, 139.20 (q,
J = 30.5 Hz), 137.11, 133.83, 128.87 (2C), 128.56 (2C), 125.76 (q,
d
2975, 1699, 1619 cmꢀ1. 1H NMR
J = 18.0 Hz, 1H), 2.28 (d, J = 22.1 Hz, 3H), 2.32–2.28 (m, 1H), 2.04–
1.96 (m, 2H), 1.48–1.42 (m, 2H), 0.93 (s, 9H). 13C NMR
202.17 (d,
d
2.88 (d, J = 15.7 Hz, 1H), 2.54 (d,
d
d
J = 5.4 Hz), 123.39 (q, J = 274.0 Hz), 12.82. 19F NMR
{lit. [20] ꢀ71.36 (s, 3F)}. HRMS (EI): calcd for C11H9F3O (M+):
214.0605, found: 214.0602. 6a; clear oil: IR (neat): 2929, 1765,
d
ꢀ71.47 (s, 3F)
J = 14.3 Hz), 166.24 (d, J = 271.6 Hz), 116.47 (d, J = 14.8 Hz), 44.42
(d, J = 1.9 Hz), 41.26 (d, J = 5.8 Hz), 32.60, 27.19 (3C), 25.19 (d,
J = 8.6 Hz), 24.27, 17.38 (d, J = 25.7 Hz). 19F NMR
d
ꢀ73.34 (q,
1692, 1205 cmꢀ1. 1H NMR
d
7.98–7.96 (m, 2H), 7.61–7.58 (m, 1H),
7.51–7.47 (m, 2H), 3.64 (t, J = 1.8 Hz, 2H), 1.65 (t, J = 3.2 Hz, 3H). 13
NMR 196.25 (dd, J = 3.4, 2.4 Hz), 153.66 (dd, J = 282.8, 282.8 Hz),
136.25, 133.40, 128.70 (2C), 128.12 (2C), 80.44 (dd, J = 22.9,
19.1 Hz), 38.26 (d, J = 2.8 Hz), 12.53 (d, J = 1.7 Hz). 19F NMR
J = 20.3 Hz, 1F). HRMS (EI): calcd for C12H19FO (M+): 198.1420,
C
found: 198.1414.
d
4.3. Reaction of 2 with dialkyl cuprates
d
ꢀ95.15 (d, J = 52.0 Hz, 1F), ꢀ94.80 (d, J = 51.9 Hz, 1F). HRMS (EI):
4.3.1. Reaction of 2b with lithium dimethyl cuprate
calcd for C11H10F2O (M+): 196.0700, found: 196.0692.
To a THF solution (5 mL) of CuBr Me2S (208 mg, 1.01 mmol) was
added at 0 8C, 1.6 M ethereal solution of MeLi (1.25 mL, 2 mmol)
and the mixture was stirred for 30 min. Then, the mixture was
4.3.4. Reaction of 2e with lithium dibutyl cuprate
The reaction was carried out as in the case of Section 4.3.2 using
2e to give (E)-3-trifluoromethyl-1-phenyl-2-hepten-1-one 5b and
4,4-difluoro-3-butyl-1-phenyl-3-buten-1-one 6b. The yield of 5b
(8%) was determined by 19F NMR using fluorobenzene as an internal
standard and the yield of 6b (64%) was obtained after isolation by
column chromatography (silica gel/hexane-ether), respectively;(E)-
5b; clear oil: IR (neat): 2962, 1677, 1318, 1279, 1176, 1128 cmꢀ1. 1H
cooled to ꢀ78 8C and
a THF solution of (E)-2b (80.2 mg,
0.488 mmol) was added. The mixture was stirred at the
temperature for 3 h and quenched by the successive addition of
MeOH (5 mL) and sat aq NH4Cl (10 mL). The mixture was extracted
with ether (20 mL ꢁ 3) and combined organic layer was washed
with brine (20 mL). The organic layer was dried over MgSO4 and
concentrated under reduced pressure. Purification by column
chromatography (silica gel/hexane-ether) gave 3-methyl-1-phe-
NMR
d7.95–7.93 (m, 2H), 7.64–7.60 (m, 1H), 7.53–7.49 (m, 2H), 7.22
(s, 1H), 2.56–2.52 (m 2H), 1.59–1.51 (m, 2H), 1.41–1.32 (m, 2H), 0.89

K. Sano et al. / Journal of Fluorine Chemistry 130 (2009) 708–713
713
(t, J = 7.3 Hz, 3H). 13C NMR
133.76, 128.85 (2C), 128.52 (2C), 126.30 (q, J = 5.5 Hz), 123.74 (q,
J = 275.6 Hz), 30.99, 27.06, 22.84, 13.62. 19F NMR
ꢀ68.92 (s, 3F).
HRMS(EI):calcdforC14H15F3O(M+):256.1075, found:256.1064. 6b;
clear oil: IR (neat): 2959, 1755, 1694, 1273, 1210 cmꢀ1 1H NMR
d 191.05, 143.76 (q, J = 28.6 Hz), 137.21,
(c) J. Ichikawa, M. Kaneko, M. Yokota, M. Itonaga, T. Yokoyama, Org. Lett. 8 (2006)
3167–3170.
[3] (a) P. Albert, J. Cousseau, Chem. Commun. (1985) 961–962;
(b) J. Cousseau, P. Albert, Bull. Soc. Chim. Fr. 6 (1986) 910–915.
[4] J.P. Gillet, R. Sauveˆtre, J.F. Normant, Synthesis (1982) 297–301.
[5] J. Ichikawa, N. Yokota, M. Kobayashi, T. Minami, Synlett (1993) 186–188.
[6] G. Alvernhe, A. Bensadat, A. Ghobsi, A. Laurent, E. Laurent, J. Fluorine Chem. 81
(1997) 169–172.
d
.
d
7.98–7.96 (m, 2H), 7.61–7.57 (m, 1H), 7.50–7.47 (m, 2H), 3.64 (t,
[7] (a) A.E. Asato, R.S.H. Liu, Tetrahedron Lett. 27 (1986) 3337–3340;
(b) R.P. Singh, U. Majumder, J.M. Shreeve, J. Org. Chem. 66 (2001) 6263–6267;
(c) R.P. Singh, J.M. Shreeve, Synthesis (2002) 2561–2578, and the references are
cited therein.
[8] (a) S. Kobayashi, A. Yoneda, T. Fukuhara, S. Hara, Tetrahedron Lett. 45 (2004)
1287–1289;
J = 1.8 Hz, 2H), 2.08–2.03 (m 2H), 1.39–1.25 (m, 4H), 0.88 (t,
J = 7.1 Hz, 3H). 13C NMR
d 196.34 (dd, J = 3.1, 2.6 Hz), 154.08 (dd,
J = 285.2, 284.2 Hz), 136.34, 133.36, 128.69 (2C), 128.14 (2C), 84.46
(dd, J = 21.9, 16.2 Hz), 36.14 (d, J = 2.9 Hz), 29.24 (dd, J = 2.2, 2.2 Hz),
26.23 (d, J = 1.6 Hz), 22.15, 13.76. 19F NMR
d
ꢀ93.96 (d, J = 50.2 Hz,
(b) S. Kobayashi, A. Yoneda, T. Fukuhara, S. Hara, Tetrahedron 60 (2004) 6923–
6930.
1F), ꢀ94.61 (d, J = 50.1 Hz, 1F). HRMS (EI): calcd for C14H16F2O (M+):
[9] H.-W. Yu, Y. Nakano, T. Fukuhara, S. Hara, J. Fluorine Chem. 126 (2005) 962–966.
[10] T. Furuya, T. Fukuhara, S. Hara, J. Fluorine Chem. 126 (2005) 720–725.
[11] A. Yoneda, T. Fukuhara, S. Hara, Chem. Commun. (2005) 3589–3590.
[12] T. Nomoto, T. Fukuhara, S. Hara, Synlett (2006) 1744–1746.
[13] Determination of the stereochemistry was unsuccessful.
[14] (a) M. Gorodetsky, Z. Luz, Y. Mazur, J. Org. Chem. 89 (1967) 1183–1189;
(b) J.C. Sloop, C.L. Bumgardner, G. Washington, W.D. Loehle, S.S. Sankar, A.B.
Lewis, J. Fluorine Chem. 127 (2006) 780–786.
238.1169, found: 238.1174.
Acknowledgment
We are grateful to Mitsubishi Gas Chemical Company Inc. for
their donation of DFMBA.
[15] (a) R.D. Clark, C.H. Heathcock, J. Org. Chem. 41 (1976) 636–643;
(b) R.K. Dieter, L.A. Silks III, J. Org. Chem. 51 (1986) 4687–4701.
[16] C.P. Casey, D.F. Marten, R.A. Boggs, Tetrahedron Lett. 23 (1973) 2071–2074.
[17] As for the metal reduction of trifluoromethyl group to difluoromethylene group,
see: H. Amii, T. Kobayashi, Y. Hatamoto, K. Uneyama, Chem. Commun. (1999)
1323–1324.
[18] L. Xiao, T. Kitazume, J. Fluorine Chem. 86 (1997) 99–104.
[19] G. Bartoli, E. Marcantoni, M. Petrini, L. Sambri, Chem. Eur. J. 2 (1996) 913–918.
[20] I.H. Jeong, S.L. Jeon, M.S. Kim, B.T. Kim, J. Fluorine Chem. 125 (2004) 1629–1638.
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