Rh-catalyzed novel α-fluoroalkylation of α,β-unsaturated ketones and its mechanism

Article abstract of DOI:10.1016/j.tet.2007.09.081

Treatment of α,β-unsaturated ketones and fluoroalkyl halides with Et₂Zn in the presence of RhCl(PPh₃)₃ gave novel reductive fluoroalkylation products at the α-position of α,β-unsaturated ketones in moderate to good yields.

Full text of DOI:10.1016/j.tet.2007.09.081

Tetrahedron 63 (2007) 12735–12739
Rh-catalyzed novel a-fluoroalkylation of a,b-unsaturated
ketones and its mechanism
Kazuyuki Sato, Yoshitaka Ishida, Eriko Murata, Yumiko Oida, Yasumitsu Mori, Miho Okawa,
*
Kayoko Iwase, Atsushi Tarui, Masaaki Omote, Itsumaro Kumadaki and Akira Ando
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Received 1 September 2007; revised 28 September 2007; accepted 28 September 2007
Available online 2 October 2007
Abstract—Treatment of a,b-unsaturated ketones and fluoroalkyl halides with Et2Zn in the presence of RhCl(PPh3)3 gave novel reductive
fluoroalkylation products at the a-position of a,b-unsaturated ketones in moderate to good yields. The rhodium hydride complex derived
from Et2Zn and Rh catalyst seems to have played an important role in this reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
O
1. Introduction
CF2COOEt
O
O
3a
THF
Et2Zn
Since fluorinated compounds have significantly interesting
properties, they attract much attention in the fields of
medicines, agricultural chemicals, and other valuable ma-
terials.1 Therefore, the method for introducing a fluorine
functional group to an organic compound has been ac-
tively investigated.2 Among the methods for the synthesis
of fluorine compounds, there are many reactions using
halodifluoroacetates such as their Reformatsky reaction,3
aldol reaction of their enolate or acetal,4 and their radical
addition reaction.5 We have reported new cross-coupling
reaction,6 Michael-type reaction,7 and radical reaction8
of ethyl bromodifluoroacetate (1) in the presence of active
copper powder.
BrCF2COOEt
1
+
HO CF2COOEt
Rh Cat.
CF2COOEt
5a
2a
4a
CH3CN
Scheme 1. Reaction of 2a with 1.
The unexpected product (3a) attracted our interest, since it
has a CF2COOEt group on the a-carbon of a,b-unsaturated
carbonyl group. Therefore, we examined the reaction of
other unsaturated ketones with 1 or other fluoroalkyl halides
(Rf–X), and found that this reaction has a wide applicability.
In this paper, first we will show the scope of this reaction
with several a,b-unsaturated ketones (2). Next, the applica-
tion of this reaction to various fluoroalkyl halides (Rf–X)
will be presented. Here, our preliminary results of a-trifluoro-
methylation reaction will be also involved. Finally, some
experiments carried out to clarify the mechanism of this
interesting reaction will be discussed.
For further expansion, we examined a new type of Michael
reaction of 1 with a,b-unsaturated ketones (2) using diethyl-
zinc (Et2Zn) in the presence of a rhodium catalyst. Interest-
ingly, the reaction of 2-cyclohexen-1-one (2a) and 1 with
Et2Zn in the presence of rhodium catalyst in THF gave an
unexpected product (ethyl 2,2-difluoro-2-(2-oxocyclohexyl)-
acetate, 3a) with a small amount of the Reformatsky type
product (4a), while the Michael-type product (5a) was not
obtained at all. When the above reaction was carried out in
acetonitrile, 4a was obtained selectively in high yields
(Scheme 1).9
2. Results and discussion
As shown in the previous communication,9 we examined the
reaction of several a,b-unsaturated ketones (2) and 1 with
Et2Zn in the presence of RhCl(PPh3)3 in THF at 0 ꢀC. The
results are shown in Table 1. As mentioned above, 3a was
obtained in a good yield by reaction with 2a (entry 1). How-
ever, 2b that has a methyl group on the b-carbon did not af-
ford the same type of product (3b), but the 1,2-addition
product (4b) in a good yield as shown in entry 2. In acyclic
enones, 2c that does not have any substituents on the
Keywords: Fluorine; Fluoroalkyl; Rhodium; a,b-Unsaturated ketone;
a-Position.
* Corresponding author. Tel.: +81 72 866 3140; fax: +81 70 850 7020;
e-mail: aando@pharm.setsunan.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.081

12736
K. Sato et al. / Tetrahedron 63 (2007) 12735–12739
Table 2. Reaction with various fluoroalkyl halides
Table 1. Reaction of 1 with several enones
Et2Zn
Et2Zn
RhCl(PPh3)3
O
O
O
O
HO CF2COOEt
RhCl(PPh3)3
+ BrCF2COOEt
R
+
Rf X +
6
R'
CF2COOEt
R
R'
3 or 7
THF
R
R'
R
R'
THF
0 °C
1
R
R'
0 °C
Rf
2
3
4
2
Entry
1
2
Time (h) Yield of 3a,b (%) Yield of 4a,b (%)
Entry Rf–X
2
Time (h) Yielda (%) Product
1
2
3
4
5
6
CF3–I 6a
CF3–I 6a
C3F7–I 6b
C3F7–I 6b
C10F21–I 6c
C10F21–I 6c
2a
2e
2a
2e
2a
2e
0.5
0.5
2
1
3
55
77
52
62
41
46
7a
7b
7c
7d
7e
7f
0.5
4
71
0
4
63
0
O
O
2a
2b
2
3
4
5
1
O
0b
7g
3
25
18
Ph
CF2 Br
6d
7
2a 22
2c
8
CI–CF2COOMe 6e 2a
5
0.5
0.5
0
7h
3a
3a
O
3
32
9
10
Br–CF2COOEt 1
I–CF2COOEt 6f
2a
2a
71c
68
Ph
2d
O
a
Isolated yield.
The 1,2-adduct (8g) was obtained in 19% yield.
The 1,2-adduct (4a) was obtained in 4% yield with 3a.
4
4
38
0
12
45
2e
Ph
b
c
O
6
2f
a
12 would be largely concerned with the formation of 3 or
7 (Table 2).
Isolated yield.
Purified by ODS column chromatography (MeOH/H2O¼7:3).
b
On the other hand, if the rhodium hydride complex (10)
could be generated by other alkylmetals or metal hydrides,
the catalytic cycle would be performed as shown by the
bold line in the circle in Figure 1. Therefore, we examined
the reaction of C10F21–I (6c) with 2e by using some alkylme-
tals or metal hydrides instead of Et2Zn to clarify the reaction
mechanism. Furthermore, we expected that if the rhodium
hydride complex (10) was formed efficiently, improvement
of the yields or expansion of scope of the reaction could
be attained.
b-carbon afforded 3c selectively, although the yield was
lower than 2a (entry 3). Using the b-monosubstituted ke-
tones such as 2d or 2e (entries 4 and 5) lead to the generation
of the objective products (3d or 3e) in low to moderate
yields, although the selectivity was low. On the other hand,
2f did not give 3f at all. Thus, presence of two carbon sub-
stituents on the b-position seems to inhibit the formation
of 3 (entries 2 and 6).
We expected that this reaction will provide a new methodo-
logy for the synthesis of fluorine compounds, if other fluo-
roalkyl halides could be used for this reaction.
Unfortunately, we could not obtain the product (7f) at all,
when we examined some alkylmetals or metal hydrides
such as Et3Al, Et3B, NaH, DIBAL-H or Et3SiH. Further-
more, use of EtMgBr or Et2Mg11 leads only to the formation
of 1,2-addition product (8f).
Recently, we have reported that the same Rh-catalyzed novel
a-trifluoromethylation of a,b-unsaturated ketones pro-
ceeded, and the a-CF3 ketones were obtained in good
yields.10 As the next step, we examined the similar reaction
using other fluoroalkyl halides (Rf–X, 6) to afford the a-fluo-
roalkylated products (7). The results are shown in Table 2.
On the other hand, we could obtain the objective product
(7f) by using EtMgBr with ZnCl2,12 although the yield
was low (19%). So, we examined the reaction by using
In entries 3–6, C3F7–I (6b) or C10F21–I (6c) reacted with 2 to
give the corresponding products (7c–f) in moderate to good
yields. Thus, this reaction was found to be applied to com-
mon perfluoroalkyl halides. So, we examined the reaction
of a,a-difluoro halogen compounds (1 and 6d–f) as shown
in entries 7–10. The acetylenic compound (6d) did not
give 7g but the 1,2-addition product (8g) in a low yield.
Next, we examined the effect of halogens (entries 8–10). Al-
though we detected the formation of cyclohexanone which
might be derived from 2a on GLC, the corresponding prod-
uct (7h) was not obtained with the chloride (6e) (entry 8). On
the other hand, the bromide (1) or the iodide (6f) gave 3a in
good yields.
Et-MX' or H-MX'
RhCl(PPh3)3
O
O
C
10F21 I +
6c
Ph
C10F21
THF
Ph
2e
Rf
7f
X
1 or 6
(I)
(III)
RhL
O
R
O
n
RhL
n
X
R
Rf
R'
H
11
R'
12
H
O
O
R
R'
R
X
MX' H MX'
Rf
3 or 7
LnRh(I)
H
LnRh(I)
X
R'
2
10
Et MX'
MX'
In the previous report,10 we speculated the reaction mecha-
nism of the a-trifluoromethylation as shown in outer circle of
Figure 1. The above result shows that the ease of oxidative
addition of Rf–X to 11 and/or reductive elimination from
LnRh(I) CH2CH3
9
CH2 CH2
X
Figure 1. Tentative reaction mechanism of a-fluoroalkylation.

K. Sato et al. / Tetrahedron 63 (2007) 12735–12739
12737
CD3CD2MgBr with ZnCl2 for confirmation of the reaction
mechanism. As expected, we obtained the product (7f-d1)
that a deuterium atom was introduced at the b-position of
2e (Scheme 2). This means that the reaction proceeded via
our proposed mechanism as shown in Figure 1, and the trans-
metalation of a deuterated alkylzinc and rhodium catalyst
induced the formation of the rhodium deuteride complex
(10-d1).
temperature for 1 h. The solution was quenched with 10%
HCl, and extracted with Et2O. The Et2O layer was washed
with satd NaCl and dried with MgSO4. The solvent was re-
moved in vacuo and ODS column chromatographic purifica-
tion (MeOH/H2O¼7:3) to give 3a (312 mg, 71%) and 4a
(16 mg, 4%).
4.2.2. Spectral data.
4.2.2.1. Ethyl 2,2-difluoro-2-(2-oxocyclohexyl)acetate
(3a). A colorless oil; H NMR (CDCl3) d: 1.35 (t, 3H,
1
CD3CD2MgBr
ZnCl2
O
D
O
J¼7.2 Hz), 1.69 (m, 2H), 1.86 (m, 1H), 2.08 (m, 2H), 2.35
(m, 2H), 2.45 (m, 1H), 3.33 (m, 1H), 4.34 (m, 2H); 13C
NMR (CDCl3) d: 13.8, 23.9, 25.3 (m), 26.5, 41.6 (m), 54.4
(m), 62.7, 114.1 (m), 163.6 (m), 206.4 (m); 19F NMR
(CDCl3) d: ꢂ46.2 (dd, 1F, J¼273.8, 7.6 Hz), ꢂ55.3 (dd,
1F, J¼273.8, 19.3 Hz); MS m/z: 220 (M+); HRMS calcd
C
10F21 I +
Ph
C10F21
RhCl(PPh )
Ph
3 3
6c
2e
7f-d1
THF
Scheme 2. Certification of the reaction mechanism.
3. Conclusion
C10H14O3F2: 220.09 (M+), found: 220.09; IR (neat) cmꢂ1
1778, 1760, 1720, 1318, 1222, 1140.
:
In conclusion, we found that various fluoroalkyl groups
could be introduced at the a-position of a,b-unsaturated
ketones (2) by using a new rhodium catalyzed reaction, al-
though presence of two carbon substituents on the b-position
of 2 seems to inhibit the formation of 3. Furthermore, we
could obtain the information supporting our proposed mech-
anism of the a-fluoroalkylation reaction of 2. The rhodium
hydride complex (10) which was easily generated by the
transmetalation of alkylzinc with rhodium catalyst played
an important role, since the reaction was induced by
Et2Zn. The a-fluoroalkylation reaction of a,b-unsaturated
ketones has never been reported, and we expect that this re-
action will be useful as a new methodology for introduction
of a fluorine group to organic compounds.
4.2.2.2. Ethyl 2,2-difluoro-3-methyl-4-oxoheptanoate
(3c). A colorless oil; 1H NMR (CDCl3) d: 0.92 (t, 3H,
J¼7.3 Hz), 1.35 (d, 3H, J¼7.5 Hz), 1.35 (t, 3H, J¼7.2 Hz),
1.61 (sextet, 2H, J¼7.3 Hz), 2.52 (m, 2H), 3.39 (m, 1H),
4.33 (q, 2H, J¼7.2 Hz); 13C NMR (CDCl3) d: 9.8 (m), 13.5,
13.9, 16.7, 43.4 (m), 50.7 (m), 62.9, 114.8 (m), 163.3 (m),
207.1 (m); 19F NMR (CDCl3) d: ꢂ43.7 (dd, 1F, J¼268.3,
12.5 Hz), ꢂ50.5 (dd, 1F, J¼268.3, 15.2 Hz); MS m/z: 222
(M+); HRMS calcd C10H16O3F2: 222.11 (M+), found:
222.11; IR (neat) cmꢂ1: 2968, 1776, 1720.
4.2.2.3. Ethyl 3-benzoyl-2,2-difluorohexanoate (3d). A
1
colorless oil; H NMR (CDCl3) d: 0.90 (t, 3H, J¼7.3 Hz),
1.27 (t, 3H, J¼7.2 Hz), 1.35 (m, 2H), 1.85 (m, 1H), 1.99
(m, 1H), 4.22–4.34 (m, 3H), 7.50 (m, 2H), 7.62 (m, 1H),
7.96 (m, 2H); 13C NMR (CDCl3) d: 13.8, 14.1, 20.8, 29.0
(m), 50.3 (m), 63.0, 115.1 (dd, J¼259.1, 252.0 Hz), 128.4,
128.7, 133.7, 136.8, 163.3 (m), 197.3 (m); 19F NMR
(CDCl3) d: ꢂ40.1 (dd, 1F, J¼265.5, 13.1 Hz), ꢂ46.2 (dd,
1F, J¼265.5, 13.8 Hz); MS m/z: 284 (M+); HRMS calcd
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on JNM-
GX400 spectrometer. Tetramethylsilane (TMS) was used
as an internal standard. 19F NMR spectra were recorded on
Hitachi FT-NMR R-1500 and JEOL-ECA-600SN spectrom-
eters. Benzotrifluoride (BTF) was used as an internal stan-
dard. Mass spectra were obtained on JEOL JMS-700T
spectrometer. IR spectra were recorded on Hitachi 270-30
Infrared spectrophotometer. Gas–liquid chromatography
(GLC) was carried out on a Hitachi 263-50 gas chromato-
graph (column: 5% SE-30 3 mmꢁ2 m, carrier: N2 at
30 mL/min). Peak areas were calculated on a Hitachi
D-2000 Chromato-Integrator. Melting points were measured
on Yanagimoto micro melting point apparatus MP-S3. All
the solvents were purified by standard procedure under Ar
atmosphere, and other commercially available reagents
were used without further purification.
C15H18O3F2: 284.12 (M+), found: 284.12; IR (neat) cmꢂ1
1770, 1692, 1240.
:
4.2.2.4. Ethyl 3-benzyl-2,2-difluoro-4-oxopentanoate
(3e). A colorless oil; H NMR (CDCl3) d: 1.35 (t, 3H,
1
J¼7.2 Hz), 2.01 (s, 3H), 3.08 (d, 2H, J¼7.8 Hz), 3.66
(m, 1H), 4.31 (q, 2H, J¼7.2 Hz), 7.17–7.32 (m, 5H); 13C
NMR (CDCl3) d: 13.9, 31.8 (t, J¼4.6 Hz), 31.9 (t,
J¼2.6 Hz), 58.1 (t, J¼20.8 Hz), 63.3, 114.4 (t, J¼
255.0 Hz), 127.0, 128.7, 128.8, 137.0, 162.9 (t, J¼
31.6 Hz), 204.2 (t, J¼3.7 Hz); 19F NMR (CDCl3) d: ꢂ44.2
(d, 2F, J¼13.1 Hz); MS m/z: 270 (M+); HRMS calcd
C14H16O3F2: 270.11 (M+), found: 270.11; IR (neat) cmꢂ1
1772, 1726.
:
4.2.2.5. Ethyl 2,2-difluoro-2-(1-hydroxycyclohex-2-
enyl)acetate (4a). A colorless oil; H NMR (CDCl3) d:
1
4.2. Synthesis of a,a-difluoro-g-keto esters (3)
1.37 (t, 3H, J¼7.1 Hz), 1.73–1.92 (m, 4H), 1.96–2.16 (m,
2H), 2.40 (br s, 1H), 4.36 (dq, 2H, J¼7.1, 0.9 Hz), 5.84 (d,
1H, J¼9.8 Hz), 6.14 (m, 1H); 19F NMR (CDCl3) d: ꢂ54.9
(s, 1F), ꢂ54.9 (s, 1F); MS m/z: 203 (M+ꢂOH), 175
(M+ꢂOEt); HRMS calcd C10H14O3F2: 220.09 (M+),
C10H13F2O2: 203.09 (M+ꢂOH), C8H9F2O2: 175.06
(M+ꢂOEt), found: 203.09 (M+ꢂOH), 175.06 (M+ꢂOEt).
4.2.1. Typical procedure. Under Ar atmosphere, 1
(0.38 mL, 3 mmol) and 2a (0.19 mL, 2 mmol) were added
to the solution of RhCl(PPh3)3 (37 mg, 2 mol %) in THF
(8 mL) at 0 ꢀC and the mixture was stirred for 0.5 h. Then
1.0 M Et2Zn in hexane (3.0 mL, 3 mmol) was gradually
added to the mixture, and the mixture was stirred at same

12738
K. Sato et al. / Tetrahedron 63 (2007) 12735–12739
4.2.2.6. Ethyl 2,2-difluoro-(1-hydroxy-3-methylcyclo-
13C NMR (CDCl3) d: 31.8 (q, J¼1.6 Hz), 31.9 (q,
J¼2.7 Hz), 57.6 (q, J¼24.9 Hz), 124.4 (q, J¼280.3 Hz),
127.1, 128.7, 128.8, 136.4, 201.3 (q, J¼1.9 Hz); 19F NMR
(CDCl3) d: ꢂ4.42 (d, 3F, J¼8.3 Hz); MS m/z: 216 (M+);
HRMS calcd C11H11OF3: 216.08 (M+), found: 216.08; IR
(neat) cmꢂ1: 1734, 1264.
hex-2-enyl)acetate (4b). A colorless oil; 1H NMR
(CDCl3) d: 1.36 (t, 3H, J¼7.3 Hz), 1.76 (s, 3H), 1.75–1.82
(m, 4H), 1.94–2.00 (m, 2H), 2.35 (br s, 1H), 4.35 (m, 2H),
5.57 (s, 1H); 19F NMR (CDCl3) d: ꢂ54.7 (s, 1F), ꢂ54.9 (s,
1F); MS m/z: 234 (M+); HRMS calcd C11H16F2O3: 234.11
(M+), found: 234.11.
4.4. Synthesis of other a-fluoroalkylated ketones (7)
4.2.2.7. Ethyl (E)-2,2-difluoro-3-hydroxy-3-phenyl-
hept-4-enoate (4d). A colorless oil; 1H NMR (CDCl3)
d: 1.01 (t, 3H, J¼7.5 Hz), 1.16 (t, 3H, J¼7.2 Hz), 2.13 (m,
2H), 3.35 (br s, 1H), 4.19 (q, 2H, J¼7.2 Hz), 5.99 (dt, 1H,
J¼15.2, 6.2 Hz), 6.10 (d, 1H, J¼15.2 Hz), 7.30–7.38 (m,
3H), 7.56–7.58 (m, 2H); 19F NMR (CDCl3) d: ꢂ51.5 (s,
2F); MS m/z: 284 (M+); HRMS calcd C15H18O3F2: 284.12
(M+), found: 284.12.
4.4.1. Typical procedure. Under Ar atmosphere, 6b
(0.43 mL, 3 mmol) and 2e (292 mg, 2 mmol) were added
to the solution of RhCl(PPh3)3 (37 mg, 2 mol %) in THF
(8 mL) at 0 ꢀC and the mixture was stirred for 0.5 h. Et2Zn
of 1.0 M in hexane (3.0 mL, 3 mmol) was gradually added
to the solution at 0 ꢀC, and then the solution was stirred at
rt for 1 h. The solution was quenched with 10% HCl, and ex-
tracted with Et2O. The Et2O layer was washed with satd
NaCl and dried with MgSO4. The solvent was removed
in vacuo and the residue was purified by column
chromatography (AcOEt/hexane¼1:9) to give 7d (394 mg,
62%).
4.2.2.8. Ethyl (E)-2,2-difluoro-3-hydroxy-3-methyl-5-
phenylpent-4-enoate (4e). A colorless oil; 1H NMR
(CDCl3) d: 1.29 (t, 3H, J¼7.2 Hz), 1.54 (t, 3H, J¼1.6 Hz),
2.86 (br s, 1H), 4.31 (q, 2H, J¼7.2 Hz), 6.30 (dd, 1H,
J¼16.5, 1.6 Hz), 6.80 (d, 1H, J¼16.5 Hz), 7.25–7.41 (m,
5H); 19F NMR (CDCl3) d: ꢂ54.3 (s, 1F), ꢂ54.4 (s, 1F);
MS m/z: 270 (M+); HRMS calcd C14H16O3F2: 270.11
(M+), found: 270.11.
4.4.2. Spectral data.
4.4.2.1. 2-Heptafluoropropylcyclohexanone (7c). A
colorless oil; 1H NMR (CDCl3) d: 1.69–1.80 (m, 1H),
1.84–1.93 (m, 1H), 2.01 (m, 3H), 2.26 (m, 1H), 2.40–2.59
(m, 2H), 3.13–3.24 (m, 1H); 19F NMR (CDCl3) d: ꢂ17.9
(t, 3F, J¼11.0 Hz), ꢂ51.0 (m, 2F), ꢂ61.3 (m, 2F); MS
m/z: 266 (M+); HRMS calcd C9H9OF7: 266.05 (M+), found:
266.05; IR (neat) cmꢂ1: 1732, 1226.
4.2.2.9. Ethyl 2,2-difluoro-3-hydroxy-3,5-dimethylhex-
4-enoate (4f). A colorless oil; H NMR (CDCl3) d: 1.35 (t,
1
3H, J¼7.2 Hz), 1.47 (t, 3H, J¼1.5 Hz), 1.74 (d, 3H,
J¼1.2 Hz), 1.89 (d, 3H, J¼1.5 Hz), 2.63 (br s, 1H), 4.35
(m, 2H), 5.34 (m, 1H); 19F NMR (CDCl3) d: ꢂ55.1 (s,
2F); MS m/z: 222 (M+); HRMS calcd C10H16F2O3: 222.11
(M+), found: 222.11.
4.4.2.2.
3-Heptafluoropropyl-4-phenylbutan-2-one
1
(7d). A colorless oil; H NMR (CDCl3) d: 1.96 (s, 3H),
3.16 (m, 2H), 3.62 (m, 1H), 7.14–7.33 (m, 5H); 19F NMR
(CDCl3) d: ꢂ17.57 (m, 3F), ꢂ51.40 (m, 2F), ꢂ61.61 (m,
2F); MS m/z: 316 (M+); HRMS calcd C13H11OF7: 316.07
(M+), found: 316.07; IR (neat) cmꢂ1: 1736, 1354, 1228,
1178, 1122, 1082.
4.3. Synthesis of a-trifluoromethylated ketones (7)10
4.3.1. Typical procedure. Under Ar atmosphere, a solution
of 6a (ca. 1 mL) in THF (2 mL) was added to a solution of 2e
(292 mg, 2 mmol) and RhCl(PPh3)3 (37 mg, 2 mol %) in
THF (6 mL) at ꢂ30 ꢀC. Et2Zn of 1.0 M in hexane
(3.0 mL, 3 mmol) was gradually added to the solution at
0 ꢀC, and then the solution was stirred at rt for 0.5 h. The so-
lution was quenched with 10% HCl, and extracted with
Et2O. The Et2O layer was washed with satd NaCl and dried
with MgSO4. The solvent was removed in vacuo and the res-
idue was purified by column chromatography (AcOEt/
hexane¼1:9) to give 7b (332 mg, 77%).
4.4.2.3. 2-Perfluorodecylcyclohexanone (7e). A color-
1
less solid; mp¼73.5–74.0 ꢀC; H NMR (CDCl3) d: 1.69–
2.09 (m, 5H), 2.26 (m, 1H), 2.49 (m, 2H), 3.20 (m, 1H);
19F NMR (CDCl3) d: ꢂ18.0 (m, 3F), ꢂ49.4 (m, 1F),
ꢂ51.1 (m, 1F), ꢂ57.2 (m, 2F), ꢂ58.9 (m, 8F), ꢂ59.1 (m,
2F), ꢂ59.9 (m, 2F), ꢂ63.3 (m, 2F); MS m/z: 616 (M+);
HRMS calcd C16H9OF21: 616.03 (M+), found: 616.03; IR
(neat) cmꢂ1: 1724, 1216, 1154.
4.3.2. Spectral data.
4.4.2.4. 3-Perfluorodecyl-4-phenylbutan-2-one (7f). A
colorless solid; mp¼63.8–64.2 ꢀC; 1H NMR (CDCl3)
d: 1.96 (s, 3H), 3.17 (m, 2H), 3.63 (m, 1H), 7.15–7.17 (m,
2H), 7.25–7.33 (m, 3H); 19F NMR (CDCl3) d: ꢂ18.0 (m,
3F), ꢂ49.4 (m, 1F), ꢂ52.0 (m, 1F), ꢂ57.4 (m, 2F), ꢂ58.9
(m, 10F), ꢂ59.9 (m, 2F), ꢂ63.3 (m, 2F); MS m/z: 666
(M+); HRMS calcd C20H11OF21: 666.05 (M+), found:
666.05; IR (neat) cmꢂ1: 1726, 1222, 1154.
4.3.2.1. 2-Trifluoromethylcyclohexanone (7a). A color-
less oil; 1H NMR (CDCl3) d: 1.67–1.88 (m, 3H), 1.99–2.03
(m, 1H), 2.07–2.15 (m, 1H), 2.31–2.39 (m, 2H), 2.48–2.53
(m, 1H), 3.08 (m, 1H); 13C NMR (CDCl3) d: 23.8, 27.1,
27.6 (q, J¼2.5 Hz), 42.2 (q, J¼1.6 Hz), 53.7 (q,
J¼25.5 Hz), 124.6 (q, J¼278.6 Hz), 202.9; 19F NMR
(CDCl3) d: ꢂ6.02 (d, 3F, J¼8.3 Hz); MS m/z: 166 (M+);
HRMS calcd C7H9OF3: 166.06 (M+), found: 166.06; IR
(neat) cmꢂ1: 2956, 2880, 1730, 1394, 1274.
4.4.2.5. (E)-2-Perfluorodecyl-4-phenylbut-3-en-2-ol
(8f). A colorless solid; mp¼88.0–90.0 ꢀC; 1H NMR
(CDCl3) d: 1.62 (s, 3H), 2.29 (s, 1H), 6.33 (d, 1H,
J¼16.2 Hz), 6.86 (d, 1H, J¼16.2 Hz), 7.25–7.43 (m, 5H);
19F NMR (CDCl3) d: ꢂ18.0 (m, 3F), ꢂ55.4 to ꢂ56.7 (m,
3F), ꢂ58.2 to ꢂ59.1 (m, 11F), ꢂ59.9 (s, 2F), ꢂ63.3 (m,
4.3.2.2. 3-Trifluoromethyl-4-phenylbutan-2-one (7b).
A colorless oil; H NMR (CDCl3) d: 2.07 (s, 3H), 3.06
1
(dd, 1H, J¼13.9, 4.2 Hz), 3.18 (dd, 1H, J¼13.9, 10.9 Hz),
3.56 (dqd, 1H, J¼10.9, 8.3, 4.2 Hz), 7.12–7.32 (m, 5H);

K. Sato et al. / Tetrahedron 63 (2007) 12735–12739
12739
2F); MS m/z: 666 (M+); HRMS calcd C20H11OF21: 666.05
Eds.; Elsevier: Amsterdam, 1993; (c) Welch, J. T.
Tetrahedron 1987, 43, 3123–3197.
(M+), found: 666.05; IR (neat) cmꢂ1: 3616, 1346, 1148.
2. (a) Uneyama, K. Organofluorine Chemistry; Blackwell
Publishing: Oxford, 2006; (b) Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; ACS Publications Division and
Oxford University Press: Washington, DC, 2005; (c) Tozer,
M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683.
3. (a) Cuenca, A. B.; D’Hooge, F.; Gouge, V.; Castelot-
Deliencourt, G.; Oulyadi, H.; Leclerc, E.; Jubault, P.;
Pannecoucke, X.; Quirion, J.-C. Synlett 2005, 2627–2630; (b)
Braun, M.; Vonderhagen, A.; Waldmhller, D. Liebigs Ann.
1995, 1447–1450; (c) Morikawa, T.; Uejima, M.; Kobayashi,
Y.; Taguchi, T. J. Fluorine Chem. 1993, 65, 79–89; (d) Lang,
E. W.; Schaub, B. Tetrahedron Lett. 1988, 29, 2943–2946; (e)
Hallinan, E. A.; Fried, J. Tetrahedron Lett. 1984, 25, 2301–
2302.
4.4.2.6.
1-(1,1-Difluoro-3-phenylprop-2-ynyl)cyclo-
hex-2-enol (8g). A pale yellow oil; 1H NMR (CDCl3)
d: 1.77–1.84 (m, 2H), 1.94–1.97 (m, 2H), 2.04–2.19 (m,
2H), 2.15 (br s, 1H), 5.86 (m, 1H), 6.16 (m, 1H), 7.33–
7.43 (m, 3H), 7.50–7.53 (m, 2H); 19F NMR (CDCl3) d:
ꢂ35.4 (s, 1F), ꢂ35.5 (s, 1F); MS m/z: 248 (M+); HRMS
calcd C15H14OF2: 248.10 (M+), found: 248.10; IR (neat)
cmꢂ1: 3464, 2948, 2244, 1294, 1138, 1052.
4.5. Reaction by using deuterated alkylzinc reagent
4.5.1. Typical procedure. Under Ar atmosphere, a solution
of 1.0 M ZnCl2 in Et2O (3.0 mL, 3 mmol) was added to a so-
lution of 2.0 M CD3CD2MgBr in Et2O (3.0 mL, 6 mmol).
The resulting suspension was stirred overnight at rt. To the
solution of RhCl(PPh3)3 (9 mg, 2 mol %), 2e (73 mg,
0.5 mmol), and 6c (484 mg, 0.75 mmol) was gradually
added the clear supernatant portion of the Zn reagent
(1.5 mL, 0.75 mmol) at 0 ꢀC, and then the solution was
stirred at rt for 1 h. The solution was quenched with 10%
HCl, and extracted with Et2O. The Et2O layer was washed
with satd NaCl and dried with MgSO4. The solvent was
removed in vacuo and the residue was purified by
column chromatography (AcOEt/hexane¼1:9) to give
7f-d1 (62 mg, 19%).
4. (a) Iseki, K. Tetrahedron 1998, 54, 13887–13914; (b) Iseki, K.;
Kuroki, Y.; Asada, D.; Kobayashi, Y. Tetrahedron Lett. 1997,
38, 1447–1448; (c) Kitagawa, O.; Taguchi, T.; Kobayashi, Y.
Tetrahedron Lett. 1988, 29, 1803–1806.
5. (a) Uneyama, K. J. Organomet. Chem. 2000, 611, 158–163; (b)
Itoh, T.; Sakabe, K.; Kudo, K.; Zagatti, P.; Renou, M.
Tetrahedron Lett. 1998, 39, 4071–4074; (c) Itoh, T.; Ohara,
H.; Emoto, S. Tetrahedron Lett. 1995, 36, 3531–3534; (d)
Arnone, A.; Bravo, P.; Cavicchio, G.; Frigerio, M.; Viani, F.
Tetrahedron 1992, 48, 8523–8540; (e) Yang, Z.-Y.; Burton,
D. J. J. Chem. Soc., Chem. Commun. 1992, 233–234; (f)
Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1991, 56, 5125–
5132; (g) Kitagawa, O.; Miura, A.; Kobayashi, Y.; Taguchi,
T. Chem. Lett. 1990, 1011–1014.
6. Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.;
Kumadaki, I. Chem. Pharm. Bull. 1999, 47, 1013–1016.
7. (a) Sato, K.; Nakazato, S.; Enko, H.; Tsujita, H.; Fujita, K.;
Yamamoto, T.; Omote, M.; Ando, A.; Kumadaki, I.
J. Fluorine Chem. 2003, 121, 105–107; (b) Sato, K.; Tamura,
M.; Tamoto, K.; Omote, M.; Ando, A.; Kumadaki, I. Chem.
Pharm. Bull. 2000, 48, 1023–1025.
4.5.2. Spectral data.
4.5.2.1. 4-Deutero-3-perfluorodecyl-4-phenylbutan-2-
one (7f-d1). A colorless solid; H NMR (CDCl3) d: 1.96
(s, 3H), 3.17 (m, 1H), 3.63 (m, 1H), 7.15–7.17 (m, 2H),
7.25–7.33 (m, 3H); 19F NMR (CDCl3) d: ꢂ18.0 (m, 3F),
ꢂ49.4 (m, 1F), ꢂ51.9 (m, 1F), ꢂ57.4 (m, 2F), ꢂ58.9 (m,
10F), ꢂ59.9 (m, 2F), ꢂ63.3 (m, 2F); MS m/z: 667 (M+);
HRMS calcd C20H10DOF21: 667.05 (M+), found: 667.05.
1
8. Sato, K.; Ogawa, Y.; Tamura, M.; Harada, M.; Ohara, T.;
Omote, M.; Ando, A.; Kumadaki, I. Collect. Czech. Chem.
Commun. 2002, 67, 1285–1295.
Acknowledgements
9. Sato, K.; Tarui, A.; Kita, T.; Ishida, Y.; Tamura, H.; Omote, M.;
Ando, A.; Kumadaki, I. Tetrahedron Lett. 2004, 45, 5735–
5737.
10. (a) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Synth.
2006, 83, 177–183; (b) Sato, K.; Omote, M.; Ando, A.;
Kumadaki, I. Org. Lett. 2004, 6, 4359–4361.
This work was partially supported by Pfizer Award in Syn-
thetic Organic Chemistry, Japan. We gratefully acknowledge
to TOSOH F-TECH, Inc., for generous gift of CF3I.
References and notes
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€
€
11. (a) Bohm, V. P. W.; Schulze, V.; Bronstrup, M.; Muller, M.;
Hoffmann, R. W. Organometallics 2003, 22, 2925–2930; (b)
Tobia, D.; Baranski, J.; Rickborn, B. J. Org. Chem. 1989, 54,
4253–4256.
1. (a) Chemistry of Organic Fluorine Compounds II: A Critical
ꢀ
Review; Hudlicky, M., Pavlath, A. E., Eds.; ACS Publications
Division: Washington, DC, 1995; (b) Organofluorine
Compounds in Medicinal Chemistry and Biomedical
Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M.,
12. (a) Gais, H.-J.; B
€ulow, G.; Raabe, G. J. Am. Chem. Soc. 1993,
115, 7215–7218; (b) Westerhausen, M.; Rademacher, B.
J. Organomet. Chem. 1991, 421, 175–188.