Synthesis and hydrogenation of (E)-γ-aryl-γ-morpholino-α-trifluoromethylated allyl alcohols through the reaction of trifluoroacetaldehyde ethyl hemiacetal with enamines

Article abstract of DOI:10.1016/j.tet.2010.03.019

Treatment of trifluoroacetaldehyde ethyl hemiacetal with enamines, derived from acetophenone derivatives, at room temperature gave (E)-1,1,1-trifluoro-4-morpholino-4-aryl-but-3-en-2-ols, which are intermediates for preparation of the β-trifluoromethylated aldol products, 4,4,4-trifluoro-3-hydroxy-1-aryl-butan-1-ones. The structure of the intermediate (E)-1,1,1-trifluoro-4-morpholino-4-(4-nitrophenyl)-but-3-en-2-ols could be assigned by ¹H, ¹³C NMR, IR, and X-ray crystallography. Furthermore, hydrogenation and reductive deamination of the intermediate (E)-1,1,1-trifluoro-4-morpholino-4-aryl-but-3-en-2-ols with hydrogen in the presence of a catalytic amount (10 mol %) of palladium on carbon in trifluoroethanol proceeded smoothly at room temperature to give 1,1,1-trifluoro-4-aryl-2-butanols in good to excellent yields.

Full text of DOI:10.1016/j.tet.2010.03.019

Tetrahedron 66 (2010) 3283–3289
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and hydrogenation of (E)-g-aryl-g-morpholino-a-trifluoromethylated
allyl alcohols through the reaction of trifluoroacetaldehyde ethyl hemiacetal
with enamines
,
a
a
a
b
Kazumasa Funabiki a , Yoshihiro Murase , Yudai Furuno , Yasuhiro Kubota , Masahiro Ebihara ,
*
Masaki Matsui a
a Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
b Department of Chemistry, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of trifluoroacetaldehyde ethyl hemiacetal with enamines, derived from acetophenone de-
Received 18 December 2009
Received in revised form 4 March 2010
Accepted 4 March 2010
rivatives, at room temperature gave (E)-1,1,1-trifluoro-4-morpholino-4-aryl-but-3-en-2-ols, which are
intermediates for preparation of the b-trifluoromethylated aldol products, 4,4,4-trifluoro-3-hydroxy-1-
aryl-butan-1-ones. The structure of the intermediate (E)-1,1,1-trifluoro-4-morpholino-4-(4-nitrophenyl)-
but-3-en-2-ols could be assigned by 1H, 13C NMR, IR, and X-ray crystallography. Furthermore, hydro-
genation and reductive deamination of the intermediate (E)-1,1,1-trifluoro-4-morpholino-4-aryl-but-3-
en-2-ols with hydrogen in the presence of a catalytic amount (10 mol %) of palladium on carbon in
trifluoroethanol proceeded smoothly at room temperature to give 1,1,1-trifluoro-4-aryl-2-butanols in
good to excellent yields.
Available online 10 March 2010
Keywords:
Trifluoroacetaldehyde
Hemiacetal
Enamine
Ó 2010 Elsevier Ltd. All rights reserved.
Hydrogenation
Reductive deamination
1. Introduction
versatility for introduction of the functional groups. Therefore,
there is still a need for the development of effective, stereo- and/or
Trifluoroacetaldehyde (CF3CHO) is one of the most important
building blocks for the construction of -trifluoromethylated al-
regio-selective, and atom-economical methods for the direct use of
CF3CHO hemiacetal in carbon–carbon bond-forming reactions.
Recently, we reported that an equimolar amount of enamine
promoted the efficient in situ generation of CF3CHO under mild
reaction conditions and the successive carbon–carbon bond-
forming reaction with regenerated enamines without any addi-
tives, followed by hydrolysis with 10% HCl aqueous solution to give
a
cohols.1,2 However, CF3CHO normally exists as a hydrate or hemi-
acetal, due to the strong electron-withdrawing properties of the
trifluoromethyl group.3 Therefore, the direct use of commercially
available CF3CHO ethyl hemiacetal with some reagents, such as
Grignard reagents, lithium reagents, and enolates, is sometimes not
suitable for the preparation of
to the difficulty of the elimination of the
alkoxide resulting in the generation of CF3CHO, although Kitazume
et al. reported that -difluoromethylated alcohols can be synthe-
a
-trifluoromethylated alcohols, due
the corresponding b-hydroxy-b-trifluoromethylated ketones in
a
-trifluoromethlyted
good to excellent yields.10 However, before hydrolysis, the exact
structures of the intermediate products, produced by reacting
CF3CHO ethyl hemiacetal and enamine, have not yet been assigned.
This information should be worthwhile to develop the organo-
catalytic direct aldol reactions of CF3CHO ethyl hemiacetal with
ketones.11
a
sized by the direct use of difluoroacetaldehyde ethyl hemiacetal
with Grignard reagents and lithium acetylide.4
There are scattered examples of the direct reaction of CF3CHO
ethyl hemiacetal with some nucleophiles, such as nitroalkane,5
anilines,6 phenols,7 hydrazones,8 and so on.9 Some of these
methods suffer from a need of a strong base or acid, a high reaction
temperature, low regioselectivities, low stereoselectivities, and low
In this paper, we report the structure of the intermediate (E)-1,1,1-
trifluoro-4-morpholino-4-aryl-but-3-en-2-ols based on NMR, IR, and
X-ray data, which were obtained by reacting CF3CHO ethyl hemiacetal
with enamine derived from acetophenone derivatives, as well as the
reactivities, such as not only hydrolysis but successive hydrogenation
and reductive deamination of the intermediate (E)-1,1,1-trifluoro-4-
morpholino-4-aryl-but-3-en-2-ols, which represents a convenient
method for the one-pot synthesis of 1,1,1-trifluoro-4-aryl-2-butanols.
* Corresponding author. Tel.: þ81 293 2599; fax: þ81 293 2794; e-mail address:
funabiki@gifu-u.ac.jp.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.019

3284
K. Funabiki et al. / Tetrahedron 66 (2010) 3283–3289
2. Results and discussion
However, methylation did not occur at all, followed by hydrolysis to
give the corresponding aldol product 4 in 57% yield.
2.1. Assignment of the structure and reactivity of the
intermediate product by reacting CF3CHO ethyl hemiacetal
1a with enamine 2 derived from acetophenones
To confirm the exact structure of 3, including the stereochem-
istry of the carbon–carbon double bond, the following reaction was
carried out. Treatment of CF3CHO ethyl hemiacetal 1a with en-
amine 2c carrying a nitro group on the phenyl group in toluene at
room temperature for 24 h gave (E)-1,1,1-trifluoro-4-morpholino-
4-(4-nitrophenyl)but-3-en-2-ol (3ac) in 71% yield in the form of
a solid as a single isomer, as shown in Scheme 3.
When CF3CHO ethyl hemiacetal 1a was treated with an equi-
molar amount of enamine 2a or 2b, prepared from acetophenone
and morpholine or diethylamine, in toluene at room temperature,
1,1,1-trifluoro-4-morpholino-4-phenyl-but-3-en-2-ol (3aa) or 1,1,1-
trifluoro-4-diethylamino-4-phenyl-but-3-en-2-ol (3ab) was ob-
served after 1 h. The products 3aa and 3ab could be produced by
a Friedel–Crafts-type reaction of enamine, as in the reaction of the
enol silyl ether or vinyl ether with CF3CHO.1o,p Notably, the product
3aa and 3ab were each observed as only single isomer in the crude
reaction mixture, by 1H, 13C, and 19F NMR (Scheme 1), although the
E/Z ratios of the product obtained by reacting enol silyl ether and
enol methyl ether with CF3CHO ranged from 33/67 to 14/86. The
reason for complete E-selectivity of is not clear at the present time.
NO2
O
1) toluene
rt, 24 h
OH
OH
OEt
N
2) filtration
+
F3C
N
F3C
1a
O
2c
NO2
(E)- isomer
3ac (71%)
Friedel-Crafts-type
reaction of CF3CHO
Scheme 3. Reaction of 1a with enamine 2c.
The structural assignment of the isolated 3ac was based on the
results of 1H, 13C, and 19F NMR, IR, and X-ray crystallography,13
where the morpholino and 1-hydroxy-2,2,2-trifluoroethyl groups
are situated trans to each other.
NR1R2
OH
OEt
OH Ph
rt
+
F3C
F3C
NR1R2
toluene
Ph
1a
only one isomer
2a NR1R2 = morphilino
2b NR1R2 = Et2N
3aa NR1R2 = morphilino
3ab NR1R2 = Et2N
2.2. Synthesis and hydrogenation of (E)-
g-aryl-g-
morpholino- -trifluoromethylated allyl alcohols through
a
the reaction of CF3CHO ethyl hemiacetal and enamine
to give 4-aryl-1,1,1-trifluoro-2-butanols (5)
stirring
without H+
OH
O
The oily intermediate (E)-1,1,1-trifluoro-4-morpholino-4-aryl-
but-3-en-2-ols (3) could not be purified by flash chromatography
on silica gel, because 3 was easily hydrolyzed during the chroma-
tography to give the corresponding aldol products 4. Therefore (E)-
F3C
Ph
4
Scheme 1.
g
-aryl-g-morpholino-a-trifluoromethylated allyl alcohols were
The reactivities of thus-obtained products 3aa and 3ab were
examined by simple stirring without addition of any acids or bases.
As a result, hydrolysis of the intermediate (E)-1,1,1-trifluoro-4-
diethylamino-4-aryl-but-3-en-2-ols (3ab) occurred after 50 h to
give the corresponding aldol product 4 in 75% yield, together with
3ab in 9% yield, probably due to the high acidity of the hydroxyl
group attached by the trifluoromethyl group. Compared with this
result, the hydrolysis of 4-morpholino-substituted 3aa is much
slower than that of the diethylamino-substituted 3ab, and gave 4 in
69% yield, together with the remaining 3aa, even after 11 days.
Thus, the morpholino-substituted product 3aa is much more stable
than the diethylamino-substituted 3ab under this conditions.12
As another reaction of 3aa, methylation using iodomethane
(3 equiv) was carried out in acetonitrile as shown in Scheme 2.
used as crude products for next hydrogenation reaction.
The mixture of CF3CHO ethyl hemiacetal 1a with enamine 2a was
stirred in hexane at room temperature, followed by concentration in
vacuum, the addition of trifluoroethanol (TFE) as a solvent, and
hydrogenation with hydrogen in the presence of a catalytic amount
(10 mol %) of palladium on carbon (Merck Ltd., loading: 10 wt %) at
room temperature for 1 h to give 1,1,1-trifluoro-4-phenylbutan-2-ol
Table 1
Screening of the hydrogenation
O
OH
OEt
N
concentration
O
+
F3C
Ph
hexane
rt, 1 h
O
2a
1a
10 wt%
OH Ph
OH
OEt
N
Pd/C (10 mol%)
H2 (1 atm)
OH
OH
N
+
+
F3C
N
F3C
MeI
solvent
MeCN
rt, 5 h
F3C
Ph
F3C
Ph
rt, time
O
1a
2a
5aa
6aa
3aa
Entry
Solvent
Time (h)
5aa, yielda (%)
6aa, yieldb (%), dr
OH
O
OH O
1
2
3
4
5
TFE
TFE
THF
EtOH
Hexane
1
18
18
18
18
62
84
55
65
57
23 (18:82)
d
(3 equiv) 10% HCl
+
F3C
Ph
F3C
Ph
MeCN
MeCN
38 (16:84)
23 (10:90)
23 (12:88)
rt, 14 h
rt, 5 h
Me
(0%)
4 (57%)
a
All reaction was carried out with hemiacetal 1a (1 mmol) and enamine 2a (1 mmol).
b
19F NMR yields.
Scheme 2. Methylation of 3aa.

K. Funabiki et al. / Tetrahedron 66 (2010) 3283–3289
3285
Table 2
Table 2 (continued)
Synthesis of 4-aryl-1,1,1-trifluoro-2-butanols 5
Entry
Enamine 2
Product 5
Yielda (%)
O
1) hexane, rt, 1 h
O
N
2) concentration
3) 10 wt% Pd/C (10 mol%),
H2 (1 atm), TFE, rt, 18 h
OH
OEt
OH
N
OH
Me
Me
+
F3C
F3C
R
R
F3C
7
87 (75)
1a
2
5
5ai
Entry
Enamine 2
Product 5
Yielda (%)
2i
O
O
OH
N
OH
N
F3C
1
84 (70)
F3C
8
65 (63)
5aa
2a
5aj
2j
a
19F NMR yields. Values in paratheses stand for yields of isolated products.
O
OH
(5aa) in 62% NMR yield and 1,1,1-trifluoro-4-morpholino-4-phe-
nylbutan-2-ol (6aa) in 23% NMR yield (Table 1, entry 1).
N
F3C
2
76 (68)
Anincrease in thereaction time from 1 h to 18 h forhydrogenation
resulted in an increased yield of trifluoromethylated alcohol 5aa as
well as the disappearance of amino alcohol 6aa. Among the solvents
examined, which included ethanol, tetrahydrofuran (THF), hexane,
and TFE, the use of TFE gave the best yield of the product 5aa (entry
2).14 Ethanol, THF, and hexane were also used as a solvent, but were
not as effective in the deamination of amino alcohol 6aa (entries 3–5).
The results of hydrogenation leading to 4-aryl-1,1,1-trifluoro-2-
butanols (5) are summarized in Table 2.
Me
Me
5ad
2d
O
OH
N
F3C
Other enamines 2d–j, derived from 40, 30, and 20-substituted ace-
tophenones as well as 1-acetonaphthone, successfully participated in
the one-pot three-components coupling reactions to give the corre-
sponding 1,1,1-trifluoro-4-(40, 30, and 20-substituted aryl)-2-butanols
5aa, 5ad, 5ae, 5ag, 5ah, 5ai, and 5aj in good to excellent yields. The
reaction of enamine 2f carrying a 4-chlorophenyl group also pro-
ceeded smoothly to give not 4-chlorophenylated alcohol 5af but
rather phenylated alcohol 5aa in 64% yield, which could be obtained
by the reduction of the chlorine atom on the phenyl group (entry 4).
As shown in Scheme 4, in the case of enamine 2k, reductive
deamination was very sluggish under the same reaction conditions,
3
90 (89)
OMe
OMe
5ae
2e
O
OH
N
F3C
4
86 (64)
due to the effect of the fluorine atom on the phenyl group.15
A
Cl
5aa
prolonged reaction time (five days) was required to obtain the
product 5ak in good yield.
2f
When difluoroacetaldehyde ethyl hemiacetal 1b was treated
with enamine 2j in hexane at room temperature and hydrogenated
in the presence of a catalytic (10 mol %) amount of palladium on
carbon at room temperature, 1,1-difluoro-4-(naphthalen-1-yl)bu-
tan-2-ol (5bj) was obtained in 53% yield, together with a compound,
O
OH
N
F3C
5
94 (92)
that is, dehydroxylated at the a-carbon of the difluoromethyl group,
1-(4,4-difluorobutyl)naphthalene (7), and a defluorinated com-
pound, 1-butylnaphthalene (8), in respective yields of 9% and 7%
(Scheme 5). Comparable dehydroxylated and defluorinated com-
pounds were not detected in the case of CF3CHO ethyl hemiacetal 1a.
The weaker bond energy of the carbon–fluorine bond of the
difluoromethylated group as well as carbon–oxygen bond, com-
pared with that of the trifluoromethyl group, may cause the dehy-
droxylation as well as defluorination of the product 5bj.16
Hydrogenation of the product, which was obtained by the reaction
of trifluoroactaldehyde ethyl hemiacetal 1a with enamine 2l derived
from cyclohexanone, was carried out under the same reaction con-
ditions. Consequently, hydrogenation of the carbon–carbon double
bond smoothlyproceeded. But reductive deamination did notoccurat
all to give amino alcohol 6al in 47% yield (Scheme 6).
CF3
Me
CF3
Me
5ag
2g
O
N
OH
F3C
6
79 (66)
5ah
2h

3286
K. Funabiki et al. / Tetrahedron 66 (2010) 3283–3289
Based on these findings, we can propose the following reaction
O
N
mechanism. As shown in Scheme 7, the reaction of CF3CHO ethyl
hemiacetal 1a with enamine 2a gives the oily intermediate, 1,1,1-
trifluoro-4-morpholino-4-phenylbut-3-en-2-ol (3aa), as a single
isomer. The intermediate 3aa is hydrogenated with hydrogen in the
presence of a catalytic amount (10 mol %) of palladium on carbon to
give the amino alcohol 6aa. The amino alcohol 6aa undergoes
palladium-catalyzed deamination at the benzyl position with hy-
drogen to produce 1,1,1-trifluoro-4-phenylbutan-2-ol (5aa). TFE
was effective in the deamination process of 6.
1) hexane, rt
OH
OEt
2) concentration
+
F3C
1a
F
2k
10 wt%
Pd/C (10 mol%)
H2 (1 atm)
TFE
O
rt, time
O
N
OH Ph
N
OH
OEt
F3C
N
+
OH
OH
F3C
O
F3C
F3C
+
F
1a
2a
3aa
O
N
6ak
5ak
F
OH
OH
H H
cat. Pd/C, H2
cat. Pd/C, H2
H
a
6ak, yield (%) , drb
a
F3C
Ph
time
18 h
5ak, yield (%)
F3C
Ph
hydrogenation
reductive
H H
6aa
H H
5aa
deamination
39 (23)
46 (39), 91 : 9
24 (15), 79 : 21
5 days 71 (50)
Scheme 7. Proposed reaction mechanism.
a
Measured by 19F NMR. Values in
3. Conclusion
parentheses stand for the yields of isolated
products.
b
Determined by 19F NMR before isolation.
In conclusion, the structure of the intermediate (E)-1,1,1-trifluoro-
4-morpholino-4-(4-nitrophehyl)but-3-en-2-ol (3ac), obtained by
reacting CF3CHO ethyl hemiacetal 1a with enamine 2 derived from
acetophenones, could be assigned based on the results of an X-ray
analysis. Furthermore, we have developed a new method for the
synthesis of 4-aryl-1,1,1-trifluoro-2-butanols based on the tandem
effective in situ generation of CF3CHO and successive carbon–carbon
bond-formation reactions with enamines, followed by hydrogenation
and deaminationwith hydrogen in the presence of a catalytic amount
(10 mol %) of palladium on carbon at room temperature. The use of
a fluorine atom ora trifluoromethyl groupgave interesting results:(1)
In the step of deamination, trifluoroethanol (TFE) was more effective
than other usual organic solvents. (2) A fluorine atom on the phenyl
group apparently disturbed the deamination process at the benzyl
positions of the intermediates. The diastereoselective and enantio-
Scheme 4. Reaction of 1a with enamine 2k carrying a fluorine atom on the phenyl
group.
1) hexane, rt
O
2) concentration
3) 10 wt% Pd/C (10 mol%),
OH
OEt
H2 (1 atm), TFE, rt, 18 h
N
+
F2HC
1b
2j
OH
F2HC
5bj (53%)
F2HC
+
selective synthesis of
a-trifluoromethylated alcohol based on this
hydrogenation reaction is currently being investigated in our
laboratory.
7 (9%)
4. Experimental section
4.1. General
+
8 (7%)
Melting points were obtained on a Yanagimoto MP-S2 micro
melting point apparatus and are uncorrected. IR spectra were
recorded on a SHIMADZU FT-IR 8100A spectrometer. 1H (400 MHz)
Scheme 5. Reaction of difluoroacetaldehyde ethyl hemiacetal 1b with enamine 2j.
or 13C (100 MHz) NMR spectra were measured with a JEOL
a-400 FT
NMR spectrometer in deuteriochloroform (CDCl3) solutions with
tetramethylsilane (Me4Si) as an internal standard. 19F NMR
(376 MHz) spectra were recorded on a JEOL a-400 FT NMR in CDCl3
O
N
O
N
1) hexane, rt, 1 h
2) concentration
solutions using trichlorofluoromethane (CFCl3) as an external
standard. HRMS were measured on a JEOL JMS-700 mass spec-
trometer. Pure products were isolated by column chromatography
using Silica Gel 60 (spherical, 270–325 mesh, KANTO CHEMICAL
CO., INC.) or Wakogel C200 (100–200 mesh, Wako Pure Chemical
Ind., Ltd.). Analytical TLC was performed on Merck precoated
(0.25 mm) silica gel 60 F254 plates. All chemicals were of reagent
3) 10 wt% Pd/C (10 mol%),
H2 (1 atm), TFE, rt, 18 h
OH
OH
OEt
+
F3C
F3C
1a
6al (47%)
2l
Scheme 6. Reaction of 1a with enamine 2l.

K. Funabiki et al. / Tetrahedron 66 (2010) 3283–3289
3287
grade and, if necessary, purified in the usual manner prior to use.
(s), 128.4 (s), 128.5 (s), 134.9 (s); 19F NMR (376 MHz, CDCl3)
(3F, d, J¼7.6 Hz).
d
ꢁ77.6
Palladium on carbon was purchased from Merck Ltd. (loading:
10 wt %). Anhydrous tetrahydrofuran (THF), dichloromethane, and
diethyl ether were purchased from Kanto Chemical Co.
4.3.3. 1,1,1-Trifluoro-4-p-tolylbutan-2-ol (5ad). Rf 0.23 (hexane–
EtOAc¼6:1); IR (NaCl) 3435 (OH) cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.2. Preparation of (E)-1,1,1-trifluoro-4-morpholino-4-
(4-nitrophenyl)but-3-en-2-ol (9j)
d
1.96–2.14 (2H, m), 2.43 (3H, s), 2.79 (1H, dt, J¼13.9, 8.2 Hz), 2.97
(1H, ddd, J¼13.9, 8.7, 5.3 Hz), 3.96 (1H, ddq, J¼16.4, 6.5, 3.2 Hz), 7.19–
7.24 (4H, m); 13C NMR (100 MHz, CDCl3)
20.9 (s), 30.3 (s), 31.0 (s)
69.5 (q, J¼31.1 Hz),125.2 (q, J¼281.8 Hz),128.3 (s),129.3 (s),135.8 (s),
137.2 (s); 19F NMR (376 MHz, CDCl3)
d
To a toluene (2 ml) solution of enamine 2c (0.234 g,1 mmol) was
slowly added CF3CHO ethyl hemiacetal 1a (0.144 g, 1 mmol) at
room temperature. After the mixture was stirred for one day, the
precipitate was filtered, and washed with toluene (1 ml) to give (E)-
1,1,1-trifluoro-4-morpholino-4-(4-nitrophenyl)but-3-en-2-ol (3ac)
in 71% yield.
d
ꢁ79.9 (3F, d, J¼6.5 Hz); HRMS
(EI) found: m/z 218.0916, calcd for C11H13F3O: MꢁH, 218.0919.
4.3.4. 1,1,1-Trifluoro-4-(4-methoxyphenyl)butan-2-ol (5ae). Rf 0.17
(hexane–EtOAc¼6:1); IR (NaCl) 3436 (OH) cmꢁ1
;
1H NMR
1.83–2.04 (2H, m), 2.66 (1H, ddd, J¼14.0, 8.3,
(400 MHz, CDCl3)
d
4.2.1. (E)-1,1,1-trifluoro-4-morpholino-4-(4-nitrophenyl)but-3-en-
8.2 Hz), 2.84 (1H, ddd, J¼14.0, 8.8, 8.7 Hz), 3.78 (3H, s), 3.85 (1H,
2-ol (3ac). Mp 155–156 ꢀC; IR (KBr) 3391 (OH), 1628 (C]C), 1524,
ddq, J¼16.4, 6.5, 3.3 Hz), 6.82–7.13 (4H, m); 13C NMR (100 MHz,
and 1350 (NO2), cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.31 (1H, s),
CDCl3)
d
29.8 (s), 31.1 (s), 55.2 (s), 69.4 (q, J¼31.1 Hz), 114.0 (s), 125.0
2.83–2.85 (4H, m), 3.71–3.73 (4H, m), 4.02–4.11 (1H, m), 4.83 (1H, d,
(q, J¼281.8 Hz), 129.4 (s), 132.5 (s), 158.0 (s); 19F NMR (376 MHz,
J¼9.9 Hz), 7.61, and 8.32 (4H, AB quartet, J¼8.7 Hz); 13C NMR
CDCl3)
d
ꢁ79.7 (3F, d, J¼6.5 Hz); HRMS (EI) found: m/z 234.0873,
(100 MHz, CDCl3)
d
48.9 (s), 66.5 (s), 68.8 (q, J¼32.8 Hz), 97.1 (s),
calcd for C11H13F3O2: MꢁH, 234.0868.
123.3 (s), 124.7 (q, J¼281.8 Hz), 130.5 (s), 142.1 (s), 148.2 (s), 155.1
(s); 19F NMR (376 MHz, CDCl3)
d
ꢁ78.4 (3F, d, J¼6.1 Hz); HRMS (EI)
4.3.5. 1,1,1-Trifluoro-4-(4-(trifluoromethyl)phenyl)butan-2-ol
found: m/z 332.0989, calcd for C14H15F3O4N2, 332.0985.
(5ag). Rf 0.18 (hexane–EtOAc¼6:1); IR (NaCl) 3390 (OH) cmꢁ1
;
1H
NMR (400 MHz, CDCl3)
d
1.91–2.07 (2H, m), 2.26 (1H, dd, J¼5.8,
4.3. A typical procedure
5.8 Hz), 2.81 (1H, ddd, J¼13.9, 8.3, 8.2 Hz), 2.98 (1H, ddd, J¼13.9,
8.8, 5.3 Hz), 3.89 (1H, ddq, J¼16.0, 6.5, 3.3 Hz), 7.33, and 7.57 (4H, AB
To a solution of 4-(1-phenylvinyl)morpholine (2a) (0.189 g,
1 mmol) in hexane (2 ml) was added CF3CHO ethyl hemiacetal 1a
(0.144 g,1 mmol) at room temperature under argon. After stirring at
room temperature for 1 h, the reaction mixture was concentrated by
distillation under reduced pressure. To a resultant reaction mixture
was added of a catalytic amount (10 mol %, 0.106 g) of palladium on
carbon (Merck, loading: 10 wt %) and trifluoroethanol (10 ml). After
replacementofairwithhydrogen, themixturewasvigorouslystirred
atroomtemperature underordinaryhydrogenpressure(balloon)for
18 h. The reaction mixture was filtered using CeliteÒ 545RVS and the
filtratewas concentrated under pressure to provide 1,1,1-trifluoro-4-
phenylbutan-2-ol (5aa). After the measurement of the residue by 19F
NMR using benzotrifluoride (5aa:84%), purification by flash chro-
matography on silica gel (hexane–EtOAc¼10:1) gave 1,1,1-trifluoro-
4-phenylbutan-2-ol (5aa) (70%, 0.143 g).
quartet, J¼8.1 Hz); 13C NMR (100 MHz, CDCl3)
d 30.6 (s), 69.4 (q,
J¼31.1 Hz), 124.9 (q, J¼281.8 Hz), 125.5 (s), 125.6 (s), 128.8 (q,
J¼32.8 Hz), 144.5 (s); 19F NMR (376 MHz, CDCl3)
d
ꢁ62.3 (3F, s),
-79.8 (3F, d, J¼6.5 Hz); HRMS (EI) found: m/z 272.0647, calcd for
C11H10F6O: MꢁH, 272.0636.
4.3.6. 1,1,1-Trifluoro-4-m-tolylbutan-2-ol (5ah). Rf 0.20 (hexane–
EtOAc¼6:1); IR (NaCl) 3408 (OH) cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.97–2.10 (2H, m), 2.38 (3H, s), 2.61 (1H, s), 2.73 (1H, ddd, J¼13.9,
8.5, 8.3 Hz), 2.92 (1H, ddd, J¼13.9, 8.8, 5.3 Hz), 3.91 (1H, ddq, J¼9.9,
6.5, 3.3 Hz), 7.04–7.26 (4H, m); 13C NMR (100 MHz, CDCl3)
d
21.2 (s),
30.7 (s), 30.9 (s), 69.5 (q, J¼31.1 Hz), 125.2 (q, J¼281.8 Hz), 125.4 (s),
127.1 (s), 128.5 (s), 129.2 (s), 138.2 (s), 140.3 (s); 19F NMR (376 MHz,
CDCl3)
d
ꢁ79.9 (3F, d, J¼6.5 Hz); HRMS (EI) found: m/z 218.0911,
calcd for C11H13F3O: MꢁH, 218.0919.
4.3.1. 1,1,1-Trifluoro-4-phenylbutan-2-ol (5aa)17. Rf 0.20 (hexane–
EtOAc¼10:1); IR (NaCl) 3399 (OH) cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.3.7. 1,1,1-Trifluoro-4-o-tolylbutan-2-ol (5ai). Rf 0.28 (hexane–
EtOAc¼8:1); IR (NaCl) 3389 (OH) cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.80–1.99 (2H, m), 2.42 (1H, s), 2.65 (1H, dt, J¼13.9, 8.2 Hz), 2.83
d
1.91–2.11 (2H, m), 2.42 (3H, s), 2,73 (1H, s), 2.81 (1H, ddd, J¼14.0,
(1H, ddd, J¼13.9, 8.7, 5.3 Hz), 3.79 (1H, ddq, J¼9.9, 6.5, 3.2 Hz), 7.11–
7.24 (5H, m); 13C NMR (100 MHz, CDCl3)
30.7 (s), 30.9 (s), 69.5 (q,
J¼31.1 Hz), 125.2 (q, J¼281.8 Hz), 126.3 (s), 128.4 (s), 128.6 (s), 140.4
(s); 19F NMR (376 MHz, CDCl3)
9.4, 7.5 Hz), 3.00 (1H, ddd, J¼14.2, 9.4, 5.0 Hz), 4.00, (1H, m), 7.11–
7.24 (4H, m); 13C NMR (100 MHz, CDCl3)
19.1 (s), 28.2 (s), 29.7 (s),
69.9 (q, J¼31.1 Hz), 125.2 (q, J¼281.8 Hz), 126.1 (s), 126.5 (s), 128.8
(s), 130.4 (s), 136.0(s), 138.6 (s); 19F NMR (376 MHz, CDCl3)
d
d
d
ꢁ79.8 (3F, d, J¼6.9 Hz); HRMS (EI)
d
ꢁ79.8
found: m/z 204.0755, calcd for C10H11F3O, 204.0762.
(3F, d, J¼6.9 Hz); HRMS (EI) found: m/z 218.0924, calcd for
C11H13F3O: MꢁH, 218.0919.
4.3.2. 1,1,1-Trifluoro-4-morpholino-4-phenylbutan-2-ol (6aa). Rf 0.20
(hexane–EtOAc¼10:1); IR (NaCl) 3375 (OH) cmꢁ1; HRMS (EI) found:
m/z 289.1293, calcd for C14H18F3O2N: MꢁH, 289.1290; major isomer
4.3.8. 1,1,1-Trifluoro-4-(naphthalen-1-yl)butan-2-ol (5aj). Rf 0.15
(hexane–CH2Cl2¼7:1); IR (NaCl) 3419 (OH) cmꢁ1
;
1H NMR
1H NMR (400 MHz, CDCl3)
d
1.82 (1H, ddd, J¼14.3, 2.7, 2.7 Hz), 2.34
(400 MHz, CDCl3) d 1.89–2.08 (2H, m), 2.45 (1H, s), 3.04 (1H, ddd,
(2H, s), 2.48 (1H, ddd, J¼14.3, 11.8, 11.1 Hz), 2.67–2.72 (2H, m), 3.68
(4H, m), 3.89 (1H, dd, J¼11.8, 2.7 Hz), 4.24–4.33 (1H, m), 7.14–7.41
J¼14.1, 8.3, 8.2 Hz), 3.28 (1H, ddd, J¼14.1, 9.2, 5.1 Hz), 3.83 (1H, ddq,
J¼20.0, 6.8, 3.3 Hz), 7.23–7.93 (7H, m); 13C NMR (100 MHz, CDCl3)
(6H, m); 13C NMR (100 MHz, CDCl3)
d
27.6 (s), 66.9 (s), 68.5 (s), 71.5
d
27.9 (s), 30.3 (s), 69.8 (q, J¼31.1 Hz),125.2 (q, J¼281.8 Hz),123.4 (s),
(q, J¼31.1 Hz), 124.5 (q, J¼280.2 Hz), 128.3 (s), 128.6 (s), 134.3 (s); 19F
125.5 (s), 125.6 (s), 126.2 (s), 127.2 (s), 128.9 (s), 131.7 (s), 133.9 (s),
NMR (376 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d
ꢁ80.8 (3F, d, J¼6.9 Hz); minor isomer 1H
1.99 (1H, ddd, J¼5.4, 4.6, 3.1 Hz), 2.39 (2H,
136.5 (s); 19F NMR (376 MHz, CDCl3)
d
ꢁ79.6 (3F, d, J¼6.8 Hz); HRMS
d
(EI) found: m/z 254.0926, calcd for C14H13F3O: MꢁH, 254.0919.
s), 2.50 (1H, ddd, J¼15.3, 11.2, 4.6 Hz), 2.62–2.67 (2H, m), 3.68–3.74
(4H, m), 4.08 (1H, dd, J¼11.2, 3.1 Hz), 4.23–4.32 (1H, m), 7.18–7.20
4.3.9. 1,1,1-Trifluoro-4-(4-fluorophenyl)butan-2-ol (5ak). Rf 0.23
(hexane–EtOAc¼8:1); IR (NaCl) 3389 (OH) cmꢁ1; 1H NMR (400 MHz,
(2H, m), 7.32–7.40 (4H, m); 13C NMR (100 MHz, CDCl3)
d 27.5 (s), 49.6
(s), 66.2 (s), 66.9 (s), 69.5 (q, J¼30.3 Hz), 125.7 (q, J¼282.6 Hz), 128.3
CDCl3)
d
1.92–2.09 (2H, m), 2.77 (1H, ddd, J¼14.0, 8.3, 8.2 Hz), 2.86

3288
K. Funabiki et al. / Tetrahedron 66 (2010) 3283–3289
(1H, s), 2.95 (1H, ddd, J¼14.0, 8.3, 5.1 Hz), 3.93 (1H, m), 7.01–7.24 (4H,
m); 13C NMR (100 MHz, CDCl3)
30.0 (s), 31.0 (s), 69.4 (q, J¼31.1 Hz),
support. We thank Professors T.I. and T. Konno of the Kyoto Institute
of Technology for the HRMS measurements.
d
115.2 (s), 115.4 (s),125.1 (q, J¼281.8 Hz),129.8 (s), 129.9 (s), 136.0 (s),
161.5 (d, J¼244.1 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢁ117.0 (1F, ddt,
Supplementary data
J¼8.4, 5.3, 5.3 Hz), ꢁ79.9 (3F, d, J¼6.1 Hz); HRMS (EI) found: m/z
222.0671, calcd for C10H10F4O: MꢁH, 222.0668.
Supplementary data associated with this articles can be found in
the online version, at doi:10.1016/j.tet.2010.03.019.
4.3.10. 1,1,1-Trifluoro-4-(4-fluorophenyl)-4-morpholinobutan-2-ol
(6ak). Rf 0.04 (hexane–EtOAc¼8:1); IR (NaCl) 3375 (OH) cmꢁ1
;
References and notes
HRMS (EI) found: m/z 307.1203, calcd for C14H17F4O2N: MꢁH,
307.1196; major isomer 1H NMR (400 MHz, CDCl3)
d 1.84 (1H, ddd,
1. For the reaction with boron enolates, see: (a) Iseki, K.; Oishi, S.; Kobayashi, Y.
Chem. Pharm. Bull. 1996, 44, 2003–2008; (b) Iseki, K.; Oishi, S.; Kobayashi, Y.
Tetrahedron 1996, 52, 71–84; (c) Makino, Y.; Iseki, K.; Oishi, S.; Fujiki, K.; Hirano,
T.; Kobayashi, Y. Tetrahedron Lett. 1995, 36, 6527–6530; For with a lithium
enolate, see: (d) Qian, C.-P.; Liu, Y.-Z.; Tomooka, K.; Nakai, T. Org. Synth. 1999, 76,
151–158; (e) Qian, C. P.; Nakai, T.; Dixon, D. A.; Smart, B. E. J. Am. Chem. Soc.
1990, 112, 4602–4604; (f) Patel, D. V.; Rielley-Gauvin, K.; Ryono, D. E.; Free, C.
A.; Smith, S. A.; Petrillo, E. W. J. Med. Chem. 1993, 36, 2431–2447; (g) Patel, D. V.;
Rielley-Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1988, 29, 4665–4668; (h)
Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv. Chem. Acta
1987, 70, 237–261; (i) Yamazaki, T.; Takita, K.; Ishikawa, N. Nippon Kagaku Kaishi
1985, 2131–2139; (j) Tius, M. A.; Savariar, S. Tetrahedron Lett. 1985, 26, 3635–
3638; For with a zinc enolate, see: (k) Watanabe, S.; Sakai, Y.; Kitazume, T.;
Yamazaki, T. J. Fluorine Chem. 1994, 68, 59–61; (l) Kitazume, T. Ultrasonics 1990,
28, 322–325; For with a nickel enolate, see: (m) Soloshonok, V. A.; Kukhar, V. P.;
Galushko, S. V.; Svistunova, N. Y.; Avilov, D. V.; Kuz’mina, N. A.; Raevski, N. I.;
Struchkov, Y. T.; Pysarevsky, A. P.; Belokon, Y. N. J. Chem. Soc., Perkin Trans. 1
1993, 3143–3155; For with ketene silyl acetal, see: (n) Mikami, K.; Yajima, T.;
Takasaki, T.; Matsukawa, S.; Terada, M.; Uchimaru, T.; Maruta, M. Tetrahedron
1996, 52, 85–98; For with enol silyl ether, see: (o) Ishii, A.; Kojima, J.; Mikami, K.
Org. Lett. 1999, 1, 2013–2016; For with vinyl ether, see: (p) For titanium enolate,
see Ishii, A.; Mikami, K. J. Fluorine Chem. 1999, 97, 51–55; (q) Itoh, Y.; Yamanaka,
M.; Mikami, K. Org. Lett. 2003, 5, 4807–4809; For with enamines, see: (r)
Molines, H.; Wakselman, C. J. Fluorine Chem. 1980, 16, 97–101.
2. For with sodium cyanide, see: (a) Kitazume, T. J. Fluorine Chem. 1987, 35, 287–
294 For with active methylene-compounds, see: (b) Hager, C.; Miethchen, R.;
Reinke, H. J. Fluorine Chem. 2000, 104, 135–142; (c) Uneyama, K.; Itano, N. Denki
Kagaku 1994, 62, 1151–1153; (d) Cen, W.; Dai, X.; Shen, Y. J. Fluorine Chem. 1993,
65, 49–52; (e) Ogoshi, H.; Mizushima, H.; Toi, H.; Aoyama, Y. J. Org. Chem. 1986,
51, 2366–2368; For with lithium or zinc reagents, see: (f) Steves, A.; Oestreich,
M. Org. Biomol. Chem. 2009, 7, 4464–4469; (g) Tomoyasu, T.; Tomooka, K.;
Nakai, T. Synlett 1998, 1147–1149; (h) Obrecht, D.; Gerber, F.; Sprenger, D.;
Masqelin, T. F. Helv. Chim. Acta 1997, 80, 531–537; (i) Kitazume, T.; Lin, J. T.;
Yamazaki, T. J. Fluorine Chem. 1989, 43, 177–187; (j) Hanzawa, Y.; Ishizawa, S.;
Kobayashi, Y. Chem. Pharm. Bull. 1988, 36, 4209–4212; (k) Ishikawa, N.; Koh, M.
G.; Kitazume, T. J. Fluorine Chem. 1984, 24, 419–430; For with vinyl aluminum
reagents, see: (l) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T.; De Alaniz, J.
R. Tetrahedron Lett. 1998, 39, 8791–8794; (m) For boran reagents, see Rama-
chandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem. Commun. 1999, 1979–1980;
(n) Ramachandran, P. V.; Chatterjee, A. Org. Lett. 2008, 10, 1195–1198; (o)
Ramachandran, P. V.; Padiya, K. J.; Rauniyar, V.; Reddy, M. V. R.; Brown, H. C.
Tetrahedron Lett. 2004, 45, 1015–1017; (p) Ramachandran, P. V.; Padiya, K. J.;
Reddy, M. V. R.; Brown, H. C. J. Fluorine Chem. 2004, 125, 579–583 For Morita–
Baylis–Hillman Reaction, see: (q) Reddy, M. V. R.; Rudd, M. T.; Ramachandran,
P. V. J. Org. Chem. 2002, 67, 5382–5385; For Friedel–Crafts reaction, see: (r)
Shermolovich, Y. G.; Yemets, S. V. J. Fluorine Chem. 2000, 101, 111–116; For
asymmetric Friedel–Crafts reaction, see: (s) Ishii, A.; Soloshonok, A. V.; Mikami,
K. J. Org. Chem. 2000, 65, 1597–1599 For ene reaction, see: (t) Hayashi, E.; Ta-
kahashi, Y.; Itoh, H.; Yoneda, N. Bull. Chem. Soc. Jpn. 1994, 67, 3040–3043; (u)
Ogawa, K.; Nagai, T.; Nonomura, M.; Takagi, T.; Koyama, M.; Ando, A.; Miki, T.;
Kumadaki, I. Chem. Pharm. Bull. 1991, 39, 1707–1712; (v) Pautrat, R.; Marteau, J.;
Cheritat, R. Bull. Soc. Chim. Fr. 1968, 1182–1186; For asymmetric ene reaction for
with alkenes see: Ref. 1n and with vinyl sulfides see: (w) Mikami, K.; Yajima, T.;
Siree, N.; Terada, M.; Suzuki, Y.; Kobayashi, I. Synlett 1996, 837–838; For Hetero
Diels–Alder reaction, see: (x) Leveque, L.; Le Blanc, M.; Pastor, R. Tetrahedron
Lett. 1997, 38, 6001–6002; (y) Jeong, I. H.; Kim, Y. S.; Cho, K. Y.; Kim, K. J. Bull.
Korean Chem. Soc. 1991, 12, 125–126; For Asymmetric Hetero Diels–Alder re-
action, see: (z) Mikami, K.; Yajima, T.; Matsukawa, S.; Terada, M. 72nd National
Meeting of the Chemical Society of Japan, Tokyo, March, 1997; Abstr. No.
4H332.
J¼15.2, 5.2, 3.1 Hz), 2.16–2.31 (2H, m), 2.34–2.43 (1H, m), 2.49–2.59
(2H, m), 3.56–3.65 (4H, m), 3.98 (1H, dd, J¼11.3, 3.1 Hz), 4.13–4.23
(1H, m), 6.97–7.11 (4H, m); 13C NMR (100 MHz, CDCl3)
d 27.9 (s), 49.3
(s), 65.1 (s), 66.9 (s), 69.1 (q, J¼31.1 Hz),115.1 (s),125.7(q, J¼283.5 Hz)
130.1 (s),130.2 (s),130.8 (s),162.4 (d, J¼47.4 Hz); 19F NMR (376 MHz,
CDCl3)
d
ꢁ113.7–(ꢁ113.6) (1F, m), ꢁ77.7 (3F, d, J¼7.6 Hz); minor
isomer1HNMR(400 MHz, CDCl3)
d
1.72 (1H, ddd, J¼14.4, 2.8, 2.7 Hz),
2.16–2.31 (2H, m), 2.34–2.43 (1H, m), 2.49–2.59 (2H, m), 3.56–3.65
(4H, m), 3.80 (1H, dd, J¼11.3, 3.1 Hz), 4.23–4.33 (1H, m), 6.97–7.11
(4H, m); 13C NMR (100 MHz, CDCl3)
d 27.9 (s), 49.3 (s), 66.8 (s), 67.6
(s), 71.2 (q, J¼31.1 Hz),115.3 (s),124.5 (q, J¼280.2 Hz) 130.0 (s),130.1
(s), 130.4 (s), 162.5 (d, J¼47.4 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢁ113.4–(ꢁ113.3) (1F, m), ꢁ80.7 (3F, d, J¼6.9 Hz).
4.3.11. 1,1-Difluoro-4-(naphthalen-1-yl)butan-2-ol (5bj). Rf 0.18
(hexane–CH2Cl2¼7:1); mp 56–58 ꢀC; IR (KBr) 3371 (OH) cmꢁ1
;
1H
NMR (400 MHz, CDCl3) 1.84–2.03 (2H, m), 2.72 (1H, s), 3.08 (1H,
ddd, J¼14.0, 9.2, 7.3 Hz), 3.32 (1H, ddd, J¼14.0, 9.4, 5.1 Hz), 3.68–
3.77 (1H, m), 5.54 (1H, dt, J¼56.0, 4.1 Hz), 7.29–8.04 (7H, m); 13C
NMR (100 MHz, CDCl3) 27.9 (s), 30.8 (s), 60.4 (t, J¼22.9 Hz), 116.3 (t,
J¼244.1 Hz), 123.5 (s), 125.5 (s), 126.0 (s), 126.1 (s), 126.9 (s), 128.8
(s), 131.6 (s), 133.9 (s), 137.0 (s); 19F NMR (376 MHz, CDCl3) ꢁ129.3
(1F, dd, J¼56.0, 9.9 Hz), ꢁ129.3 (1F, dd, J¼56.0, 12.2 Hz); HRMS (EI)
found: m/z 236.1008, calcd for C14H14F2O: MꢁH, 236.1013.
4.3.12. 1-(4,4-Difluorobutyl)naphthalene (7). Rf 0.68 (hexane–
CH2Cl2¼7:1); 1H NMR (400 MHz, CDCl3);
d 1.90–1.97 (4H, m), 3.13
(2H, t, J¼7.2 Hz), 5.82 (1H, tt, J¼57.0, 4.1 Hz), 7.24–8.01 (7H, m); 13C
NMR (100 MHz, CDCl3)
(t, J¼239.2 Hz),123.5 (s), 125.5 (s),125.5 (s),125.9 (s), 126.1 (s), 127.0
d
23.0 (s), 32.2 (s), 33.9 (t J¼20.5 Hz), 117.2
(s), 128.8 (s), 131.7 (s), 133.9 (s), 137.3 (s); 19F NMR (376 MHz, CDCl3)
d
ꢁ116.0–(ꢁ115.7) (2F, m); HRMS (EI) found: m/z 220.1060, calcd for
C14H14F2: MꢁH, 220.1064.
4.3.13. 1-Butylnaphthalene (8)18. Rf 0.83 (hexane–CH2Cl2¼7:1); 1H
NMR (400 MHz, CDCl3)
d
0.97 (3H, dd, J¼7.5, 7.4 Hz), 1.41–1.51 (2H,
m), 1.70–1.78 (2H, m), 3.07 (2H, dd, J¼7.7, 7.7 Hz), 7.31–8.06 (7H,
m); 13C NMR (100 MHz, CDCl3)
d
14.0 (s), 22.9 (s), 32.8 (s), 33.0 (s),
123.9 (s), 125.3 (s), 125.5 (s), 125.6 (s), 125.8 (s), 126.4 (s), 128.7 (s),
131.9 (s), 133.9 (s), 139.0 (s); HRMS (EI) found: m/z 184.1257, calcd
for C14H16, 184.1253.
4.3.14. 2,2,2-Trifluoro-1-(2-morpholinocyclohexyl)ethanol (6al). Rf
0.18 (hexane–EtOAc¼4:1); IR (KBr) 3441 (OH) cmꢁ1; LRMS (EI)
found: m/z 267. 1H NMR (400 MHz, CDCl3)
d 0.81–1.62 (8H, m),
3. (a) Landge, S. M.; Borkin, D. A.; To¨ro¨k, B. Tetrahedron Lett. 2007, 48, 6372–6376;
(b) Mimura, H.; Watanabe, A.; Kawade, K. J. Fluorine Chem. 2006, 127, 519–523;
(c) Ishii, A.; Terada, Y. J. Synth. Org. Chem. Jpn. 1999, 57, 898–900; (d) Braid, M.;
Iserson, H.; Lawlor, F. E. J. Am. Chem. Soc. 1954, 76, 4027; (e) Henne, A. L.; Pelley,
R. L.; Alm, R. M. J. Am. Chem. Soc. 1950, 72, 3370; (f) Shechter, H.; Conrad, F. J. Am.
Chem. Soc. 1950, 72, 3371–3373.
4. Kaneko, S.; Yamazaki, T.; Kitazume, T. J. Org. Chem. 1993, 58, 2302–2312.
5. For selected examples, see: (a) Guenter, S. Chem. Ber. 1973, 106, 2960–2968; (b)
Ogoshi, H.; Mizushima, H.; Toi, H.; Aoyama, Y. J. Org. Chem. 1986, 51, 2366–2368;
(c) Iwata, S.; Ishiguro, Y.; Utsugi, M.; Mitsuhashi, K.; Tanaka, K. Bull. Chem. Soc.
Jpn. 1993, 66, 2432–2435; (d) Molteni, M.; Consonni, R.; Giovenzana, T.;
Malpezzi, L.; Zanda, M. J. Fluorine Chem. 2006, 127, 901–908.
1.79–1.87 (2H, m), 2.16 (1H, br), 2.39–2.42 (2H, m), 2.80 (1H, br),
3.58–3.81 (4H, m), 4.26 (1H, qd, J¼8.94, 7.00 Hz), 8.97 (1H, br); 13C
NMR (100 MHz, CDCl3)
d 20.1 (s), 24.0 (s), 25.2 (s), 27.3 (s), 31.2 (s),
49.2 (s), 51.7 (s), 66.7 (s), 67.2 (2C, s), 70.4 (q, J¼28.7 Hz), 125.9 (q,
J¼283.5 Hz); 19F NMR (376 MHz, CDCl3)
d
ꢁ2.71 (3F, d, J¼7.00 Hz).
Acknowledgements
We are grateful to Central Glass Co., Ltd., for the gift of CF3CHO
ethyl hemiacetal and trifluoroethanol as well as for financial
6. Gong, Y.; Kato, K.; Kimoto, H. Synlett 1999, 1403–1404.

K. Funabiki et al. / Tetrahedron 66 (2010) 3283–3289
7. Gong, Y.; Kato, K.; Kimoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 377–383 and Ref. 5.
3289
Soloshonok, V. A., Mikami, K., Yamazaki, T., Welch, J. T., Honek, J. F., Eds.; Oxford/
American Chemical Society: Washington DC, 2007; pp 141–355; (c) For direct
aldol reaction, see Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
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e-mail:
deposit@ccdc.cam.ac.jp):
Deposition
number
CCDC-761515.
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