Direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones by use of the combination of amines and acids

Article abstract of DOI:10.1016/j.tet.2006.03.053

Trifluoroacetaldehyde ethyl hemiacetal reacts with unmodified ketones in the presence of 30-50 each mol % of amines and acids at ambient temperature, affording the corresponding β-hydroxy-β-trifluoromethylated ketones in good yields with good to excellent diastereoselectivities.

Full text of DOI:10.1016/j.tet.2006.03.053

Tetrahedron 62 (2006) 5049–5053
Direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal
with ketones by use of the combination of amines and acids
*
Kazumasa Funabiki, Hideyuki Nagaya, Mika Ishihara and Masaki Matsui
Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received 20 February 2006; revised 16 March 2006; accepted 16 March 2006
Available online 17 April 2006
Abstract—Trifluoroacetaldehyde ethyl hemiacetal reacts with unmodified ketones in the presence of 30–50 each mol % of amines and acids
at ambient temperature, affording the corresponding b-hydroxy-b-trifluoromethylated ketones in good yields with good to excellent dia-
stereoselectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
to excellent syn-diastereoselectivities. Importantly, this
method could achieve a reduction of the steps for in situ gen-
eration of CF3CHO and successive carbon–carbon bond for-
mation reactions. That is, a single manipulation may include
multi steps in the reaction, such as (1) the formation of en-
amine or imine, (2) the enamine- or imine-assisted in situ
generation of CF3CHO, (3) the successive carbon–carbon
bond formation reaction of CF3CHO, and (4) the hydrolysis
of the intermediates, producing b-hydroxy-b-trifluoro-
methylatedketones as wellas reproductionof amineand acid.
Despite significant progress in the area of efficient synthesis
of trifluoromethylated molecules using trifluoroacetalde-
hyde (CF3CHO), the method for the generation of CF3CHO
from its hemiacetal or hydrate is still dependent on the early
protocol, which includes a serious indispensable condition
such as use of an excess amount of concentrated sulfuric
acid under high reaction temperature.1 Therefore, an envi-
ronmentally-friendly, practical, and efficient method for
the in situ generation of CF3CHO attended by its simulta-
neous stereoselective carbon–carbon bond formation reac-
tion is really required. Recently, we have found that
a stoichiometric amount of enamines or imines react well
with CF3CHO ethyl hemiacetal via the regio- and/or stereo-
selective carbon–carbon bond formation reaction under mild
conditions without any additives, producing b-hydroxy-b-
trifluoromethylated ketones in good to excellent yields.3
This reaction can serve as a new expedient method for the
general, practical, and regio- and/or stereoselective synthesis
of b-hydroxy-b-trifluoromethylated ketones. However, in
this method a couple of steps for the preparation of enamines
and imines as well as for the hydrolysis of the intermediates
producing b-hydroxy-b-trifluoromethylated ketones are
absolutely necessary. For the further development of a new
atom-economical method for the synthesis of b-trifluoro-
methylated aldol adducts, we describe herein the direct aldol
reaction of CF3CHO ethyl hemiacetal with unmodified
ketones by the use of the combination of a small amount
(30–50 mol %) of amine and acid,3–6 affording the good
yields of b-hydroxy-b-trifluoromethyl ketones with good
2. Results and discussion
CF3CHO ethyl hemiacetal 1a reacted smoothly with acetone
2a in the presence of 50 each mol % of piperidine and acetic
acid at room temperature for 24 h to produce the b-hydroxy-
b-trifluoromethylated ketone 3a in 60% yield, together with
a trace amount of 1,1,1,7,7,7-hexafluoro-2,6-dihydroxy-4-
heptanone 4 (Table 1, entry 3). The direct aldol reactions
of CF3CHO ethyl hemiacetal 1a with acetone 2a under the
various reaction conditions are summarized in Table 1.
The use of only piperidine gave no product 3a with a trace
amount of bis-adduct 4 at various temperatures (entries 1
and 2). Other organic acids, such as trifluoroacetic acid
and p-toluenesulfonic acid were not effective to give a trace
amount of or no product (entries 4 and 5). Among the solid
acids examined, such as silica gel (Wakogel C200),5 Mont-
morillonite K10, H4SiW12O40, and Nafion R-50 (entries 6–
9), Wakogel C200 was most effective for the direct aldol
reaction with acetone to provide the aldol product 3a in 58%
yield, along with a 10% yield of 4 (entry 6). Out of a variety
of amines screened in both cases of acetic acid and Wakogel
C200, cyclic secondary amines, such as morpholine and
Keywords: Trifluoromethyl group; Aldol reaction.
* Corresponding author. Fax: +81 58 2301893; e-mail: kfunabik@apchem.
gifu-u.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.053

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K. Funabiki et al. / Tetrahedron 62 (2006) 5049–5053
Table 1. In situ generation of trifluoroacetaldehyde from its hemiacetal 1a and successive direct aldol reaction with acetone using the combination of amines and
acids under the various conditionsa
OH
O
OH
OEt
OH
O
OH
CF3
OH
OH
O
+
+
+
F3C
F3C
F3C
F3C
rt, 24 h
1a
2a
3a
4
1b
Entry
Amine
Acid
Solvent
Yield (%)b
1
2c
3
4
5
6
7
8
9
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
Piperidine (50 mol %)
None
None
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
3a (0), 4 (10), 1b (22), 1a (16)
3a (0), 4 (6), 1b (17), 1a (13)
3a (60), 4 (5), 1b (0), 1a (0)
3a (1), 4 (0), 1b (32), 1a (14)
3a (0), 4 (0), 1b (45), 1a (11)
3a (58), 4 (10), 1b (0), 1a (0)
3a (32), 4 (22), 1b (0), 1a (0)
3a (9), 4 (18), 1b (18), 1a (9)
3a (0), 4 (8), 1b (16), 1a (19)
CH3CO2H (50 mol %)
CF3CO2H (50 mol %)
p-TsOH$H2O (50 mol %)
Silica gel (120 mg)
Montmorillonite K 10 (120 mg)
H4SiW12O40 (120 mg)
Nafion R-50 (120 mg)
10
11
12
13
14
15d
16
17
18
n-PrNH2 (50 mol %)
c-HexNH2 (50 mol %)
t-BuNH2 (50 mol %)
Morpholine (50 mol %)
1-Methylpiperazine (50 mol %)
Et2NH (50 mol %)
i-Pr2NH (50 mol %)
Ph2NH (50 mol %)
Et3N (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
3a (65), 4 (3), 1b (0), 1a (0)
3a (65), 4 (1), 1b (0), 1a (0)
3a (17), 4 (11), 1b (19), 1a (22)
3a (61), 4 (1), 1b (0), 1a (2)
3a (53), 4 (7), 1b (0), 1a (0)
3a (30), 4 (18), 1b (0), 1a (0)
3a (1), 4 (1), 1b (49), 1a (22)
3a (0), 4 (0), 1b (21), 1a (57)
3a (0), 4 (0), 1b (56), 1a (24)
19
20
21
22
23
24
25
26
27
n-PrNH2 (50 mol %)
c-HexNH2 (50 mol %)
t-BuNH2 (50 mol %)
Morpholine (50 mol %)
1-Methylpiperazine (50 mol %)
Et2NH (50 mol %)
i-Pr2NH (50 mol %)
Ph2NH (50 mol %)
Et3N (50 mol %)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Silica gel (120 mg)
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
3a (53), 4 (3), 1b (0), 1a (0)
3a (50), 4 (14), 1b (0), 1a (0)
3a (3), 4 (13), 1b (23), 1a (5)
3a (52), 4 (0), 1b (0), 1a (0)
3a (67), 4 (0), 1b (0), 1a (0)
3a (28), 4 (27), 1b (0), 1a (0)
3a (0), 4 (0), 1b (28), 1a (24)
3a (0), 4 (0), 1b (39), 1a (8)
3a (0), 4 (0), 1b (26), 1a (9)
28
29
30
31
Piperidine (30 mol %)
n-PrNH2 (30 mol %)
Piperidine (30 mol %)
n-PrNH2 (30 mol %)
CH3CO2H (30 mol %)
CH3CO2H (30 mol %)
Silica gel (72 mg)
Acetone
Acetone
Acetone
Acetone
3a (53), 4 (21), 1b (0), 1a (0)
3a (62), 4 (3), 1b (0), 1a (0)
3a (38), 4 (21), 1b (0), 1a (0)
3a (16), 4 (14), 1b (6), 1a (17)
Silica gel (72 mg)
32
33
34
35
Piperidine (50 mol %)
n-PrNH2 (50 mol %)
Piperidine (50 mol %)
n-PrNH2 (50 mol %)
CH3CO2H (50 mol %)
CH3CO2H (50 mol %)
Silica gel (120 mg)
Silica gel (120 mg)
Acetone–DMSO
Acetone–DMSO
Acetone–DMSO
Acetone–DMSO
3a (23), 4 (34), 1b (0), 1a (0)
3a (18), 4 (23), 1b (0), 1a (0)
3a (0), 4 (2), 1b (19), 1a (8)
3a (14), 4 (23), 1b (4), 1a (2)
a
All the reaction was carried out with trifluoroacetaldehyde ethyl hemiacetal 1a (1 mmol) with amine 2 and organic acid or solid acid in dry acetone (10 ml) or
in the mixed solvent of DMSO (8 ml) and dry acetone (2 ml).
Yields were measured by 19F NMR.
Carried out at reflux.
Many unidentified by-products were formed.
b
c
d
1-methylpiperazine (entries 13, 14, 22, and 23) as well as
acetal 1a via not only in situ generation of CF3CHO but
also carbon–carbon bond formation reaction to give the cor-
responding b-hydroxy-b-trifluoromethyl ketones.2 The reac-
tion of hemiacetal 1a with acetone 2a in the presence of
30 each mol % of piperidine or n-propylamine and acetic
acid afforded the corresponding aldol product 3a in accept-
able yields (53–62%) (entries 28 and 29). Reducing the
amount of amines to 30 mol % and the amount of silica
gel to 60% of the former amount gave rise to lowering the
yield of 2a, together with the formation of bis-adduct 4
(entries 30 and 31). Irrespective of the amines as well as
the acids, the use of DMSO as a polar co-solvent resulted
in decreasing the yield of 3a, along with the increase of bis-
adduct 4. In all cases, mass balances in the yield are
not good, probably due to these high volatility and self-poly-
merization of CF3CHO.
primary amines bearing n-propyl or c-hexyl group were suit-
able for the reaction to give acceptable yields of the aldol
product 3a (entries 10, 11, 19, and 20). The use of diethyl-
amine as an acyclic secondary amine resulted in the increase
of the formation of bis-adduct 4, together with 3a in 28–30%
yields (entries 15 and 24).
The reaction with tert-butylamine (entries 12 and 21) or dii-
sopropylamine (entries 16 and 25) having the bulky group
produced only trace amount of the aldol product. Diphenyl-
amine also was not effective for the reaction to afford no
product, probably due to its low nucleophilicity (entries 17
and 26). The use of triethylamine also gave no product (en-
tries 18 and 27). These results may suggest that (1) the reac-
tion proceeds via enamine or imine, which is produced from
the corresponding ketone in the presence of the acid and the
corresponding secondary or primary amine, and (2) the re-
sulting enamine or imine reacts with CF3CHO ethyl hemi-
The results of cyclic ketones as well as other polyfluoroalkyl-
aldehyde hemiacetal or hydrate are summarized in Table 2.

K. Funabiki et al. / Tetrahedron 62 (2006) 5049–5053
5051
Table 2. In situ generation of polyfluoroalkylaldehyde from its hemiacetal or hydrate and successive direct aldol reaction with ketones using the combination of
amines and acidsa
O
OH O
OH
OX
+
R2
Rf
R2
Rf
rt, 24 h
R1
R1
3,5,6
1
2
Entry
1
Rf
X
2
R1, R2
Methodb
3,5,6
Yield (%)c
syn:antid
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1d
1a
1a
1a
1b
1c
1d
1a
CF3
CF3
CF3
CF3
CHF2
CF3CF2
CF3
CF3
CF3
Et
Et
Et
H
Et
H
Et
Et
Et
H
Et
H
2a
2b
2c
2b
2b
2b
2a
2b
2c
2b
2b
2b
2b
H, Me
A
A
A
A
A
A
B
B
B
B
B
B
C
3a
3b
3c
3b
5
60
—
–(CH2)3–
–(CH2)4–
–(CH2)3–
–(CH2)3–
–(CH2)3–
H, Me
–(CH2)3–
–(CH2)4–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
82 (41)
45
88
47 (46)
77 (50)
58
86 (42)
33
77 (40)
74 (71)
70 (61)
85
93:7
40:60
92:8
78:22
94:6
—
90:10
54:46
89:11
74:26
93:7
79:26
6
3a
3b
3c
3b
5
9
10
11
12
13
CF3
CHF2
CF3CF2
CF3
6
3b
Et
a
All the reaction was carried out with polyfluoroalkylaldehyde ethyl hemiacetal (1 mmol) or hydrate (1 mmol) in the corresponding ketone (10 ml).
Method A; piperidine (50 mol %) and acetic acid (50 mol %). Method B; piperidine (50 mol %) and Wakogel C200. Method C; n-PrNH2 (50 mol %) and
acetic acid (50 mol %).
b
Measured by 19F NMR using benzotrifluoride. Values in parentheses stand for the yields of isolated products.
Determined by 19F NMR.
c
d
Cyclopentanone 2b could also participate well in the direct
tography. Degree of syn-diastereoselectivities of the products
3b, 5, and 6, derived from cyclopentanone, may depend on
the bulkiness of the fluoroalkyl groups8 in the following
orders under the same conditions: the pentafluoroethyl
(syn:anti¼94:6, 88% de)>trifluoromethyl (syn:anti¼93:7,
86% de)>difluoromethyl (syn:anti¼78:22, 56% de) group
(entries 2, 5, and 6), though the reason for this syn-selective
outcome is not clear at this present.
aldol reaction of CF3CHO ethyl hemiacetal 1a to produce
the corresponding b-hydroxy-b-trifluoromethyl ketone 5 in
good yields with high syn-diastereoselectivities by the use
of acetic acid (Method A) or Wakogel C200 (Method B) (en-
tries 2 and 8). Major diastereomer of 3b could be assigned
syn-isomer by comparison with the chemical shift of b-me-
thine proton of aldol product attached to the hydroxyl group
(CF3CH(OH)–) in 1H NMR according to the reported
values.4 This result could also be supported by the literature
by Denmark.7 The literature describes that in the aldol prod-
ucts, derived from cyclopentanone or cyclohexanone, the
methine proton at b-carbon of syn-products appears in the
lower field than those of anti-products in 1H NMR. The re-
action of CF3CHO ethyl hemiacetal 1a with cyclohexanone
2c gave a 45% yield of the aldol product 3c with low dia-
stereoselectivity, because many unidentified by-products
were produced (entries 3 and 9).
3. Conclusions
In summary, we have achieved the direct aldol reaction of
CF3CHO ethyl hemiacetal, with unmodified ketones by the
use of small amount of acids and amines without any
strong acid and high reaction temperature, producing b-
hydroxy-b-trifluoromethylated ketones in good yields. Stud-
ies addressing catalytic process for the asymmetric direct
aldol reaction of CF3CHO ethyl hemiacetal will be reported
in due course.
syn-Selective direct aldol reaction of CF3CHO ethyl hemi-
acetal 1a with cyclopentanone 2b by using n-propylamine
in place of piperidine also occurred to produce the aldol prod-
uct 3b in 85% yield with slight reduction of diastereoselec-
tivity (entry 13). CF3CHO hydrate 1b also reacted well
with cyclopentanone 2b to produce the aldol product 3b in
the similar yields with similar diastereoselectivities (entries
4 and 10). The direct aldol reaction of difluoroacetaldehyde
ethyl hemiacetal 1c as well as pentafluoropropionaldehyde
hydrate 1d with cyclopentanone 2b, also successfully oc-
curred to produce the corresponding b-difluoromethyl or
pentafluoroethyl aldol adduct 5 or 6 in good yields with
good to excellent syn-diastereoselectivities in both cases of
acetic acid and silica gel with piperidine (entries 5, 6, 11,
and 12). The yields of isolated trifluoromethylated aldol
product, derived from cyclopentanone, are lower than those
of difluoromethylated or pentafluoroethylated aldol ones,
because it is troublesome to isolate the trifluoromethylated
aldol product from the reaction mixtures by column chroma-
4. Experimental
4.1. General
1H NMR spectra were measured with a JEOL a-400
(400 MHz) FT-NMR spectrometer,
a
JNM-AL400
(400 MHz) FT-NMR spectrometer, or a JNM-ECA500
(500 MHz) FT-NMR spectrometer in deuteriochloroform
(CDCl3) solutions with tetramethylsilane (Me4Si) as the
internal standard. 13C NMR spectra were measured with
a JEOL a-400 (100 MHz) FT-NMR spectrometer, a
JNM-AL400 (100 MHz) FT-NMR spectrometer, or a
JNM-ECA500 (126 MHz) FT-NMR spectrometer in
CDCl3 solutions with tetramethylsilane (Me4Si) as the inter-
nal standard. 19F NMR spectra were recorded on a JEOL
a-400 (376 MHz) FT-NMR spectrometer, a JNM-AL400

5052
K. Funabiki et al. / Tetrahedron 62 (2006) 5049–5053
(372 MHz) FT-NMR spectrometer, or a JNM-ECA500
(471 MHz) FT-NMR spectrometer in CDCl3 solutions using
trifluoroacetic acid as the external standard.
4.2.5. 2-(2,2-Difluoro-1-hydroxyethyl)cyclopentanone
(5). IR (KBr) 3439.1 (OH), 1736.1 (C]O) cmꢁ1; syn Iso-
mer: H NMR (400 MHz, CDCl3) d 1.74–1.88 (4H, m),
1
2.32–2.41 (2H, m), 3.74 (1H, br s), 4.26 (1H, br s), 5.76
(1H, dt, J¼55.78, 4.59 Hz); 13C NMR (100 MHz, CDCl3)
d 20.5 (s), 22.7 (s), 38.1 (s), 49.3 (t, J¼2.5 Hz), 68.5 (t,
J¼24.6 Hz), 115.7 (t, J¼244.1 Hz), 220.0 (d, J¼6.6 Hz);
19F NMR (372 MHz, CDCl3) d ꢁ52.9 (2F, ddd, J¼55.8,
4.2. A typical procedure
To a solution of a catalytic amount of silica gel (Wakogel
C200) (0.120 g) and piperidine (0.043 g, 0.5 mmol) in dry
acetone 2a (10 ml) was added trifluoroacetaldehyde ethyl
hemiacetal 1a (0.144 g, 1 mmol) at room temperature under
an inert atmosphere. After being stirred at room temperature
for 24 h, the reaction mixture was quenched with NH4Cl aq
solution (40 ml), followed by extraction with Et2O
(30 mlꢀ3). The organic layer was dried over Na2SO4 and
the solvents were removed by distillation under reduced
pressure with cold ice bath. After the measurement of the
residue by 19F NMR using benzotrifluoride (58% of 3a
and 10% of 4), purification by flash chromatography on sil-
ica gel (hexane–Et2O¼3:1) gave 3a (44%, 0.068 g) and trace
amount of 4.
1
22.1, 11.5 Hz); anti Isomer: H NMR (400 MHz, CDCl3)
d 1.78–1.88 (2H, m), 2.10–2.31 (3H, m), 2.38–2.46 (2H,
m), 3.87–3.95 (1H, m), 4.05 (1H, br s), 5.92 (1H, dt,
J¼55.78, 3.86 Hz); 13C NMR (100 MHz, CDCl3) d 21.6
(s), 27.0 (d, J¼2.5 Hz), 39.1 (s), 48.8 (t, J¼2.9 Hz), 72.4
(t, J¼25.0 Hz), 116.0 (dd, J¼245.0, 241.7 Hz), 222.4 (s);
19F NMR (372 MHz, CDCl3) d ꢁ51.4 (1F, ddd, J¼289.2,
55.8, 10.3 Hz), ꢁ55.6 (1F, ddd, J¼289.2, 55.8, 11.4 Hz);
HRMS (EI) Found: m/z 164.0656. Calcd for C7H10O2F2:
M, 164.0649.
4.2.6. 2-(2,2,3,3,3-Pentafluoro-1-hydroxypropyl)cyclo-
pentanone (6). syn Isomer: mp 58–58.5 ꢂC; IR (KBr)
1
3457.0 (OH), 1736.1 (C]O) cmꢁ1; H NMR (400 MHz,
4.2.1. 5,5,5-Trifluoro-4-hydroxy-2-pentanone (3a).9 IR
(KBr) 1716.9 (C]O), 3411.2 (OH) cmꢁ1
;
1H NMR
CDCl3) d 1.74–1.88 (1H, m), 2.05–2.27 (4H, m), 2.35–
2.50 (2H, m), 3.50 (1H, d, J¼6.28 Hz), 4.70 (1H, dt,
J¼20.77, 6.28 Hz); 13C NMR (100 MHz, CDCl3) d 20.5
(s), 22.6 (d, J¼2.5 Hz), 37.8 (s), 49.3 (s), 66.5 (dd,
J¼27.4, 21.7 Hz), 114.0 (ddq, J¼260.5, 255.6, 36.1 Hz),
118.7 (qt, J¼286.7, 36.1 Hz), 218.8 (s); 19F NMR
(372 MHz, CDCl3) d ꢁ6.1 (3F, s), ꢁ45.9 (1F, dd,
J¼275.4, 20.6 Hz), ꢁ52.4 (1F, ddd, J¼275.4, 20.6,
2.3 Hz); HRMS (EI) Found: m/z 232.0528. Calcd for
C8H9O2F5: M, 232.0523.
(500 MHz, CDCl3) d 2.24 (3H, s), 2.78 (1H, dd, J¼17.83,
3.01 Hz), 2.84 (1H, dd, J¼17.83, 8.88 Hz), 3.41 (1H, br s),
4.44–4.51 (1H, m); 13C NMR (100 MHz, CDCl3) d 30.6
(s), 42.8 (s), 66.3 (q, J¼32.2 Hz), 124.6 (q, J¼280.6 Hz),
206.4 (s); 19F NMR (471 MHz, CDCl3) d ꢁ1.8 (3F, d,
J¼6.9 Hz); HRMS (CI) Found: m/z 157.0476. Calcd for
C5H8F3O2: M+H, 157.0479.
4.2.2. 1,1,1,7,7,7-Hexafluoro-2,6-dihydroxy-4-heptanone
(4). Mp 70–71 ꢂC; IR (KBr) 3392.9 (OH), 1732.3
(C]O) cmꢁ1; 1H NMR (400 MHz, CDCl3) d 2.84 (1Hꢀ2,
ddd, J¼7.08, 2.69 Hz), 2.94 (1Hꢀ2, dd, J¼17.57,
9.27 Hz), 3.06 (1Hꢀ2, br s), 4.50–4.60 (1Hꢀ2, m); 13C
NMR (100 MHz, CDCl3) d 43.0 (s), 66.4 (q, J¼32.8 Hz),
66.4 (q, J¼32.5 Hz), 124.3 (q, J¼279.5 Hz), 204.7 (s);
19F NMR (376 MHz, CDCl3) d ꢁ1.99 (3F, d, J¼6.8 Hz),
ꢁ2.02 (3F, d, J¼6.8 Hz); HRMS (EI) Found: m/z
254.0374. Calcd for C7H8O3F6: M, 254.0377.
Acknowledgments
This work was partially supported by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science, and
Technology of Japan, the OGAWA Science and Technology
Foundation and Gifu University. We are grateful to the Cen-
tral Glass Co., Ltd, for the gift of CF3CHO ethyl hemiacetal
and hydrate as well as financial support. We thank Professors
T. Ishihara, T. Konno, and H. Yamanaka of the Kyoto Insti-
tute of Technology for the HRMS measurements.
4.2.3. 2-(2,2,2-Trifluoro-1-hydroxyethyl)cyclopentanone
(3b).4 syn Isomer: IR (KBr) 1713.0 (C]O), 3458.8
(OH) cmꢁ1; 1H NMR (400 MHz, CDCl3) d 1.72–1.89 (1H,
m), 2.06–2.23 (4H, m), 2.34–2.51 (1H, m), 3.17–3.27 (1H,
m), 4.58 (1H, m); 13C NMR (100 MHz, CDCl3) d 20.5 (s),
22.3 (s), 38.0 (s), 49.2 (s), 67.7 (q, J¼31.7 Hz), 125.0 (q,
J¼282.0 Hz), 218.6 (s); 19F NMR (471 MHz, CDCl3) d
ꢁ0.3 (3F, d, J¼7.5 Hz); HRMS (EI) Found: m/z 182.0555.
Calcd for C7H9F3O2: M, 182.0555.
References and notes
1. (a) Braid, M.; Iserson, H.; Lawlor, F. E. J. Am. Chem. Soc.
1954, 76, 4027; (b) Henne, A. L.; Pelley, R. L.; Alm, R. M.
J. Am. Chem. Soc. 1950, 72, 3370; (c) Shechter, H.; Conrad,
F. J. Am. Chem. Soc. 1950, 72, 3371.
4.2.4. 2-(2,2,2-Trifluoro-1-hydroxyethyl)cyclohexanone
(3c).10 anti Isomer: IR (KBr) 1792.1 (C]O), 3447.2
(OH) cmꢁ1; 1H NMR (400 MHz, CDCl3) d 1.64–1.81 (3H,
m), 1.93–1.98 (1H, m), 2.14–2.24 (2H, m), 2.37–2.49 (2H,
m), 2.74–2.80 (1H, m) 4.00–4.09 (1H, m), 4.38 (1H, d,
J¼5.85 Hz); 13C NMR (100 MHz, CDCl3) d 24.9 (s), 28.1
(s), 31.6 (s), 43.0 (s), 50.3 (s), 71.8 (q, J¼31.4 Hz), 124.7
(q, J¼282.9 Hz), 213.7 (s); 19F NMR (376 MHz, CDCl3)
d 2.0 (3F, d, J¼7.6 Hz); HRMS (EI) Found: m/z 196.0711.
Calcd for C8H11F3O2: M, 196.0711.
2. (a) Funabiki, K.; Nojiri, M.; Matsui, M.; Shibata, K. Chem.
Commun. 1998, 2051; (b) Funabiki, K.; Matsunaga, K.;
Matsui, M.; Shibata, K. Synlett 1999, 1477; (c) Funabiki, K.;
Matsunaga, K.; Nojiri, M.; Hashimoto, W.; Yamamoto, H.;
Shibata, K.; Matsui, M. J. Org. Chem. 2003, 68, 2853;
(d) Funabiki, K.; Hashimoto, W.; Matsui, M. Chem. Commun.
2004, 2056; (e) Funabiki, K. Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; ACS Symposium Series 911, Ameri-
can Chemical Society/Oxford University Press: Washington,
DC, 2005, p 342. (f) Funabiki, K.; Hasegawa, K.; Murase, Y.;

K. Funabiki et al. / Tetrahedron 62 (2006) 5049–5053
5053
Nagaya, H.; Matsui, M. J. Fluorine Chem. (special issue),
in press.
7. For cyclohexanone, see: (a) Denmark, S. E.; Stavenger, R. A.;
Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982. For cy-
clopentanone, see: (b) Denmark, S. E.; Stavenger, R. A.; Wong,
K.-T. Tetrahedron 1998, 54, 10389.
8. MacPhee, J. A.; Panaye, A.; Dubois, J.-E. Tetrahedron 1978,
34, 3553.
3. For catalytic direct aldol reactions of fluorine-free aldehydes
with ketones using the combination of amines and organic
acids, see: (a) Ji, C.; Peng, Y.; Huang, C.; Wang, N.; Jiang, Y.
Synlett 2005, 986; (b) Mase, N.; Tanaka, F.; Barbas, C. F., III.
Angew. Chem., Int. Ed. 2004, 43, 2420; (c) Mase, N.; Tanaka,
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4. During our work, an example dealing with the catalytic
generation of trifluoroacetaldehyde as well as only one pro-
line-derived tetrazole catalyzed direct aldol reaction with cy-
clopentanone has been reported, see: Torii, H.; Nakadai, M.;
Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed.
2004, 43, 1893.
5. Forsilica gel-catalyzed aldol reaction, see: (a) Kubota, Y.; Goto,
K.; Miyata, S.; Goto, Y.; Fukushima, Y.; Sugi, Y. Chem. Lett.
2003, 32, 234; (b) Ishitani, H.; Iwamoto, M. Tetrahedron Lett.
2002, 44, 299 and references cited therein.
6. Presented partially at the 84th National Meeting of the
Chemical Society of Japan, Hyougo, Japan, March 2004, Abstr.
No. 2, 1259.
9. (a) Kiehlmann, E.; Menon, B. C.; McGillivray, N. Can. J.
Chem. 1973, 51, 3177; (b) Bucciarelli, M.; Forni, A.; Moretti,
I.; Prati, F.; Torre, G. Gazz. Chim. Ital. 1990, 120, 99; (c) Van
der Zeijden, A. A. H.; Veghini, Dario; Berke, Heinz Inorg.
Chem. 1992, 31, 5106; (d) Bucciarelli, M.; Forni, A.; Moretti,
I.; Prati, F.; Torre, G. Biocatalysis 1994, 9, 313; (e) Forni, A.;
Moretti, I.; Prati, F.; Torre, G. Tetrahedron 1994, 50, 11995;
(f) Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39,
9151; (g) Kitazume, T.; Tamura, K.; Jiang, Z.; Miyake, N.;
Kawasaki, I. J. Fluorine Chem. 2002, 115, 49; (h) Hess, R.;
Diezi, S.; Mallat, T.; Baiker, A. Tetrahedron: Asymmetry
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E.; Mallat, T.; Baiker, A. Catal. Lett. 2005, 102, 121.
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