Asymmetric synthesis of β-hydroxy-β-trifluoromethylated ketones via in situ generation of trifluoroacetaldehyde and its asymmetric carbon-carbon bond formation reaction with chiral imines in aqueous media

Article abstract of DOI:10.1016/j.jfluchem.2005.12.020

Asymmetric synthesis of β-hydroxy-β-trifluoromethylated ketones via in situ generation of trifluoroacetaldehyde from its hemiacetal as well as the simultaneous asymmetric carbon-carbon bond formation reaction in aqueous media is described.

Full text of DOI:10.1016/j.jfluchem.2005.12.020

Journal of Fluorine Chemistry 127 (2006) 545–547
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Asymmetric synthesis of b-hydroxy-b-trifluoromethylated ketones
via in situ generation of trifluoroacetaldehyde and its
asymmetric carbon–carbon bond formation reaction
with chiral imines in aqueous media
*
Kazumasa Funabiki , Kazutoshi Hasegawa, Yoshihiro Murase,
Hideyuki Nagaya, Masaki Matsui
Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1, Yanagido, Gifu 501-1193, Japan
Received 28 December 2005; accepted 29 December 2005
Available online 21 February 2006
Abstract
Asymmetric synthesis of b-hydroxy-b-trifluoromethylated ketones via in situ generation of trifluoroacetaldehyde from its hemiacetal as well as
the simultaneous asymmetric carbon–carbon bond formation reaction in aqueous media is described.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Fluorine and compounds; Asymmetric synthesis
1. Introduction
2. Results and discussion
Much attention has been addressed to the synthesis of
trifluoromethylated compounds, because the introduction of the
trifluoromethyl group often improve the chemical, physical and
biological properties of the organic molecules [1]. Recently,
although various types of asymmetric synthesis of these
compounds have been reported [2], there is only few literatures
concerning with asymmetric synthesis of trifluoromethylated
compounds in aqueous media [3]. In our continuing studies on
the in situ generation of trifluoroacetaldehyde from its
hemiacetal or hydrate as well as successive carbon–carbon
bond formation reaction with imines or enamines [4], we have
found that in situ generation of trifluoroacetaldehyde and its
simultaneous asymmetric carbon–carbon bond formation
reaction with chiral imines occurred in aqueous media. Herein
we wish to describe asymmetric synthesis of b-hydroxy-b-
trifluoromethylated ketones by the reaction of trifluoroacetal-
dehyde ethyl hemiacetal with chiral imines in aqueous media.
Chiral imines 2 were prepared according to our previous
report [5]. That is, treatment of acetophenone with chiral amine
in the presence of a catalytic amount of p-toluenesulfonic acid
for overnight or 2 days gave the corresponding chiral imine 2 in
good yields via distillation or recrystallization.
When trifluoroacetaldehyde ethyl hemiacetal 1 was treated
with an equimolar amount of chiral imine 2a, derived from (S)-
1-phenylethylamine, at ambient temperature in a buffer
solution (pH 4.01), after hydrolysis of the reaction mixture,
b-hydroxy-b-trifluoromethylated ketone 3a was obtained in
45% yield with 49.6% ee (Table 1, entry 3). The absolute
configuration of 3a could be determined as R by the comparison
with the reported optical rotation value [6]. The results of the
reaction between trifluoroacetaldehyde ethyl hemiacetal 1 and
an equimolar amount of chiral imine 2a in various aqueous
media are summarized in Table 1. Using other buffer solutions
(pH 9.18 and 6.86) gave similar yields as well as the
enantioselectivities (entries 1 and 2). The use of distilled water
resulted in slight reduction of the yield (entry 4). Enantiomer
ratios of the aldol product 3a are equally good to high in every
instance under different pH conditions, when compared with
the reported results by other reactions in aqueous media [3].
* Corresponding author. Fax: +81 58 293 2599.
E-mail address: kfunabik@apchem.gifu-u.ac.jp (K. Funabiki).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.12.020

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K. Funabiki et al. / Journal of Fluorine Chemistry 127 (2006) 545–547
Table 1
Asymmetric synthesis of (3-hydroxy-(3-trifluoromethylated) ketones via in situ generation of CF3CHO and its asymmetric reaction with chiral imines in aqueous
media
Entrya
1
2
R*
R
pH of a buffer solution
9.18
Time (h)
24
3
Yield of 3b (%)
Isomer ratio (S:R)c
2a
Ph
3a
39
25.0:75.0
2
3
4
5
6.86
24
24
24
48
41
45
35
62
25.3:74.7
25.2:74.8
25.0:75.0
25.0:75.0
4.01
Distilled water
4.01
6
2b
4-ClC6H4
4.01
48
3b
12
81.4:18.6
a
All the reaction was conducted with trifluoroacetaldehyde ethyl hemiacetal 1 (0.5 mmol) and imine 2 (0.5 mmol) in solvent (2 ml).
Yields of isolated products.
b
c
Determined by HPLC analysis with CHIRALCEL OD-H (hexane:i-PrOH = 95/5).
Interestingly, although the reaction of hemiacetal 1 with chiral
Optical rotations were measured on a HORIBA SEPA-300 in
Uvasol grade CHCl3 (Merck). HPLC was achieved using a
Daicel CHIRALCEL OD (Daicel, 0.46 cm  25 cm) column
on a SHIMADZU LC-4A using n-hexane:i-PrOH = 95:5 as an
eluent with the flowing rate of 0.8 ml/min and detected at
254 nm. Melting points were obtained on a Yanagimoto MP-S2
micro melting point apparatus and were uncorrected. The IR
spectra were recorded on a SHIMADZU FT-IR 8100A
spectrometer.
imine 2a in aqueous media proceeded more slowly than those in
organic solvents, such as hexane, toluene, dichloromethane
(CH2Cl2) and acetonitrile (MeCN), the enanitoselectivities of
3a in aqueous media are slightly better than those in MeCN
(S:R = 71.9:28.1) and CH2Cl2 (S:R = 71.3:28.7) [4a]. Pro-
longed reaction time (48 h) resulted in the increase of the
product 3a (entry 5). The reaction of hemiacetal 1 with other
chiral imine 2b, derived from 4-chloroacetophenone and (R)-1-
(1-naphthyl)ethylamine, was sluggish to produce the product
3b in only 12% yield, due to the low solubility of the solid chiral
imine 2b (entry 6). However, the enantioselectivity
(S:R = 81.4:18.6) of the aldol adduct 3b was much higher
than that of 3a, because the 1-(1-naphthyl)ethyl group is much
bulkier than the 1-phenylethyl one.
4.2. Reaction of trifluoroacetaldehyde ethyl hemiacetal
with chiral imines in aqueous media
Trifluoroacetaldehyde ethyl hemiacetal
1
(0.074 g,
0.500 mmol) was added to a mixture of chiral imine 2a
(0.112 g, 0.500 mmol) in a buffer solution was added at room
temperature. After being stirred at the same temperature for
48 h, the reaction mixture was hydrolyzed with 10% HCl aq.
(2 ml) for 3 h, followed by extraction with Et2O (30 ml  3),
dried over Na2SO4, and concentration under vacuum. The
residue was chromatographed on silica gel using hexane–
EtOAc, giving 3a in 62% yield (0.067 g, 50.0% ee). The ee of
the product was determined by chiral HPLC analysis.
3. Conclusion
In summary, we have demonstrated the first example of the
in situ generation of trifluoroacetaldehyde from its hemiacetal
as well as the simultaneous asymmetric carbon–carbon bond
formation reaction in aqueous media, affording a novel
asymmetric synthetic route to b-hydroxy-b-trifluoromethy-
lated ketones.
4.2.1. (R)-4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butanone
((R)-3a)
4. Experimental
Chiral HPLC (Daicel, CHIRALCEL OD, n-hexane:i-
PrOH = 95:5, 0.8 ml/min, 254 nm, tR = 15.0 min (S),
17.5 min (R)); 41.0–42.0 8C (92.8% ee (S), hexane), IR
4.1. Measurements
1H (400 MHz) or 13C (100 MHz) NMR spectra were
measured with a JEOL a-400 FT-NMR spectrometers in CDCl3
solutions with TMS as the internal standard. 19F NMR
(376 MHz) spectra were recorded on a JEOL a-400 FT-
NMR in CDCl3 solutions using TFA as the external standard.
(KBr) 1686.5 (C O), 3390.3 (OH) cmÀ1; H NMR (CDCl3)
1
d 3.33 (dd, J = 17.93, 3.17 Hz, 1H), 3.39 (dd, J = 17.93,
8.79 Hz, 1H), 3.47 (d, J = 2.92 Hz, 1H), 4.65–4.74 (m, 1H),
7.49–7.53 (m, 2H), 7.62–7.66 (m, 1H), 7.97–7.99 (m, 2H); 13
NMR (CDCl3) d 38.22 (s), 67.03 (q, J = 31.98 Hz), 124.69 (q,
C

K. Funabiki et al. / Journal of Fluorine Chemistry 127 (2006) 545–547
547
J = 280.37 Hz), 128.21 (s), 128.88 (s), 134.18 (s), 135.96 (s),
197.56 (s); 19F NMR (CDCl3) d 1.80 (d, J = 6.87 Hz, 3F); MS
(EI) m/z (rel intensity) 218 (M+; 11.7), 200 (4.0), 198 (12.2),
162 (3.8), 106 (7.9), 105 (100.0), 78 (4.1), 77 (38.9). HRMS
(EI) Calcd for C10H9F3O2: M, 218.0555. Found: m/z 218.0533.
Anal. Calcd for: C, 55.05; H, 4.21. Found: C, 54.99; H, 4.21.
Technology of Japan, the OGAWA Science and Technology
Foundation and Gifu University. We are grateful to the
Central Glass Co. Ltd., for the gift of trifluoroacetaldehyde
ethyl hemiacetal as well as financial support. We thank
Professors H. Yamanaka and T. Ishihara as well as Dr T.
Konno of the Kyoto Institute of Technology for the HRMS
measurements.
4.2.2. (S)-1-(4-chlorophenyl)-4,4,4-trifluoro-3-hydroxy-1-
butanone ((S)-3b)
References
Chiral HPLC (tR = 14.5 min (S), 15.5 min (R)); mp 57.0–
58.0 8C (>99.9% ee (S), hexane); IR (KBr) 1688.3 (C O),
1
3383.7 (OH) cmÀ1; H NMR (CDCl3) d 3.27 (dd, J = 17.63,
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