Practical asymmetric synthesis of β-hydroxy-β-trifluoromethylated ketones via the first example of the in situ generation of trifluoroacetaldehyde and its successive asymmetric carbon-carbon bond formation reaction with chiral imines

Article abstract of DOI:10.1039/b408226e

Not only trifluoroactaldehyde ethyl hemiacetal or hydrate but also other polyfluoroalkylaldehydes acetals or hydrates react with an equimolar amount of various chiral imines, followed by hydrolysis to produce the corresponding (S)-β-hydroxy-β-polyfluoroal

Full text of DOI:10.1039/b408226e

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Practical asymmetric synthesis of b-hydroxy-b-trifluoromethylated
ketones via the first example of the in situ generation of trifluoro-
acetaldehyde and its successive asymmetric carbon–carbon bond
formation reaction with chiral imines
Kazumasa Funabiki,* Wataru Hashimoto and Masaki Matsui
Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido,
Gifu 501–1193. E-mail: kfunabik@apchem.gifu-u.ac.jp; Fax: 181 58 230 1893
Received (in Cambridge, UK) 1st June 2004, Accepted 29th June 2004
First published as an Advance Article on the web 13th August 2004
Not only trifluoroactaldehyde ethyl hemiacetal or hydrate but
group of the imine 2c brought about a higher yield, but with much
lower selectivity (entry 7). The (R)-1-(1-naphthyl)ethyl group was
the most effective chiral auxiliary for this reaction to provide 3a
in 66% yield with the best enantioselectivity (S : R ~ 85.5 : 14.5)
(entry 8).
Carrying out the reaction at 0 uC afforded 3a with higher
selectivity, although a longer reaction time (7 d) is required (entry
9).{ An even lower temperature (215 uC) was not so effective in
also other polyfluoroalkylaldehydes acetals or hydrates react
with an equimolar amount of various chiral imines, followed
by hydrolysis to produce the corresponding (S)-b-hydroxy-
b-polyfluoroalkyl ketones in good yields with good
enantioselectivities; furthermore, the ee of the products can be
improved by simple recrystallization.
The enantioselective synthesis of a-trifluoromethylated alcohols or
amines is of primary significance since these chiral synthons are
among the most important and commonly found subunits in chiral
drugs or materials.1 Particularly, efficient and selective synthesis
using trifluoroacetaldehyde or its hemiacetal as a C2 building block
is an extremely useful approach toward functionalized trifluoro-
methylated compounds.2 However, just before trifluoroacetalde-
hyde is employed, it should be generated from its hemiacetal or
hydrate using an excess amount of conc. sulfuric acid under a high
reaction temperature.3 Moreover, careful treatment of the aldehyde
is required due to its troublesome properties, such as its gaseous
state at room temperature, high miscibility with moisture and high
reactivity leading to self-polymerization.3 Although the develop-
ment of much more convenient and environmentally-benign
methods has been investigated for some time, to the best of our
knowledge, there is only one report on the generation of
trifluoroacetaldehyde from its hemiacetal or hydrate accompanied
by a simultaneous asymmetric carbon–carbon bond formation
reaction, which has the serious disadvantage of extremely low
enantioselectivity.4 Recently, we have found that the enamines
or imines are very effective for both the in situ generation of
trifluoroacetaldehyde and its carbon–carbon bond formation
reaction.2
Herein we wish to describe the first example of chiral imine-
assisted in situ generation of trifluoroacetaldehyde from its
hemiacetal and the successive asymmetric carbon–carbon bond
formation reaction of the aldehyde with chiral imines to afford
b-hydroxy-b-trifluoromethylated ketones with excellent enantios-
electivities (Scheme 1).
Scheme 1
Table 1 The reaction of trifluoroacetaldehyde ethyl hemiacetal with
chiral imines derived from acetophenone under various conditions
The results of the reaction of trifluoroacetaldehyde ethyl
hemiacetal 1a with chiral imine 2a derived from acetophenone
and (R)-1-phenylethylamine under various conditions are summar-
ized in Table 1. The reaction in hexane at room temperature for 7 h
proceeded smoothly to give the ketone 3a in 62% yield with good
enantioselectivity (S : R ~ 80.1 : 19.9) (entry 1). Among other
solvents examined, toluene is also usable for the reaction with a
slight decrease of ee (entry 2). Employing dichloromethane
(CH2Cl2) or acetonitrile (MeCN) reduced the ee of 3a (entries 4
and 5). The reaction in THF was enormously sluggish to give an
only trace amount of 3a (entry 3). These results apparently suggest
that less polar solvents such as hexane and toluene are more
suitable for the reaction, giving higher yields as well as higher
enantioselectivities of the product than polar solvents. When the
reaction was performed with imine 2b derived from (S)-1-phenyl-
ethylamine, the absolute configuration of the major isomer was
completely reversed (entries 1 and 6). The (R)-1-cyclohexylethyl
Yield
(%)b
Isomer ratio
(S : R)c
Entrya
Imine
Solvent
Conditions
1
2
3
4
5
6
7
8
9
10
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
Hexane
PhMe
THF
CH2Cl2
MeCN
Hexane
Hexane
Hexane
Hexane
Hexane
rt, 7 h
rt, 7 h
rt, 7 h
rt, 7 h
rt, 7 h
rt, 7 h
rt, 7 h
rt, 7 h
62
64
8
61
56
73
92
66
57
48
80.1 : 19.9
77.6 : 22.4
73.3 : 26.7
71.3 : 28.7
71.9 : 28.1
20.6 : 79.4
62.5 : 37.5
85.5 : 14.5
90.5 : 9.5
0 uC, 7 d
215 uC, 7 d
89.3 : 10.7
a All the reactions were conducted with trifluoroacetaldehyde ethyl
hemiacetal 1a (0.5 mmol) and imine 2 (0.5 mmol). b Yields of iso-
lated products. c Determined by HPLC analysis with CHIRALCEL
OD (hexane : i-PrOH ~ 95 : 5).
2 0 5 6
C h e m . C o m m u n . , 2 0 0 4 , 2 0 5 6 – 2 0 5 7
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 The reaction of polyfluoroalkylaldehyde hemiacetal or hydrate 1 with various chiral imines 2
Enatiomer ratio
(S : R)c
Entry
1
Rf
X
Imine
R1
Product
Yield (%)b
Eec
Eec,d
92.8
1
2
3
4
5
6
7
8
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1c
1d
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CHF2
CF3CF2
Et
H
2d
2d
2e
2f
2g
2h
2i
2j
2k
2l
Ph
Ph
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
57
57
68
64
51
37
14
70
73
59
24
53
51
90.5 : 9.5
89.1 : 10.9
89.4 : 10.6
87.6 : 12.4
86.0 : 14.0
90.3 : 9.7
56.9 : 43.1
90.6 : 9.4
93 : 7e
81.0
78.2
78.8
75.2
72.0
80.6
13.8
81.2
86
76
84
51.0
79.4
—
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
H
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2-Thienyl
2-MeC6H4
3-MeC6H4
c-Hex
i-Pr
t-Bu
Ph
Ph
w99.9
w99.9
93.8
w99.9
—
—
—
—
—
9
10
11
12
13
88 : 12e
2m
2d
2d
3j
4a
5a
92 : 8e
75.5 : 24.5
89.7 : 10.3
—
95.6
a All the reactions were carried out with 1 (0.5 mmol) and 2 (0.5 mmol) at 0 uC for 7 d. b Yields of isolated products. c Determined by HPLC
analysis with CHIRALCEL OD (hexane : i-PrOH ~ 95 : 5). d After recrystallization. e Determined by 19F NMR.
improving the selectivity, and ketone 3a was obtained in 48% yield
(entry 10).
generation of trifluoroacetaldehyde as well as its simultaneous
asymmetric carbon–carbon bond formation reaction with chiral
imines, producing the corresponding b-hydroxy-b-trifluoromethyl
ketones in good yields with high enantioselectivities. The major
advantages of this process are good yields as well as high enantio-
selectivities, the absence of a generation step for the trifluoroace-
taldehyde, the use of only stoichiometric amounts of chiral imines
and the easy recovery of the chiral auxiliary.
This work was partially supported by Grant-in-Aid for
Encouragement of Young Scientists (B) (Grant No.14750665)
from the Ministry of Education, Culture, Sports, Science and the
Gifu University. We also thank the Central Glass Co., Ltd., for the
gift of trifluoroacetaldehyde ethyl hemiacetal and hydrate.
The results of the reaction between hemiacetal 1a and various
chiral imines 2 under the optimized conditions are summarized in
Table 2. The reaction of 1a with chiral imines 2d–h,j having 4- and
3-substituted phenyl groups as well as the thienyl one afforded the
corresponding b-hydroxy-b-trifluoromethyl ketones 3a–e,g in good
yields with good enantioselectivities (entries 1,3–6 and 8). However,
the use of chiral imine 2i with a 2-methylphenyl group provided 3f
in only 14% yield with extremely low ee (entry 7). At the present
stage, the exact reason for the low yield and selectivity is not clear.
Chiral imines 2k–m carrying aliphatic substituents, such as c-hexyl,
i-propyl, and t-butyl group, underwent reaction with the hemiacetal
1a to give the corresponding b-hydroxy-b-trifluoromethyl ketones
3h–j with uniformly good enantioselectivities (entries 9–11).
However, using imine 2m with a t-butyl group produced 3j in
only 24% yield (entry 11).
Notes and references
The absolute configuration for 3a with a phenyl group was
determined as S by comparison with the reported optical rotation.5
It is likely that the absolute configuration for the remaining
products having other aromatic substituents can be assigned as the
same by analogy. The absolute configurations and the ee values of
3g–i with aliphatic groups were determined by the Mosher method.
The present protocol can be applied to trifluoroacetaldehyde
hydrate as well as other polyfluoroalkylaldehyde acetals or
hydrates. The use of trifluoroacetaldehyde hydrate 1b in place of
the hemiacetal 1a gave the same yield (57%) of the ketone 3a
with similar enantioselectivity (entries 1 and 2). Compared with
trifluoroacetaldehyde ethyl hemiacetal 1a, the reaction of difluor-
oacetaldehyde ethyl hemiacetal 1c with the imine 2d provided a
lower stereoselectivity of the product 4a in 53% yield (entries 1 and
12). In contrast, treatment of pentafluoropropioaldehyde hydrate
1d with the imine 2d gave the corresponding b-hydroxy-b-
pentafluoroethyl ketone 5a in 51% yield with similar enantioselec-
tivity to that of the trifluoromethylated one (entries 1 and 13).
Furthermore, simple recrystallization of the ketone 3a using hot
hexane (30 ml g21 of 3a) yields a highly enantioenriched product
(92.8% ee). Ee values of other b-hydroxy-b-polyfluoroalkyl ketones
3,5 with aromatic substituents could also be improved by the same
method (up to 99.9% ee). In the case of 3d, changing the polarity of
the solvent by using hexane–AcOEt (v/v ~ 50/1) (30 ml g21 of 3d)
is required. Unfortunately, this method was not effective for
difluoromethylated ketone 4 due to its lower melting point than
those of the trifluoromethylated ones. Noteworthy is that higher ee
values of the ketones are obtained from the mother liquor in all
cases.6
{ To a solution of chiral imine 2d (0.137 g, 0.5 mmol) in hexane (2 ml) was
added trifluoroacetaldehyde ethyl hemiacetal 1a (0.074 g, 0.5 mmol) at 0 uC
under argon atmosphere. After being stirred at 0 uC for 7 d, the reaction
mixture was hydrolyzed with 10% HCl aq. (4 ml) for 3 h, followed by
extraction with Et2O (30 ml 6 3), drying over Na2SO4, and concentration
under vacuum. The residue was chromatographed on silica gel using
hexane–EtOAc, giving 3a in 57% yield (0.062 g, 81.0% ee). The ee of the
product was determined by chiral HPLC analysis (Daicel, CHIRALCEL
OD, n-hexane : i-PrOH ~ 95 : 5, 0.8 ml min21, 254 nm). On the other
hand, the aqueous layer and the precipitate at hydrolysis were treated with
solid NaOH to make them alkaline, followed by extraction with Et2O
(30 ml 6 3), drying over Na2SO4, and concentration under vacuum, (R)-1-
(1-naphthyl)ethylamine was recovered in 88%. 3a; [a]D23 220.3u (92.8% ee
(S), c ~ 1.0, CHCl3).
1 K. Iseki, Tetrahedron, 1998, 54, 13887; V. A. Soloshonok, Enantiocon-
trolled Synthesis of Fluoro-organic Compounds, John Wiley & Sons,
Chichester, UK, 1999; P. V. Ramachandran, Asymmetric Fluoroorganic
Chemistry: Synthesis, Application, and Future Directions, American
Chemical Society, Washington, DC, 1999; K. Mikami, Y. Itoh and
M. Yamanaka, Chem. Rev., 2004, 104, 1.
2 K. Funabiki, K. Matsunaga, M. Nojiri, W. Hashimoto, H. Yamamoto,
K. Shibata and M. Matsui, J. Org. Chem., 2003, 68, 2853 and references
cited therein.
3 M. Braid, H. Isersone and F. E. Lawlore, J. Am. Chem. Soc., 1954, 76,
4027; A. L. Henne, R. L. Pelley and R. M. Alm, J. Am. Chem. Soc., 1950,
72, 3370.
4 R. Ferna´ndez, E. Mart´ın-Zamora, C. Pareja, M. Alcarazo, J. Mart´ın and
J. M. Lassaletta, Synlett, 2001, 1158.
5 J. T. Lin, T. Yamazaki and T. Kitazume, J. Org. Chem., 1987, 52, 3211.
6 A. Ishii, M. Kanai, K. Higashiyama and K. Mikami, Chirality, 2002, 14,
709.
In summary, we have achieved the stoichiometric in situ
C h e m . C o m m u n . , 2 0 0 4 , 2 0 5 6 – 2 0 5 7
2 0 5 7