Enamine-assisted facile generation of trifluoroacetaldehyde from trifluoroacetaldehyde ethyl hemiacetal and its carbon-carbon bond forming reaction leading to β-hydroxy-β-trifluoromethyl ketones

Article abstract of DOI:10.1039/a804922j

Trifluoroacetaldehyde ethyl hemiacetal 1 readily reacts with various enamines 2 in hexane at room temperature for l h to give the corresponding β-hydroxy-β-trifluoromethyl ketones in good yields.

Full text of DOI:10.1039/a804922j

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Enamine-assisted facile generation of trifluoroacetaldehyde from
trifluoroacetaldehyde ethyl hemiacetal and its carbon–carbon bond forming
reaction leading to b-hydroxy-b-trifluoromethyl ketones
Kazumasa Funabiki,*† Miwa Nojiri, Masaki Matsui and Katsuyoshi Shibata*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu, 501-1193, Japan
Trifluoroacetaldehyde ethyl hemiacetal 1 readily reacts with
various enamines 2 in hexane at room temperature for 1 h to
give the corresponding b-hydroxy-b-trifluoromethyl ketones
in good yields.
addition, trifluoroacetaldehyde is gaseous (bp 218 °C) and very
miscible with water, and therefore it must be carefully
handled.
Here we describe for the first time the enamine-assisted facile
generation of trifluoroacetaldehyde under extremely mild
conditions from trifluoroacetaldehyde ethyl hemiacetal,‡ and its
carbon–carbon bond forming reaction with enamines in the
absence of additives, which permits highly efficient and
convenient access to b-hydroxy-b-trifluoromethyl ketones.
When hemiacetal 1a was allowed to react with an equimolar
amount of enamine 2a, prepared from acetophenone with
morpholine, in hexane at room temperature for 1 h, the
corresponding b-hydroxy-b-trifluoromethyl ketone 3a was
obtained in 88% yield (Scheme 1 and Table 1, entry 1).
The use of other solvents, such as dichloroethane, THF,
PhMe and MeCN, gave comparable yields of 3a, irrespective of
their polarities (entries 2–5). It is noteworthy that the reaction of
1a proceeded smoothly to furnish the product 3a in satisfactory
yield in the presence of water (entry 6). The substituents on the
nitrogen atom of the enamines did not influence the yields of 3a
(entries 1 and 7). Various enamines bearing aromatic and
heteroaromatic substituents could successfully participate in the
reaction to afford the corresponding b-hydroxy-
b-trifluoromethyl ketones 3 in good to excellent yields (entries
8–11, 14–15). The reaction with enamine 2f carrying a nitro
group on the aromatic ring was very sluggish, producing 3e in
only 13% yield because of the lower solubility of 2f, which
could be improved by replacing hexane with toluene as solvent
(entries 12 and 13). The electronic character of the aromatic ring
has little influence on the rate of the reaction, according to the
yields of 2 for the same reaction time (p-NO2 < 2-thienyl =
Much attention has been recently addressed to trifluoromethy-
lated compounds, since they are widely used for the construc-
tion of new types of biologically active compounds and liquid
crystals. In connection with these circumstances, the develop-
ment of new strategies and methodologies for the efficient
synthesis of trifluoromethylated molecules has become the
subject of growing interest.1 Among the many approaches to
such compounds, trifluoroacetaldehyde is one of the most
useful compounds, and is employed for the construction of
functionalized trifluoromethylated components via reaction
with a number of reagents, such as metal enolates,2 ketene silyl
acetals3 (phenylthio)bis(trimethylsilyl)methyllithium,4 aro-
matic compounds,5 olefins3,6 and dienes.7 In previous methods
for the generation of trifluoroacetaldehyde, however, there exist
serious disadvantages, including high reaction temperatures and
the use of an excess amount of concentrated H2SO4.8 In
X
N
2
X
OH
O–
i
+
N
CF3
OEt
CF3
OEt
R
R
1a
X
O
EtO–
+
+
+
+
N
Table
1 Reactions of trifluoroacetaldehyde ethyl hemiacetal with
CF3
H
H
enaminesa
R
R
Entry Enamine X
R
Solvent
Product Yield (%)b
X
N
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2c
2c
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
hexane
ClCH2CH2Cl
THF
PhMe
MeCN
3a
3a
3a
3a
3a
88
78
73
88
75
68
86
87
87
72
86
13
52
87
75
25
O
EtOH
+
CF3
hexane–H2O (40:1) 3a
hexane
CH2 Ph
3a
3b
3b
3c
3d
3e
3e
3f
X
N
O
O
O
O
O
O
O
O
O
p-MeC6H4 hexane
p-MeC6H4 PhMe
p-MeOC6H4 hexane
p-ClC6H4 hexane
p-O2NC6H4 hexane
p-O2NC6H4 PhMe
o-MeC6H4 hexane
X
N
10 2d
11 2e
12 2f
13 2f
14 2g
15 2h
16c 2i
OH
O
and/or
OEt
R
R
+
EtOH
CF3
CF3
2-thienyl
Pri
hexane
hexane
3g
3h
H
+ and/or
OH
O
silica gel
a
All the reactions were carried out with trifluoroacetaldehyde ethyl
hemiacetal (1 mmol) and enamine (1 mmol) in solvent (4 ml) at room
temperature for 1 h. b Isolated yields of analytical pure products. c A mixture
of enamines 2i and 4 (29:71) was employed.
CF3
R
3
Scheme 1 Reagents and conditions: i, room temp., 1 h
Chem. Commun., 1998
2051

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OH
OLi
i
CF3
OEt
CF3
OEt
1a
1b
Scheme 2 Reagents and conditions: i, BunLi (1.5 equiv.), hexane, 0 °C, 15
min
p-Cl = p-H = p-Me = p-MeO). The reaction of 1a with the
mixture of aliphatic enamines 2i and 4-(3-methylbut-2-en-
2-yl)morphorine 4 (29:71) (1 equiv.) resulted in the exclusive
formation of 3h in 25% yield, and none of the product derived
from enamine 4 was detected in the reaction mixture (entry 16).
According to these results, the steric effect of the substituents at
the b-carbon of the enamines is more important for the the
reaction than the electronic effect of the substituents at the
a-carbon.
The formation of 3 can be explained by assuming the
mechanism shown in Scheme 1. It is significant that the reaction
requires only an equimolar amount of enamine, which may act
as a base, counter ammonium cation and carbon nucleophile.
More significantly, the reaction of lithium alcoholate 1b§
with the enamine 2a did not proceed at all; the acetophenone
was recovered in quantitative yield (Scheme 2). According to
this result, the ammonium cation, which is generated via
protonation of the enamine, plays a very important role in the
effective generation of trifluoroacetaldehyde in the reaction.
In conclusion, we have demonstrated the enamine-assisted in
situ generation of trifluoroacetaldehyde and its reaction with
enamines, producing the corresponding b-hydroxy-
b-trifluoromethyl ketones 3 in high yields. The present method
can serve as a synthetically useful entry to b-hydroxy-
b-trifluoromethyl ketones, with simple manipulations and high
yields of the products. Application of the present methodology
to stereoselective synthesis using asymmetric secondary amines
or b-monosubstituted enamines is currently in progress in our
laboratory.
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We thank Dr H. Muramatsu for valuable discussions.
Notes and References
† E-mail kfunabik@apchem.gifu-u.ac.jp
‡
Recent reports have presented the coupling reaction of trifluor-
oacetaldehyde ethyl hemiacetal, which is considered as an equivalent of
trifluoroacetaldehyde. These methods, however, require the use of an excess
amount of reagents and/or of limited solvents, the formation of by-products,
and relatively low yields of the products, see ref. 9.
§ Kitazume and Yamazaki reported that the tetrahedral form of 1b is too
stable to be converted to trifluoroacetaldehyde due to the strong electron-
withdrawing effect of a trifluoromethyl group, see ref 10.
10 S. Kaneko, T. Yamazaki and T. Kitazume, J. Org. Chem., 1993, 58,
2302.
1 For recent examples, see: K. Uneyama, J. Hao and H. Amii,
Tetrahedron Lett., 1998, 39, 4079; A. Ishii, F. Miyamoto, K.
Received in Cambridge, UK, 29th June 1998; 8/04922J
2052
Chem. Commun., 1998