Chemoselective reduction of ketones: Trifluoromethylketones versus methylketones

Article abstract of DOI:10.1016/j.tetlet.2005.01.013

Treatment of an equimolar mixture of trifluoromethylketones (TFMKs) and methylketones (MKs) with Et₂Zn resulted in selective reduction of the TFMKs in good yield. In contrast, treatment of an equimolar mixture of TFMKs and MKs with NaBH₄ in the presence of CeCl₃ in EtOH/H ₂O (10:1) at -10°C reduced only the MKs.

Full text of DOI:10.1016/j.tetlet.2005.01.013

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1497–1500
Chemoselective reduction of ketones: trifluoromethylketones
versus methylketones
Shigeru Sasaki,a Takayasu Yamauchi,a Hajime Kubo,a Masatomi Kanai,b
Akihiro Ishiib and Kimio Higashiyamaa,*
aInstitute of Medicinal Chemistry, Hoshi University, Ebara, Shinagawa, Tokyo 142-8501, Japan
bChemical Research Center, Central Glass Co., Ltd, Imahuku, Kawagoe, Saitama 350-1151, Japan
Received 30 April 2004; revised 5 January 2005; accepted 7 January 2005
Available online 20 January 2005
Abstract—Treatment of an equimolar mixture of trifluoromethylketones (TFMKs) and methylketones (MKs) with Et2Zn resulted
in selective reduction of the TFMKs in good yield. In contrast, treatment of an equimolar mixture of TFMKs and MKs with
NaBH4 in the presence of CeCl3 in EtOH/H2O (10:1) at À10 °C reduced only the MKs.
Ó 2005 Elsevier Ltd. All rights reserved.
The importance of organofluorine compounds in life sci-
ence is rapidly expanding, because the fluorine atom has
very peculiar properties. At present, up to 20% to 30%
of agrochemicals and pharmaceuticals contain one or
more fluorine atoms.1 Among organofluorine com-
pounds, trifluoromethylated compounds constitute an
important class because of their stereoelectronic proper-
ties and important bioavailability.1a For a long time,
TFMKs have been useful for the synthesis of organoflu-
orine compounds, and various methods for introduction
of TFMKs into organic compounds as Ôbuilding blocksÕ
have been explored.2 The LUMO energy is lower for
MKs than for TFMKs; thus, TFMKs are highly
reactive and readily susceptible to nucleophilic attack.3
chemoselective reduction of TFMKs have been
reported.4 This point led us to investigate the chemo-
selective reduction of TFMKs in mixture with MKs.
General reducing agents such as DIBAL-H, LiAlH4 and
NaBH4 were used to an equimolar mixture of trifluoro-
acetophenone and acetophenone, but chemoselectivity
was not observed (Table 2, entry 1–3). However, when
an equimolar mixture of two carbonyl compounds was
treated with Et2Zn, only TFMKs were reduced (entry
4). Therefore, we examined the chemoselective reduction
of TFMKs with various solvents and equivalent of
Et2Zn (Table 3). In all cases only TFMKs were reduced
with a very small amount of aldol byproduct 8. The
ratio of reduced product 7 was increased by less polar
solvents and an excess amount of Et2Zn. When R
was either aromatic (entries 1–13) or aliphatic (entry
14), TFMKs were reduced in good yield.
Usually, Et2Zn is not used as a reducing agent, and
MKs cannot react at room temperature. However, in
our recent research we found that Et2Zn can be used
as a reducing agent of TFMKs. For example, treatment
of 2,2,2-trifluoroacetophenone 1 with Et2Zn produced
reduced product 2 in good yield (Table 1). Moreover,
1 equiv of Et2Zn reduced 2 equiv of TFMKs (entry 2).
The chemoselective reduction of ketones in the presence
of other reducible functional groups is an important
synthetic transformation. But few methods for the
Next, we examined the chemoselective reduction of 9–11
that contained both TFMKs and MKs groups in the
same molecule with Et2Zn (Table 4). In all cases,
TFMKs reduced with good chemoselectivity. Reduction
of reactant 11 with 2 equiv Et2Zn resulted in a low yield
(entry 3). Thus, it is likely that the proton in the benzylic
position reacted with Et2Zn to produce zinc enolate,
which has low reducing ability. Therefore, 5 equiv of
Et2Zn was used, and the yield increased (entry 4).
Keywords: Chemoselective reduction; Trifluoromethylketones;
Methylketones; Diethylzinc.
A plausible mechanism for the reduction of TFMKs
with Et2Zn is shown in Scheme 1. Previously, Mosher
*
Corresponding author. Tel.: +81 3 5498 5770; fax: +81 3 5498
5768; e-mail: kimio@hoshi.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.013

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S. Sasaki et al. / Tetrahedron Letters 46 (2005) 1497–1500
Table 1. Reduction of 2,2,2-trifluoroacetophenone with Et2Zn
ful electron-attractive group such as CF3 is directly
linked with the carbonyl carbon, the carbonyl group is
less polarized, and consequently, its coordination cap-
ability is lower. However, only TFMKs were reduced.
So, the experimental result cannot be explained by the
different coordination capabilities. However, a compar-
ison of TFMKs and MKs carbonyl groups by molecular
orbital calculation shows that, although the positive
charge of TFMKs was lower, the LUMO energy level
was lower. Consequently, the electrophilicity of the
TFMKs carbonyl group is very high, resulting in reac-
tivity even though the coordination capability of zinc
was lower than that of MKs.
Entry
Et2Zn (equiv)
Reaction time (h)
Yield of 2 (%)a
1
2
1.3
0.6
6
18
91
89
a Isolated yield.
and co-workers reported a mechanism for reduction of
ketones with a Grignard reagent.5 Similarly, this
reaction was regarded as a Meerwein–Ponndorf–Verley
type reduction.
Polar solvents, such as THF, can affect Lewis acidity of
Et2Zn (16). THF coordinated with Et2Zn forms a weak
Lewis acid, weakening the coordination of the carbonyl
atom of TFMKs with Et2Zn. Consequently, the
reduction rate slows and aldol-type products increase
(Scheme 2).
In the first phase, the metal (Zn) must coordinate with
the carbonyl oxygen (15), which can be regarded as
the most important aspect of the reaction. This aspect
is different than the coordination capability of a Lewis
acid between the oxygens of the TFMKs and MKs
groups. In the past, Yamamoto and co-workers
reported a chemoselective reaction of TFMKs and
MKs.4b His work made clear the difference in coordina-
tion ability between TFMKs and MKs. When a power-
Next, we investigated the chemoselective reduction of
MKs in a mixture of TFMKs and MKs. TFMKs are
so highly reactive that they are kept in ketone-hydrate
equilibrium in an aqueous solution.6 This property is
Table 2. Reduction of the mixture of 1 and 3 with a general reducing agent
Entry
Reducing agent
Yield of 2 (%)a
Ratio of 2:4b
1
2
3
4
DIBAL-H
LiAlH4
NaBH4
Et2Zn
38
39:61
6063:37
73
85
55:45
100:0
a Isolated yield.
b The ratio was determined by 1H NMR spectra.
Table 3. Reduction of the mixture of 5 and 6 with Et2Zn
Entry
Solvent
R
Et2Zn (equiv)
Yield of 7 (%)
Ratio of 7:8a
1
THF
Ether
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1.3
1.3
85b
89b
85b
81b
60b
88:12
88:12
94:6
97:3
95:5
98:2
98:2
98:2
99:1
99:1
99:1
99:1
99:1
99:1
2
3
Toluene
CH2Cl2
Hexane
Hexane
Hexane
Hexane
Hexane
1.3
1.3
4
5
0.6
1.3
6
81b
b
7
2.098
3.098
5.099
3.073
3.079
3.064
3.072
5.093
b
b
c
8
9
10Hexane
4-MeOC
6H4
c
11
12
Hexane
Hexane
Hexane
Hexane
4-MeC6H4
4-ClC6H4
4-CF3C6H4
c-Hex
c
c
13
14d
b
a The ratio was determined by 1H NMR spectra.
b Estimated by GC.
c Isolated yield.
d The reaction was carried out for 20h.

S. Sasaki et al. / Tetrahedron Letters 46 (2005) 1497–1500
1499
Table 4. Reduction of 9–11 with Et2Zn
Entry
1
Substrates
Reaction time (h)
5
Et2Zn (equiv)
Yield of 13–17 (%)a
1.3
99 (12)
>99 (13)
14)
2
3
1.3
3b
24072.(0
29035.(0
4b
11
14)
a Isolated yield.
b Solvent was CH2Cl2.
Scheme 1. Mechanism for reduction of TFMKs with Et2Zn.
Scheme 2. Effect of the solvent on the reduction.
similar to that of ordinary aldehydes. In an earlier study,
Luche and Gemal reported selective reduction of ketones
with CeCl3 and NaBH4 in the presence of aldehydes in an
aqueous solution.7 We thought LucheÕs conditions could
be applied to the chemoselective reduction of MKs;
therefore, we used these conditions to reduce various
TFMKs and MKs derivatives (Tables 4 and 5).
was directly linked with the aromatic ring (entries 4
and 5). The reason for these differences was probably
Table 5. Reduction of mixture of 5 and 6 with NaBH4 and CeCl3
Entry
R
Yield of 17 (%)a
Ratio of 7:17b
The result showed that chemoselective reduction of
MKs occurred in all cases. CeCl3 probably converted
TFMKs into its corresponding hydrate, and the hydrate
provided adequate protection during the NaBH4 reduc-
tion steps. But the selectivity was lower when an elec-
tron-donating group such as a methoxy group was
directly linked with the aromatic ring (entries 2 and 3).
On the contrary, the selectivity was higher when an elec-
tron-attractive group such as a trifluoromethyl group
1
2
3
4
5
6
Ph
95
87
81
93
99
81
1:>99
28:72
17:83
7:93
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-CF3C6H4
c-Hex
1:>99
10:90
a Isolated yield.
b The ratio was determined by 1H NMR spectra.

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S. Sasaki et al. / Tetrahedron Letters 46 (2005) 1497–1500
Table 6. Reduction of 9–11 with NaBH4 and CeCl3
Entry
Substrate
Yield of 18–20a
1
2
3
9
89 (18)
>99 (19)
66 (20)
10
11
a Isolated yield.
the change in the LUMO energy level of TFMKs. The
LUMO energy level of TFMKs was lowered by the
electron-attractive group, and its corresponding
hydrate was stabilized (Table 6).
References and notes
1. (a) Organofluorine Chemistry; Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C.,
Eds.; Plenum: New York, 1994; (b) Organofluorine Com-
pounds in Medicinal and Biomedical Applications; Filler, R.,
Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amster-
dam, 1993; (c) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS
Editions: Washington, DC, 1996.
In conclusion, the reactions described in this study
represent a solution for chemoselective reduction of
TFMKs and MKs. This method for selective reduction
of ketones may be useful because it does not require
additional protection and deprotection steps.
´
´
2. Begue, J.-P.; Bonnet-Delpon, D. Tetrahedron 1991, 47,
3207–3258.
3. Linderman, R. J.; Jamois, E. A. J. Fluorine Chem. 1991, 53,
79–91.
Acknowledgements
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72, 3994–3999; (b) Mosher, S. H.; Stevenot, J. E.; Kimble,
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This work was supported in part by a grant from the
Ministry of Education, Science, Sports and Culture,
Japan and the Promotion and Mutual Aid Corporation
for Private Schools of Japan.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2005.
01.013.
6. Guthrie, J. P. Can. J. Chem. 1975, 53, 898–905.
7. Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101,
5848–5849.