Chemoselective reduction of aldehydes over ketones with sodium tris(hexafluoroisopropoxy)borohydride

Article abstract of DOI:10.1055/s-2008-1078217

Chemoselective reduction of aldehydes in the presence of ketones was achieved using sodium tris(hexafluoroisopropoxy)borohydride which can be stored as a THF solution. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078217

LETTER
2523
Chemoselective Reduction of Aldehydes over Ketones with Sodium
Tris(hexafluoroisopropoxy)borohydride
Chemoselective
Re
duction Using Sodiu
u
m
T
ris(hexaf
t
luorois
a
opropoxy)b
k
orohydride a Kuroiwa, Shuichi Matsumura, Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522,
Japan
Fax +81(45)5661576; E-mail: toshima@applc.keio.ac.jp
Received 10 June 2008
H
B
F3C
F3C
CF3
CF3
Abstract: Chemoselective reduction of aldehydes in the presence
of ketones was achieved using sodium tris(hexafluoroisopro-
poxy)borohydride which can be stored as a THF solution.
O
O
Na
O
Key words: reduction, sodium borohydride, hexafluoroisopro-
F3C
CF3
panol, aldehyde, ketone
Figure 1 Chemical structure of NaBH(HFIP)3
The chemoselective reduction of an aldehyde to a primary ic to be handled and stored under atmosphere for extended
alcohol in the presence of ketone and other reducible periods of time. Indeed, when we used the solid
functions is a considerably useful reaction in organic syn- NaBH(HFIP)3 for the following chemoselective reduc-
thesis. Although NaBH4 is widely used for reduction of al- tion, good reproducibility was not obtained. Therefore, we
dehydes and ketones,1 it is too reactive to chemo- prepared a 1 M NaBH(HFIP)3 in THF solution by the im-
selectively reduce aldehydes in the presence of ketones mediate addition of dry THF after the removal of the ex-
under normal conditions. Therefore, chemoselective re- cess HFIP and THF from the reaction mixture.
duction of aldehydes using NaBH4 has only been achieved
With the more stable 1 M NaBH(HFIP)3 in THF in hand,
at very low temperature2 or by addition of other reagents
we examined chemoselective reduction using the alde-
such as thiols,3 metal salts,4 resins5 or PEG.6 However, a
convenient alternative method is desirable in both aca-
demia and industry. In general, for such chemoselective
reductions, the modified hydrides, formed by the replace-
ment of hydride with sterically hindered substituents and/
or electron-withdrawing groups, must be able to discrim-
inate between the structural and electronic environment of
hyde 1 and the ketone 2. From the results summarized in
Table 1, it was shown that the aldehyde 1 was reduced us-
ing 3.0 equivalents of NaBH(HFIP)3 in THF at 25 °C for
5 hours to afford the corresponding primary alcohol 3 in
95% yield (entry 4 in Table 1). In contrast, the reduction
of the ketone 2 did not take place at all, and it was recov-
ered quantitatively under the same reaction conditions.
the carbonyl groups. In this context, we examined sodium
Although the actual role of HFIP as the solvent for the
tris(hexafluoroisopropoxy)borohydride, NaBH(HFIP)3, ow-
present chemoselective reduction reaction is not clear, its
ing to the sterically hindered and electron-withdrawing
use is essential as the solvent for this reaction. These re-
nature of the hexafluoroisopropoxyl (HFIP) group
sults clearly showed that NaBH(HFIP)3 is a very useful
(Figure 1). Although hexafluoroisopropanol (HFIP) has
and convenient new reagent for the chemoselective reduc-
tion of the aldehyde 1 over the ketone 2.
recently been used as a unique solvent,7 and NaBH(HFIP)3
was first prepared by Singaram and Williamson,8 the use of
With these favorable results in hand, we next examined
NaBH(HFIP)3 for chemoselective reduction of carbonyl
the generality of the chemoselective reduction using sev-
functions has never been demonstrated. Here, we report
eral aldehydes 5–7, 11, 13 and ketones 8–10, 12, 14, 15.
the first chemoselective reduction of aldehydes over ke-
These results are summarized in Table 2. We found that
tones using NaBH(HFIP)3 in THF in HFIP.
the aldehydes 5–7 possessing benzyl, trityl, and benzoyl
groups, as well as 1, were smoothly reduced by
NaBH(HFIP)3 in THF in HFIP to give the corresponding
We first slightly modified the preparation procedure of
NaBH(HFIP)3 reported by Singaram and Williamson.
Thus, a mixture of NaBH4 and an excess (6.0 equiv) of
primary alcohols in high yields, while the corresponding
HFIP in dry THF (1 M for NaBH4) was stirred at 0 °C for
ketones 8–10 were either not reduced at all or only slightly
reduced. At this stage, it was confirmed that an ester group
15 hours, and then evaporated in vacuo in order to remove
the excess HFIP and the solvent, THF, to give NaBH(HFIP)3
was not reduced by NaBH(HFIP)3 and THF as indicated
as a white solid in almost quantitative yield. At this stage,
in entry 4 in Table 2. Furthermore, not only aliphatic sub-
we found that the solid NaBH(HFIP)3 was too hygroscop-
strates but also aromatic ones were applicable for the
present chemoselective reduction. Thus, as shown in en-
tries 5 and 6, only the aromatic aldehydes 11 and 13 were
effectively reduced by NaBH(HFIP)3 in THF, while the
aromatic ketones 12 and 14 were recovered almost un-
SYNLETT 2008, No. 16, pp 2523–2525
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078217; Art ID: U06108ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

2524
Y. Kuroiwa et al.
LETTER
a
Table 1 Chemoselective Reductions of Aldehyde 1 over Ketone 2 Using NaBH(HFIP)3
OH
TBDPSO
CHO
TBDPSO
1
3
NaBH(HFIP)3, THF
or
or
HFIP
25 °C
O
OH
TBDPSO
TBDPSO
2
4
Entry
NaBH(HFIP)3 (equiv)
Time (h)
Yield (%)b
1
3
2
4
0
0
0
0
0
0
1
2
3
4
5
6
5.0
3.0
1.5
3.0
3.0
3.0
24
24
24
5
0
0
95
97
53
95
92
69
98
99
99
98
99
98
46
0
3
5
1
31
a The reaction using 1 or 2 was separately performed.
b Isolated yields after purification by column chromatography.
OH
TBDPSO
CHO
TBDPSO
1
3 99%
NaBH(HFIP)3, THF
(3.0 equiv)
+
+
HFIP
25 °C, 5 h
OH
O
TBDPSO
TBDPSO
4 0%
2
Scheme 1 Chemoselective reduction of aldehyde 1 in the presence of 2
changed under similar reaction conditions. In addition, the for at least three months, and similar satisfactory results
chemoselective reduction of the aldehyde 1 over the ethyl were obtained in terms of the reduction efficiency and
ketone 15 was also achieved as shown in entry 7 in chemoselectivity.
Table 2.
In conclusion, we found that NaBH(HFIP)3, easily pre-
We further examined the chemoselective reductions using pared from NaBH4 and HFIP, chemoselectively reduced
a mixture of the aldehyde 1 and the ketone 2 in the same aldehydes in the presence of ketones. Furthermore, the
reaction flask, and using the compound 16 possessing NaBH(HFIP)3 in THF solution was stable for at least three
both aldehyde and ketone functionalities in the same mol- months with no decrease in efficiency. The reaction is
ecule. It was found that even with the aldehyde 1 and the very simple and convenient. As reduction reactions of car-
ketone 2 mixed in the same reaction flask, identical bonyl groups are very important steps in organic synthe-
results (yield and chemoselectivity) were obtained sis, this chemoselective reduction method should find
using NaBH(HFIP)3 in THF as shown in Scheme 1. Fur- wide application in both academia and industry.
thermore, only the aldehyde group in compound 169 was
reduced using NaBH(HFIP)3 in THF without the reduc-
O
OTBS
tion of the ketone functionality to give the keto-alcohol
NaBH(HFIP)3, THF
(3.0 equiv)
179 in high yield (Scheme 2).
CHO
HFIP
Finally, we tested whether 1 M NaBH(HFIP)3 in THF was
stable for an extended period of time. Thus, we stored
NaBH(HFIP)3 in THF at –30 °C in a refrigerator for three
months, and we examined the time course of the chemose-
lective reduction using the stored NaBH(HFIP)3 in THF
over the same period. From the results shown in Table 3,
it was confirmed that NaBH(HFIP)3 in THF worked well
16
25 °C, 1.5 h
O
OTBS
OH
17 94 %
Scheme 2 Chemoselective reduction of the aldehyde group over the
ketone function in 16
Synlett 2008, No. 16, 2523–2525 © Thieme Stuttgart · New York

LETTER
Chemoselective Reduction Using Sodium Tris(hexafluoroisopropoxy)borohydride
2525
Table 2 Chemoselective Reductions of Aldehydes over Ketones
Using NaBH(HFIP)3
Table 3 Chemoselective Reductions of Aldehyde 1 over Ketone 2
Using the Stored NaBH(HFIP)3
a
a
NaBH(HFIP)3, THF
(3.0 equiv)
NaBH(HFIP)3, THF
(3.0 equiv)
O
O
OH
R'
OH
or
or
1 or 2
3 or 4
R
H
R
R'
R
R
H
HFIP
25 °C, 5 h
HFIP
aldehyde
ketone
1° alcohol
2° alcohol
Entry Aldehyde Ketone Temp Time Yield (%)b
Entry
Shelf life (weeks)
Yield (%)b
(°C)
(h)
3
4
1° Alco- 2°Alcohol
hol
1
2
3
4
5
6
0
1
95
96
94
92
98
90
0
0
0
0
0
0
1
2
3
4
5
6
7
1
5
2
8
25
0
5
2
5
95
87
91
89
93
82
93
0
12
0
2
6
9
25
25
25
0
3
7
10
12
14
15
0.3
24
0.5
9
4
11
13
1
2
12
14
0
a The reaction using 1 or 2 was separately performed.
b Isolated yields after purification by column chromatography.
25
5
a The reaction using aldehyde or ketone was separately performed.
b Isolated yields after purification by column chromatography.
O
References and Notes
RO
CHO
RO
(1) (a) Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949,
71, 122. (b) Toda, F.; Kiyoshige, K.; Yagi, M. Angew.
Chem., Int. Ed. Engl. 1989, 28, 320.
5 R = Bn
6 R = Tr
7 R = Bz
8 R = Bn
9 R = Tr
10 R = Bz
(2) (a) Ward, D. E.; Rhee, C. K. Synth. Commun. 1988, 18,
1927. (b) Ward, D. E.; Rhee, C. K. Can. J. Chem. 1989, 67,
1206.
O
CHO
O
CHO
(3) Maki, Y.; Kikuchi, K. Tetrahedron Lett. 1977, 263.
(4) Adams, C. Synth. Commun. 1984, 14, 1349.
(5) Zeynizadeh, B.; Shirini, F. J. Chem. Res., Synop. 2003, 335.
(6) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.;
Horaguchi, T. Synth. Commun. 2005, 35, 867.
(7) A review on fluorinated alcohols, see: Bégué, J.-P.; Bonnet-
Delpon, D.; Crousse, B. Synlett 2004, 18.
13
14
OTBDPS
OTBDPS
11
12
TBDPSO
O
15
(8) (a) Golden, J. H.; Schreier, C.; Singaram, B.; Williamson,
S. M. Inorg. Chem. 1992, 31, 1533. (b) Fuller, J. C.;
Karpinski, M. L.; Williamson, S. M.; Singaram, B.
J. Fluorine Chem. 1994, 66, 123.
(9) Analytical Data of Compounds 16 and 17
Compound 16: 1H NMR (300 MHz, CDCl3, TMS): d =
0.036 (6 H, s), 0.88 (9 H, s), 1.26–1.70 (10 H, m), 2.13 (3 H,
s), 2.42 (2 H, t, J = 7.1 Hz), 2.43 (2 H, dt, J = 7.3, 1.8 Hz),
3.65 (1 H, tt, J = 5.6 Hz), 9.77 (1 H, t, J = 1.8 Hz).
Compound 17: 1H NMR (300 MHz, CDCl3, TMS): d =
0.037 (6 H, s), 0.88 (9 H, s), 1.25–1.68 (13 H, m), 2.13 (3 H,
s), 2.42 (2 H, t, J = 7.4 Hz), 3.63 (1 H, m), 3.64 (2 H, t,
J = 6.5 Hz).
Acknowledgment
This research was supported in part by the 21st Century COE Pro-
gram ‘Keio Life-Conjugated Chemistry’ and High-Tech Research
Center Project for Private Universities: Matching Fund Subsidy,
2006-2011, from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan (MEXT).
Synlett 2008, No. 16, 2523–2525 © Thieme Stuttgart · New York