Simple Reduction of Various Ketones with Sodium Tetrahydroborate and Alumina in Hexane

Article abstract of DOI:10.1039/a709081a

A combination of NaBH₄ and alumina preloaded with a small amount of water is a highly efficient reducing agent for cycloalkanones, substituted cyclohexanones and unsaturated and aromatic ketones in hexane, affording the corresponding alcohols in excellent yields under mild conditions (20-60°C).

Full text of DOI:10.1039/a709081a

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3
22 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
Simple Reduction of Various Ketones with Sodium
Tetrahydroborate and Alumina in Hexane$
Shigetaka Yakabe, Masao Hirano,* James H. Clark and
1998, 322±323$
a
a
b
a
Takashi Morimoto
a
Department of Applied Chemistry, Faculty of Technology, Tokyo University of Agriculture
and Technology (TUAT), Koganei, Tokyo 184-8588, Japan
b
Department of Chemistry, University of York, Heslington, York YO1 5DD, UK
A combination of NaBH4 and alumina preloaded with a small amount of water is a highly efficient reducing agent
for cycloalkanones, substituted cyclohexanones and unsaturated and aromatic ketones in hexane, affording the corre-
sponding alcohols in excellent yields under mild conditions (20±60 8C).
There are many reagents and methodologies available for
the catalytic and stoichiometric reduction of a broad range
1
of functional groups. Sodium tetrahydroborate (NaBH ) is
4
2
one of the most extensively employed hydride donors,
owing to its mild reducing capability and versatility. In
addition, its insensitivity to moisture and relatively easy
‡
‡
2‡
exchangeability of the Na ion for other cations (Li , Ca ,
2‡
2‡
3‡
4‡ 2
Ba , Zn , Al , Sn
reducing power, chemo- and/or stereo-selectivities make
NaBH very attractive as a major laboratory synthetic
) to produce agents with di€erent
4
2,3
reagent.
Recently, we have observed that in situ generated
alumina-supported reagents can be successfully used for
the selective oxidation of sul®des, alcohols,
f
ketones and the regioselective nuclear monochlorination of
4
a±c
4d,e
and
4
4g,h
activated arenes
in water-free media. The remarkable
ability of alumina to catalyse the reactions under mild
conditions led us to investigate the reduction of organic
compounds with a combination of NaBH
Although alumina-supported NaBH reagents are known to
4
and alumina.
4
5,6
e€ect reductions
and some of these are now available
from commercial sources (Aldrich, Fluka, etc.), their prep-
aration is time-consuming (i.e. a few hours' thorough mixing
of alumina and aqueous NaBH , followed by overnight
4
5b
drying in vacuo) and commercial reagents are rather ex-
pensive. Consequently, it is of value to provide a convenient
Scheme 1
reduction method based on the use of NaBH
solution biphasic conditions by taking advantages of our
4
under solid-
cyclohexanone 1b, 2-methylcyclohexanone 1f, and 2-tert-
butylcyclohexanone 1i under the conditions of Entry 2
showed that their conversions were 100, 78, and 44%,
respectively, clearly indicating that their apparent reactivities
4,7
in situ method.
The reduction of a ketone 1 was carried out instantly by
eciently stirring a heterogeneous mixture of NaBH , 1,
4
towards NaBH decrease as the substituents adjacent to the
4
and hexane under a dry atmosphere in the presence of chro-
matographic neutral alumina preloaded with the optimum
amount of water (moist alumina; vide infra). The reaction
was clean and did not su€er from the formation of any
by-product, and therefore essentially pure alcohol 2 was
obtained simply by ®ltration of the insoluble materials and
removal of the solvent from the combined ®ltrate and wash-
Table 1 Reduction of ketones to the alcohols with NaBH
moist alumina in hexane
4
and
a
NaBH
Entry Ketone (mmol) T/8C t/h
4
moist
Al O /g (%)
Alcohol
b
2
3
1
2
3
4
5
6
7
8
9
1
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1n
0.3
0.3
0.3
0.5
0.6
0.4
0.3
0.3
0.8
0.5
0.3
0.3
0.3
0.4
16
20
20
20
30
60
30
20
20
40
30
40
40
40
60
60
1
1
3
3
3
3
1
1
3
3
3
3
3
3
3
0.5
0.5
0.5
1.0
0.5
1.0
0.5
0.5
1.5
1.0
0.5
0.5
0.5
0.5
10
2a (97)
2b (92)
2c (quant.)
2d (quant.)
2e (98)
2f (87)
2g (93)
2h (91)
2i (quant.)
2j (quant.)
2k (96)
ings. The applicability of the NaBH /moist alumina system
4
for typical ketones is summarised in Scheme 1 and Table 1.
Thus, simple C ±C alicyclic ketones 1a±e (Entries 1±5),
5
12
substituted cyclohexanones 1f±j (Entries 6±10), and aro-
matic ketones 1m and 1n (Entries 13 and 14, respectively)
were readily reduced to a€ord the corresponding alcohols in
excellent to quantitative yields under optimum conditions.
Successful reduction of the steroidal ketone 1k (Entry 11)
and the unsaturated ketone 1l (Entry 12) might extend the
utility of the current procedure. Independent reactions of
0
1
12
2l (quant.)
2m (98)
2n (98)
13
14
15
c
2n (quant.)
*To receive any correspondence.
a
b
Ketone 1 mmol, hexane 10 ml. Isolated yield of 2 based on the
$This is a Short Paper as de®ned in the Instructions for Authors,
c
starting 1. Benzophenone 1n: 40 mmol (7.28 g), hexane 50 ml,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
and ether washing (5 Â30 ml) were used.

View Online
J. CHEM. RESEARCH (S), 1998 323
1
carbonyls (R in Scheme 1) increase in size. This fact might
carried out under the conditions indicated in Entry 15 to a€ord 2n
quantitatively.
suggest that the steric hindrance of the alkyl groups plays
an important role in determining the reactivities of the
ketones. The current procedure can favorably be compared
to the reduction with the preformed alumina-supported
The authors wish to thank Dr Masahiro Natsume for
the provision of GC±MS facilities at TUAT. One of us
(J.H.C.) would like to thank the RAEng/EPSRC for a
Clean Technology Fellowship.
5
b
NaBH4 reagent. Indeed, the reduction of benzophenone
n gave benzhydrol 2n in superior yield (98%) to that
obtained by the earlier procedure, in which crude 2n was
1
5b
obtained in 88% yield. Finally, an attempted reduction of
n on a large (40 mmol) scale was accomplished successfully
Received, 18th December 1997; Accepted, 9th February 1998
Paper E/7/09081A
1
(
Entry 15).
In conclusion, the in situ generated alumina-supported
4
NaBH reagent serves as a convenient, inexpensive and
References
high-yielding reduction system for various ketones under
mild conditions.
1
(a) H. O. House, Modern Synthetic Reactions, W. A. Benjamin,
California, 1972, ch. 1±4, (b) J. March, Advanced Organic
Chemistry. Reactions, Mechanisms, and Structure, Wiley, New
York, 1992, 4th edn., ch. 19; (c) M B. Smith, Organic Synthesis,
McGraw-Hill, New York, 1992, ch. 4; (d) J. S. Pizey, Synthetic
Reagents, Ellis Horwood, Chichester, 1974, vol. 1, ch. 2; (e) C. F.
Lane, Synthesis, 1975, 135; ( f ) J. M. Khurana and A. Gogia,
Org. Prep. Proced. Int., 1997, 29, 3.
Experimental
1
General.ÐThe H NMR spectra were recorded on a JEOL PMX-
6
0 (60 MHz) spectrometer for solutions using deuteriochloroform
with TMS as an internal standard. Analytical gas chromatography
was performed on Shimadzu GC-14B instrument with
a
a
2 For example, see ref. 1(c), section 4.5.B.
2
m 4 mm diameter column packed with 5% PEG-20 M on
3 See Ref 1(a), ch. 2; ref. 1(b), ch. 19, pp. 1206±1223.
4 (a) M. Hirano, S. Yakabe, S. Itoh, J. H. Clark and T. Morimoto,
Synthesis, 1997, 1161; (b) M. Hirano, S. Yakabe, J. H. Clark
and T. Morimoto, J. Chem. Soc., Perkin Trans. 1, 1996, 2693;
(c) M. Hirano, S. Yakabe, J. H. Clark, H. Kudo and
T. Morimoto, Synth. Commun., 1996, 26, 1875; (d) M. Hirano,
S. Nagasawa and T. Morimoto, Bull. Chem. Soc. Jpn., 1991,
64, 2857; (e) M. Hirano, H. Kuroda and T. Morimoto, Bull.
Chem. Soc. Jpn., 1990, 63, 2433; ( f ) M. Hirano, M. Oose
and T. Morimoto, Chem. Lett., 1991, 331; (g) M. Hirano,
S. Yakabe, H. Monobe, J. H. Clark and T. Morimoto, J. Chem.
Soc., Perkin Trans. 1, 1997, 3081; (h) M. Hirano, S. Yakabe,
H. Monobe, J. H. Clark and T. Morimoto, Synth. Commun.,
1997, 27, 3749.
5 (a) F. Hodosan and N. Serban, Rev. Roum. Chim., 1969, 14, 121;
(b) E. Santaniello, F. Ponti and A. Manzocchi, Synthesis, 1978,
891; (c) E. Santaniello, C. Farachi and A. Manzocchi, Synthesis,
1979, 912.
6 See E. Santaniello, Preparative Chemistry using Supported
Reagents, ed. P. Laszlo, Academic Press, San Diego, 1987, ch. 18,
p. 181 and 182; J. M. Maud, Solid Supports and Catalysis in
Organic Synthesis, ed. K. Smith, Ellis Horwood, Chichester, 1992,
p. 356 and 357.
Chromosorb WAW-DMCS, with temperature programming. Mass
spectra were determined on a JEOL SX-102A mass spectrometer
coupled to a Hewlett-Packard GC5890 Series II GC apparatus via
a heated capillary column.
Starting Materials.ÐHexane was rigorously dried (CaCl
tilled and stored over molecular sieves. Commerical NaBH
ground to a ®ne powder in a dry-box and stored in a desiccator.
Ketones 1a±n were available from commercial sources and used
without further puri®cation. Moist alumina (water content 10 wt%)
was prepared by adding deionised water (0.05 g) to predried
2
), dis-
was
4
(
0
500 8C, 6 h) alumina (ICN BIOMEDICALS, Alumina N, Super I;
.45 g) in portions, followed by vigorous shaking of the mixture on
every addition for a few minutes until a free-¯owing powder was
obtained, which was immediately used for the reduction.
Typical Reduction Procedure.ÐA heterogeneous mixture of
benzophenone 1n (1 mmol; 0.182 g), hexane (10 ml), ®nely ground
NaBH
(
4
(0.4 mmol; 0.151 g) and freshly prepared moist alumina
0.5 g) in a 30 ml round-bottom ¯ask was vigorously stirred for 3 h
at 60 8C. The cooled reaction mixture was transferred onto a
sintered glass funnel, and the ®lter cake thoroughly washed with
portions of dry diethyl ether (ca. 60 ml). Removal of the solvent
from combined clear ®ltrate on a rotary evaporator gave satisfac-
torily pure (GC, NMR, and TLC) benzhydrol 2n in 98% yield
(
/moist alumina
7 J. H. Clark, Catalysis of Organic Reactions by Supported
Inorganic Reagents, VCH, New York, 1994; J. H. Clark, A. P.
Kybett and D. J. Macquarrie, Supported Reagents. Preparation,
Analysis, and Applications, VCH, New York, 1992; Preparative
Chemistry Using Supported Reagents, ed. P. Laszlo, Academic
Press, San Diego, 1987; Solid Supports and Catalysis in
Organic Synthesis, ed. K. Smith, Ellis Horwood, Chichester, 1992;
M. Balogh and P. Laszlo, Organic Chemistry Using Clays,
Springer, Berlin, 1993.
8
0.180 g): mp 63.2±63.8 8C (lit., mp 65±67 8C).
The reductions of ketones 1a±m with the NaBH
4
system were performed under conditions determined in terms of
their reactivity and the yield of 2, followed by the normal work-up,
a€orded alcohols 2a±m, which were fully characterised by spectro-
scopic comparisons (IR, NMR, and MS) with commercial authentic
samples. It is noteworthy that although certain ketones and alcohols
have only limited solubilities in hexane under the conditions
employed, the reduction of the ketones and work-ups of the
products were readily achieved. A large-scale reduction of 1n was
8 Dictionary of Organic Compounds, Chapman and Hall, London,
6th edn., 1996.