Cu/SiO2-catalyzed hydrogenation of cyclohexanones under very mild conditions

Article abstract of DOI:10.1016/S0040-4039(02)00671-8

Unsubstituted and alkyl-substituted cyclohexanones, including 3-oxo-steroids, can be easily hydrogenated to the corresponding alcohols at 1 atm of H₂ and 60-90°C over a 8% Cu/SiO₂ non-toxic, reusable catalyst with excellent selectivity.

Full text of DOI:10.1016/S0040-4039(02)00671-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3943–3945
Cu/SiO -catalyzed hydrogenation of cyclohexanones under very
2
mild conditions
a,
a
b
Nicoletta Ravasio, * Rinaldo Psaro and Federica Zaccheria
a
CNR ISTM, Via Golgi, 19, 20133 Milano, Italy
b
Dipartimento di Chimica IMA, Universit a` degli Studi di Milano, Via Venezian, 21, 20133 Milano, Italy
Received 25 February 2002; accepted 26 March 2002
Abstract—Unsubstituted and alkyl-substituted cyclohexanones, including 3-oxo-steroids, can be easily hydrogenated to the
corresponding alcohols at 1 atm of H and 60–90°C over a 8% Cu/SiO non-toxic, reusable catalyst with excellent selectivity.
2
2
©
2002 Published by Elsevier Science Ltd.
In the fine chemical industry, reduction of carbonyl
groups mainly relies on the use of complex metal
hydrides, sodium dihydrobis-(2-methoxyethoxy)-alumi-
All substrates were reduced to the corresponding alco-
hols at 60 or 90°C and 1 atm H , reaction rates
2
increasing with the number of alkyl groups. Preliminar
tests on 4-tert-butyl-cyclohexanone showed that this
substrate can be easily hydrogenated even at 40°C. This
high activity is coupled with excellent selectivity
towards alcohol formation. Thus, only for more substi-
tuted substrates less than quantitative yields were
obtained, probably owing to formation of dehydration
products (entry 5 and 6). However, in these cases
evaporation of the solvent allowed to remove also
volatile by-products and no further purification of the
alcohol was needed.
®
®
nate, commercialized as RedAl or Vitride , being one
1
of most used.
The catalytic hydrogenation of aliphatic ketones can be
carried out in the presence of noble metals, usually Pt
and Ru at 25–60°C and 1–5 atm H , or in the presence
2
of Cu chromites and Ni catalysts. However, non-noble
2
metal catalysts require about 50 atm of pressure and
temperatures higher than 100°C. Hydrogenation of 3-
methyl-cyclohexanone e.g. has been reported to occur
under 125 atm H and 140°C in 2 h with a 5% by
2
3
weight of catalyst whereas a 1:1 catalyst/substrate ratio
The 3-oxo group of steroidal ketones was easily
reduced, even at 60°C. This reduction was found to be
selective with respect to the hydrogenation of a 17-oxo
group (entry 9). It is also worth noting that this catalyst
is much more active than the previously reported Cu/
was needed to carry out the reduction at atmospheric
4
pressure and room temperature.
We already reported on the use of supported copper
catalysts in the chemoselective hydrogenation of a,b-
unsaturated ketones giving quantitative yields in the
corresponding saturated ketone also when another
6
Al O , that was used in a 1:1 molar ratio. Moreover
2
3
Cu/SiO was found to be reusable without loss neither
2
5
in activity nor in selectivity (entries 3a–3c).
olefinic bond is present in the molecule. Saturated
alcohols were formed only in a well separated step and
As far as stereoselectivity is concerned, the more stable
epimer was always preferred at atmospheric pressure
and 90°C, but a significant effect of the temperature
was observed for the activated substrates. Thus, at
often required the use of a higher pressure of H . Here
2
we wish to report that hydrogenation of the carbonyl
group in a series of substituted cyclohexanones can be
conveniently carried out under very mild experimental
6
0°C important amounts of the axial epimer were
conditions by using a supported 8% Cu/SiO catalyst.
2
formed particularly for 4-tert-butyl-cyclohexanone and
Results obtained for a series of substituted cyclohex-
anones are reported in Table 1.
3,3,5-trimethyl-cyclohexanone (entries 5 and 6).
Preliminary experiments on a few open chain unsatu-
rated ketones show this catalyst to be active and
chemoselective also for such compounds.
Keywords: copper catalysts; cyclohexanones; hydrogenation.
*
Corresponding author. Tel.: +39-2-50314382; fax: +39-2-50314405;
7
e-mail: nravasio@csmtbo.mi.cnr.it
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00671-8

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N. Ra6asio et al. / Tetrahedron Letters 43 (2002) 3943–3945
Table 1. Reduction of alkylcyclohexanones over Cu/SiO2
Only 2-methyl-cyclohexanone could not be hydro-
genated under these conditions (entry 2). This sub-
strate was reduced only sluggishly even under 6 atm of
active site. According to this hypothesis only cis-dihy-
drocarvone, with a methyl group at C2 but in axial
position, was readily hydrogenated under mild con-
ditions, leaving the trans isomer unaffected (Scheme
1).
H . As INDO calculations revealed that the carbonyl
2
groups of 2-, 3- and 4-methyl-cyclohexanones are
8
nearly identical in charge distribution, this may be
due to the steric hindrance of the equatorial methyl
group inhibiting the access of the substrates to the
Molecular mechanics calculations showed that in the
more stable conformers of both 2-methyl-cyclohex-

N. Ra6asio et al. / Tetrahedron Letters 43 (2002) 3943–3945
3945
anone and trans-dihydrocarvone the carbonyl group
and the methyl substituent are totally eclipsed.
(8 ml) and the solution transferred, under H
2
into a
glass reaction vessel where the catalyst (0.1 g for entries
–7; 0.05 g for entries 8 and 9) had been previously
1
reduced. Reactions were carried out at 90 or 60°C at
atmospheric pressure with magnetic stirring. Reaction
mixtures were analyzed by GC (mesitylene as internal
standard). After completion the catalyst was filtered
off, the solvent removed under reduced pressure and
Total chemoselectivity towards formation of the unsat-
urated alcohol was observed in the hydrogenation of
cis-dihydrocarvone. However, 2-PrOH was the solvent
of choice in order to avoid acid-catalyzed side reactions
9
already observed with this substrate.
1
the equatorial/axial ratio evaluated by H NMR spec-
troscopy. Recycling tests were performed starting from
The advantages of using Cu/SiO2 instead of metal
hydrides are quite evident. Thus, the latter are used in
more than stoichiometric amounts, require time-con-
suming work-up procedures, produce a large amount of
inorganic wastes and do not allow tuning of the
configuration of the products. Moreover, this copper
catalyst would be competitive also with Raney Ni that
usually requires vigorous conditions unless large
0
.4 g of substrate, washing the catalyst recovered with
diethylether and reactivating it by hydrogenation before
use. Isolated yields were determined on a 0.5 g scale
experiment. HyperChem Release 5.0 for Windows was
®
used for molecular mechanics calculations.
Acknowledgements
2
,3,10
amounts of catalyst are used.
Furthermore, safety
and environmental concerns claim for the use of this
catalyst. We can suggest Cu/SiO as an efficient alterna-
tive to metal hydrides and conventional copper and
nickel catalysts.
2
The authors gratefully thank the CNR-MIUR for
financial support through the ‘Program Chemistry
LAW 95/95-III year’
Catalyst preparation: the catalyst was prepared as
5
2+
already reported starting from a Cu(NH )
solution
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4
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Scheme 1.