Heterogeneous selective catalytic hydrogenation of aryl ketones to alcohols without additives

Article abstract of DOI:10.1016/j.tetlet.2005.03.159

A selective hydrogenation of different aryl ketones can be obtained by using a heterogeneous copper catalyst under very mild experimental conditions, namely 90°C and 1 atm of hydrogen, without using any kind of additive or poisoning agent.

Full text of DOI:10.1016/j.tetlet.2005.03.159

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3695–3697
Heterogeneous selective catalytic hydrogenation of aryl ketones
to alcohols without additives
a
Federica Zaccheria, Nicoletta Ravasio, Rinaldo Psaro and Achille Fusi
b,
b
a
*
a
Dip. CIMA, Universit a` degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
b
CNR-ISTM, Via Golgi 19, 20133 Milano, Italy
Received 21 February 2005; revised 21 March 2005; accepted 22 March 2005
Available online 6 April 2005
Abstract—A selective hydrogenation of different aryl ketones can be obtained by using a heterogeneous copper catalyst under very
mild experimental conditions, namely 90 °C and 1 atm of hydrogen, without using any kind of additive or poisoning agent.
Ó 2005 Elsevier Ltd. All rights reserved.
Selective reduction of carbonyl compounds by means of
heterogeneous catalysts rather than metal hydrides and
stoichiometric reagents still remains an important goal
for fine chemicals synthesis, both for economical and
environmental concerns. In particular, selective hydro-
genation of aromatic ketones into the corresponding
alcohols is complicated by different kind of side reac-
tions as the aromatic ring hydrogenation, as well as
hydrogenolysis of the produced alcohol (Scheme 1).
This is the case, for example, of the p-isobutylaceto-
phenone hydrogenation for the synthesis of the non-
steroidal anti-inflammatory IbuprofenÒ. Heterogeneous
catalysts reported for this transformation are usually
noble or toxic metal based systems that need the use
of additives to reach high selectivities and that are
efficient only under moderate to high pressure of
1
hydrogen.
We already reported that Cu/SiO can selectively reduce
2
Nevertheless this transformation is a very attracting
target, as it represents a key step in several industrial
processes for pharma and fine chemicals.
differently substituted cyclohexanones under very mild
2
experimental conditions. Unfortunately, with the same
protocol, copper on silica is not likewise selective
towards alcohol formation from aryl ketones. Thus,
the acidity of the catalytic system leads to the formation
of hydrogenolysis products and ethers.
O
OH
Here we wish to report that a very selective transform-
ation can be achieved with a new, milder catalyst pre-
pared by using alumina as support. In particular, Cu/
Al O with a 8% copper contents allows to obtain very
2
3
OH
O
high conversions and selectivities without the need of
any kind of basic additive. Actually, with the conven-
tional heterogeneous systems, the formation of unde-
sired hydrogenolysis products is usually avoided by
3
4
adding amines or NaOH or by designing bimetallic
catalysts in which one of the metals acts as poisoning
5
,6
Scheme 1.
agent, resulting in a more complex and sensitive sys-
tem, both during preparation and use in catalysis.
Keywords: Selective hydrogenation; Acetophenone; Copper catalysts;
Aromatic ketones.
Also with new and non-conventional catalytic systems,
such as the use of supercritical CO as solvent or of
organic polymers as catalyst supports, still remains the
*
Corresponding author. Tel.: +39 02 50314382; fax: +39 02
0314405; e-mail: n.ravasio@istm.cnr.it
2
5
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.159

3696
F. Zaccheria et al. / Tetrahedron Letters 46 (2005) 3695–3697
7
problem of selectivity and the need of basic reaction
8
conditions.
fied with Cr and Fe, in NaOMe solution at 10 atm of
H2 and 90°C to obtain 90.7% of the corresponding
alcohol.
1
1
The most interesting results obtained with Cu/Al O are
3
2
reported in Table 1.
It is worth noting that completely selective reduction of
p-chloro-acetophenone is also possible, although in
longer reaction times, without observing any hydrode-
chlorination products (entry 4a), as on the contrary
2
Respect to the case previously reported, not only the
reaction conditions are very mild, but also the catalyst
reduction can be carried out at 180 °C.
1
2,13
happens with other catalytic systems.
The reaction
rate can be suitably increased by pretreating catalyst at
higher temperature, without observing any significant
changes in selectivity (entry 4b).
Hydrogenation of unsubstituted acetophenone has been
widely studied, in particular, on Pd, Pt, Ni and Ru
9
catalytic systems, but even in this instance the most
0
selective systems are those based on mixed metals.
1
It should be underlined that selective reduction of this
substrate is only reported by using reducing agents such
1
4
15
On the contrary reduction of 4-methoxyacetophenone
has rarely been studied and toxic catalysts and basic
additives are required in order to suppress by-products
formation. Thus Kuhn and Funk report the hydrogen-
ation of 4-methoxyacetophenone with Raney Ni modi-
as metal hydrides or homogeneous systems.
In the hydrogenation of p-isobutylacetophenone, inter-
mediate in the synthesis of IbuprofenÒ, excellent selec-
tivity was obtained and Cu/Al O appears to be
2
3
a
2 3
Table 1. Hydrogenation of different aryl ketones over Cu/Al O
Entry
Substrate
Solvent
t (h)
Conv %
Sel %
O
(
(
(
a) n-Heptane
b) n-Heptane
1.5
5
98
99
98
98
97
b
1
c
c) 2-Propanol, N
2
5
100
O
2
n-Heptane
0.5
.5
96
100
97
90
1
H CO
3
O
3
4
n-Heptane
1.5
96
98
O
O
(a) n-Heptane
(
24
10
82
83
100
94
d
b) n-Heptane
Cl
5
n-Heptane
0.5
1
86
100
94
90
O
6
7
n-Heptane
n-Heptane
7
97
0
98
O
24
—
O N
2
a
b
c
2
Reaction conditions: 100 mg substrate, 100 mg catalyst, 8 mL n-heptane, 90 °C, 1 atm H .
Reaction conditions: 600 mg substrate, 120 mg catalyst, 60 mL n-heptane, 90 °C, 6 atm H
Reaction carried out under transfer hydrogenation conditions.
2
.
d
The catalyst was preactivated at 270 °C instead of 180 °C.

F. Zaccheria et al. / Tetrahedron Letters 46 (2005) 3695–3697
3697
certainly competitive with the other heterogeneous
1
and using Al O from Grace Davison as support
2 3
(BET = 280 m /g, PV = 1.75 mL/g). Before reaction,
the catalyst obtained (Cu = 8% by weight) was reduced
2
catalysts reported so far, especially for the very mild
working conditions.
at 180 °C with H (1 atm) before use, removing water
2
As far as productivity is concerned, a catalytic run with
catalyst/substrate ratio of 1/5 by weight under 6 atm of
H (entry 1b) showed that this system can be proposed
formed under reduced pressure.
Experimental conditions: a solution of the substrate
(100 mg) in anhydrous n-heptane (8 mL) was transferred
under N in the reaction vessel containing the catalyst
2
as a valuable alternative to both toxic metal based Ni
1
Raney and noble metal based Pd–C.
6
2
previously reduced (100 mg). Catalytic tests were carried
out at 90 °C at atmospheric pressure of hydrogen under
magnetic stirring. Reaction mixtures were analyzed
by GC (5% phenyl–95% methylpolysiloxan capillary
Finally the reduction of p-isobutylacetophenone can be
conveniently done also in absence of hydrogen, by using
hydrogen transfer conditions (entry 1c). In fact this cat-
alyst shows also excellent performances in secondary
alcohol dehydrogenation, that can be exploited for their
1
column, 30 m) and by H NMR.
1
7
oxidation in the presence of an hydrogen acceptor or
for selective transfer hydrogenation from 2-propanol.
References and notes
From the results obtained (entries 1, 2 and 5) is apparent
that electron donating substituents accelerate the hydro-
genation, whereas the nitro group (entry 7) completely
suppresses reaction, anyway not leading to any kind of
side products but leaving the reagent unchanged.
1
2
3
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Catal. Today 1999, 49, 49–56, and ref. therein.
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2
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. Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57,
817–4824.
4
Control experiments showed that hydrogenation of
p-isobutylacetophenone is completely inhibited by the
presence of nitrobenzene, but not by the presence of
aniline, although in this case relevant amounts of by-
products were formed. This shows that the inactivity of
p-nitro-acetophenone over Cu/Al O may be due not only
to electronic effects but also to functional group incom-
patibility of the starting compound. On the other hand
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tion rate, as shown by the slower reduction of propi-
ophenone respect to acetophenone. In this molecule,
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9
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2
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as well as in the case of cyclohexanones.
So far, no other heterogeneous catalytic system allows
such mild and simple conditions for selective and gen-
eral aryl ketones hydrogenation, avoiding the use of
any additive or poisoning agent.
1
1
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2
3
3
39.
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The catalyst can be prepared in a simple way and it is
neither pyrophoric nor pyrogenic even in the reduced
state. The use of a truly heterogeneous catalyst and its
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organic wastes.
1
1
3
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1
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1
8
2þ
already reported starting from ðCuNH3Þ4 solution
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