Bifunctional copper catalysts for an atom efficient ether synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.06.123

A direct etherification of aromatic ketones and aliphatic alcohols into the corresponding asymmetrical ethers by the use of a bifunctional heterogeneous copper catalyst is described. The reaction protocol reveals to be versatile and convenient respect to the traditional ether synthesis for both environmental and practical concerns.

Full text of DOI:10.1016/j.tetlet.2009.06.123

Tetrahedron Letters 50 (2009) 5221–5224
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Tetrahedron Letters
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Bifunctional copper catalysts for an atom efficient ether synthesis
*
Federica Zaccheria, Rinaldo Psaro, Nicoletta Ravasio
ISTM-CNR, Via Golgi 19, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct etherification of aromatic ketones and aliphatic alcohols into the corresponding asymmetrical
ethers by the use of a bifunctional heterogeneous copper catalyst is described. The reaction protocol
reveals to be versatile and convenient respect to the traditional ether synthesis for both environmental
and practical concerns.
Received 5 June 2009
Revised 24 June 2009
Accepted 29 June 2009
Available online 3 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Ether synthesis
Atom efficiency
Halide free
Heterogeneous catalysts
Bifunctional catalysts
1. Introduction
lites4 or heteropolyacids.5,6 However this method is particularly
proper for symmetrical ethers.
The search for low-waste technologies and multifunctional pro-
cesses in organic synthesis is becoming more and more pressing
for both economical and environmental concerns. In fact the use
of traditional stoichiometric reagents for the preparation of organic
molecules is still widely common, especially due to their high
activity and specificity.
Ether formation is an important reaction in organic synthesis,
for both bulk and fine chemicals preparation, and it is traditionally
performed with the Williamson reaction starting from an alcohol
and a halide by using a strong base for the alkoxide formation.1
Actually, the reaction is particularly useful for the preparation of
mixed ethers, as it involves the direct nucleophilic displacement
of halogen in the alkyl halide by the alkoxide ion. On the other
hand, it is synthetically effective only when a primary alkyl halide
is used, due to the competitive elimination reaction observed with
the secondary or tertiary ones.2 Moreover, the use of the conditions
requested strongly limits the industrial applications, but above all
imposes serious environmental and economical concerns due to
waste disposal processes.
In a recent communication, Sn-Beta has been reported as active
heterogeneous Lewis acid for the asymmetric etherification of ben-
zylic alcohols and aliphatic ones.7 This system proved to be water
resistant and highly selective with different benzylic substrates
and mainly primary aliphatic alcohols. Actually, as already pointed
out by the authors, the weak point of traditional Lewis acids re-
sides in their sensitivity to water produced during the reaction.
Another efficient and direct access to asymmetrical ethers could
be the hydroalkoxylation reaction, based on the nucleophilic attack
of an alcohol to a C–C double bond. This strategy, even if attractive,
revealed to be practicable only in the case of highly activated al-
kenes, otherwise requiring the use of strong Lewis acids8,9 or noble
metal complexes.10,11
In the particular case of aromatic compounds it is quite evident
that the optimal route should start from the carbonyl derivatives.
Actually they are the first intermediates in the functionalisation
of aromatics by means of the Friedel–Crafts acylation and their
use conveniently fits with the purpose of minimising the number
of synthetic steps.
Thus, to avoid the use of bases and halide reagents could be a
successful strategy in order to set up a cleaner and simple protocol.
Brønsted acid catalysts are known to promote ether formation
starting from the corresponding alcohols by means of a dehydra-
tion process.3 This strategy is especially employed in the vapour
phase synthesis of dialkyl ethers as ETBE or diethylether with zeo-
In this Letter, we would like to report on the use of a heteroge-
neous copper catalyst supported over commercial mixed oxides in
the one-pot transformation of an aromatic ketone and an aliphatic
alcohol into the corresponding asymmetrical ether under very mild
experimental conditions and without the need of any additive for
water removal. Actually, the use of a bifunctional system, able to
promote both hydrogenation and acid-catalysed reactions, would
allow to plan a cascade process directly starting from carbonyl
compounds. Moreover, a reliable and robust heterogeneous cata-
lyst avoids the formation of undesirable inorganic wastes.12
* Corresponding author. Tel.: +39 02 50314382; fax: +39 02 50314405.
E-mail address: n.ravasio@istm.cnr.it (N. Ravasio).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.123

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F. Zaccheria et al. / Tetrahedron Letters 50 (2009) 5221–5224
Table 2
2. Results and Discussion
Etherification reaction starting from 4-methoxyacetophenone and different alcohols
(T = 60 °C, P = 1 atm H2) in n-heptanea
The reaction between 4-methoxyacetophenone and a series of
alcohols with a copper catalyst supported over an amorphous silica
alumina allows one to easily obtain the corresponding asymmetri-
cal ether in a one-pot one-step reaction with a very high conver-
sion and selectivity (Scheme 1 and Table 1).
No symmetrical ether formation was observed, the only by-
products formed in very low amount being those resulting from
ketone deoxygenation. The minimisation of these by-products is
not trivial, as the reductive deoxygenation of ketones is particu-
larly favoured in the presence of acidic systems.13 In the present
case, the use of the alcohol, besides the synthetic role, is crucial
in order to tune the catalyst acidity. In fact, the use of an alcohol
as solvent has already been exploited in other synthetic applica-
tions in order to suppress the formation of by-products deriving
from the catalyst acidity.14
Alcohol
2-PrOH
Product
H3CO
H3CO
H3CO
t (h)
Conv (%)
100
Sel (%)
97
O
O
O
5
Ethanol
5
3
100
100
70
94
96
89
99
97
Cyclopentanol
2-Ph-Ethanolb
2-Butanol
In order to widen the application field and the pool of aliphatic
alcohols we carried out some experiments by reducing the alcohol
content and by using a hydrocarbon as solvent.
7
O
O
The reaction temperature, the solvent nature and the ketone/
alcohol molar ratio are all relevant parameters in order to selec-
tively obtain the asymmetrical ether. In particular, by lowering
the alcohol/ketone ratio the symmetrical ether formation becomes
significative. On the other hand the temperature has a significant
effect on the deoxygenation product formation. A good compro-
mise among the conditions tested was represented by the use of
n-heptane at 60 °C, with a ketone/alcohol ratio of 1/10.
H3CO
H3CO
3
90
O
Methanol
24
90
In Table 2 results obtained by varying the aliphatic alcohol are
summed up. From these data it is evident that it is possible to
use a wide series of alcohols, observing in all cases very high con-
version and selectivity values, as a general trend more nucleophilic
alcohols reacting faster. The excellent conversions obtained, show
that the water formed during etherification does not affect the cat-
alyst activity, therefore not requiring any additive or mechanical
device for its removal.
The protocol can be easily applied to different aromatic sub-
strates, as shown in Table 3. Moreover results and intermediates
obtained with the different ketones can help to elucidate some as-
pects of the reaction pathway.
The first important information derives from the very low
activity observed with 3-methoxyacetophenone and the longer
reaction times necessary for 4-isobutylacetophenone and 4-
methoxybenzaldehyde.
Moreover, the reaction profile obtained for the etherification
starting from 4-isobutylacetophenone and 2-propanol (Fig. 1),
clearly shows the formation of 4-isobutylphenylethanol as the
H3CO
a
60 °C, ketone/alcohol = 1/10 mol/mol.
Ketone/alcohol = 1/2 mol/mol.
b
intermediate, not detected with the other substrates under the
present conditions.
These evidences strongly suggest that the etherification reac-
tion proceeds through the carbonyl reduction and the nucleophilic
attack of the aliphatic alcohol to the benzylic carbon of the aro-
matic one, activated by the Lewis sites present on the catalyst sur-
face, namely Al3+ ions. The more stabilised the incipient
carbocation, the faster the reaction. Nevertheless, in the case of
highly activated substrates, a direct addition to the carbonyl com-
pound cannot be excluded.
On the other hand, some interesting insights on the active site
responsible for the reaction can be obtained by the use of different
O
100
80
60
40
20
0
R
O
R1
R2
OH
Cu cat
O
+
R
R2
1 atm H2
H3CO
R1
H3CO
O
Scheme 1. Direct ether synthesis from 4-methoxyacetophenone and alcohols.
OH
Table 1
Etherification reaction starting from 4-methoxy acetophenone and different alcohols
as solvent (T = 80 °C, P = 1 atm H2) by using Cu/SiO2–Al2O3 as catalyst
Alcohol
R
R1
R2
t (h)
Conv (%)
Sel (%)
0
5
10
15
2-PrOH
2-BuOH
Iso-BuOH
Di-iPr-carbinol
Me
Me
H
Me
Et
H
H
H
iPr
H
1.5
1.5
2.5
4
100
100
100
100
98
98
95
90
t (h)
Figure 1. Etherification reaction starting from 4-isobutylacetophenone and 2-
propanol (T = 80 °C, P = 1 atm H2) in n-heptane.
iPr
iPr

F. Zaccheria et al. / Tetrahedron Letters 50 (2009) 5221–5224
5223
Table 3
Table 4
Etherification reaction starting from different aromatic ketones and 2-propanol
Etherification reaction starting from 4-methoxyacetophenone (under H2) or 1-(4-
(T = 60 °C, P = 1 atm H2) in n-heptane or toluene.
methoxy)-phenylethanol (under N2) and 2-propanol as a solvent (T = 80 °C)
Ketone
t (h)
Conv (%)
100
Sel (%)
97
Catalyst
Substrate
t (h)
Conv (%)
Sel (%)
1
2
3
4
5
6
7
SiO2
SiO2–Al2O3
SiO2
SiO2–Al2O3
Cu/SiO2–Al2O3
Cu/SiO2
p-OMe-Acetophenone
p-OMe-Acetophenone
p-OMe-Phenylethanol
p-OMe-Phenylethanol
p-OMe-Acetophenone
p-OMe-Phenylethanol
p-OMe-Acetophenone
24
24
24
1
1.5
1.5
8
0
0
0
95
100
96
100
—
—
—
97
98
98
99
O
5
H3CO
H3CO
Cu/SiO2
O
7
100
100
98
95
tems is peculiar for the features of metal accounting for high dis-
persion of the copper phase.18,19
The chance to prepare an active copper catalyst by using an eas-
ily available silica makes these catalytic systems highly appealing
from the practical point of view.
Moreover, Cu/SiO2, although for longer reaction times, allows
one to set up the one-pot one-step reaction between 4-methoxy-
acetophenone and 2-propanol (entry 7), thus giving the ether
and showing that copper plays a major role in the reaction, pro-
moting both reduction and activation of the substrate.
It is worth underlining that the preparation of the same ether,
compound with a pleasant aniseed-like smell, is not trivial. Its syn-
thesis, scarcely described in the literature, has been recently re-
ported to be performed with a quite complex protocol based on a
multistep hydrohalogenation/hydroalkoxylation of styrene pro-
moted by a homogeneous Pd catalyst combined with a copper
one in the presence of oxygen, DCE and 2-propanol.20
O
O
O
16
O
20
90
96
OH
O
28
100
98
86
91
16a
O
24
24
92
100
13b
H3CO
3. Conclusions
O
Further studies towards a deeper insight into the reaction
mechanism, substrate scope and the synthetic application are cur-
rently ongoing, besides the opportunity to extend the catalytic
activity also to the hydroalkoxylation of C–C double bonds.
In spite of some homogeneous methods based on preformed si-
lane or alkoxysilane of the alcohol,21–23 few heterogeneous metal
catalysts effective for the direct etherification starting from ke-
tones and alcohols are reported so far. In particular, noble metal-
based systems, namely Pd and Pt, are described to be active in
the etherification of aliphatic ketones or aldehydes only with alco-
hols but request high pressure of H2,24 or water removal
solutions.25
It should be stressed that our reaction protocol is particularly
attractive if analysed from both the environmental and economical
point of view. Actually, considering that water is the only by-prod-
uct and that the catalyst can be recovered after filtration, the over-
all atom efficiency calculated in the case of 2-propanol and 4-OMe-
acetophenone reaches 90. This is even more important if we con-
sider that Cu/support allows one to perform a one-pot one-step
synthesis starting directly from the carbonyl compound.
The bifunctional process allows to substitute the use of metallic
hydrides for the hydrogenation step and to circumvent the typical
drawbacks of the traditional etherification reactions, avoiding the
use of halides and strong bases, and in consequence, the formation
of wastes demanding to be disposed off.
100
H3CO
a
Reaction carried out at 80 °C.
Main by-product being the substituted phenylethanol.
b
oxides for the catalyst preparation (Table 4). Actually, the bare
acidic support (SiO2–Al2O3), even if predictably inactive with the
ketone (entry 2), reveals a very high activity in the etherification
reaction starting from 1-(4-methoxy)-phenylethanol (entry 4),
thus showing enough acidity itself for this specific reaction. These
data are in agreement with results obtained by Corma on the for-
mation of asymmetric ethers from two alcohols over Sn-Beta
showing Lewis acid character. Actually, the here described mixed
oxides, with a very low content in alumina (0.6–1.5%) already
showed a remarkable acidic character in a-pinene oxide isomerisa-
tion, often used as a test reaction for a qualitative evaluation of
acidic sites,16 and in the ene reaction of citronellal into
isopulegol.17
The bifunctional property of the silica alumina copper sup-
ported catalyst used in the present work arises from the presence
of a redox site (copper) and an acidic one in the same system.
These two sites could in principle work one independently from
the other.
On the contrary the use of a non-doped pure silica does not lead
to any reaction (entries 1 and 3) starting from both the ketone and
the alcohol, whereas the copper catalyst prepared over the same
support (entry 6) shows an activity comparable to the one of the
bare silica alumina when starting from the two alcohols (entry 6
vs entry 4). This is a clear evidence that the well-dispersed metallic
phase can express an outstanding Lewis acidic character. Actually
the technique employed for the preparation of these catalytic sys-
4. Experimental
SiO2–Al2O3 (0,6% wt of Al2O3, PV = 1.45 mL/g, SA = 500 m2/g)
was kindly supplied by Grace Davison (Worms, D) and SiO2
(PV = 0.75 mL/g, SA = 500 m2/g) from Aldrich. Copper catalysts
were prepared by a chemisorption-hydrolysis technique as already
reported15 starting from a [Cu(NH3)4]2+ complex solution. The bare

5224
F. Zaccheria et al. / Tetrahedron Letters 50 (2009) 5221–5224
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supports were dehydrated at 270 °C in air for 30 min, then 30 min
in vacuo. The metal catalysts were treated in the same way and re-
duced before reaction at 270 °C and 1 atm H2.
All the substrates used were purchased from Sigma Aldrich, ex-
cept 4-methoxyphenylethanol which was prepared as already re-
ported by using the same class of copper catalysts described
herein.26 A typical etherification reaction with the aliphatic alcohol
as the solvent was carried out by filling the reactor containing the
pre-reduced catalyst with a solution of 4-methoxyacetophenone
(0.65 mmol) in 8 mL of alcohol and 1 atm H2. Etherification reac-
tions with higher ketone/alcohol ratio were carried out by filling
the reactor with a solution of the aromatic ketone (0.65 mmol)
and the aliphatic alcohol (6.5 mmol) in 8 mL of anhydrous n-hep-
tane or toluene (depending on the solubility of the substrate)
and 1 atm H2. The reaction mixtures were analysed by GC–MS
(Agilent 5975C) by using a HP-5 column and the products were
characterised by NMR.
18. Boccuzzi, F.; Chiorino, A.; Martra, G.; Gargano, M.; Ravasio, N.; Carrozzini, B. J.
Catal. 1997, 165, 129–139.
19. Boccuzzi, F.; Martra, G.; Coluccia, S.; Ravasio, N. J. Catal. 1999, 184, 316–
Acknowledgement
326.
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248–249.
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25. Fujii, Y.; Furugaki, H.; Yano, S.; Kita, K. Chem. Lett. 2000, 926–927.
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The authors thank the European Commission for financing the
Network of Excellence IDECAT (Contract No. NMP3-CT-2005-
011730).
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