Catalytic reductive etherification of ketones with alcohols at ambient hydrogen pressure: A practical, waste-minimized synthesis of dialkyl ethers

Article abstract of DOI:10.1055/s-2006-956484

A heterogeneous platinum catalyst was found to efficiently mediate the reductive etherification of ketones at ambient hydrogen pressure. In this environmentally benign transformation, water is released as the only by-product, and this is trapped with molecular sieves. The preparative utility of the new reaction protocol is demonstrated by the synthesis of ten unsymmetrical ethers from the corresponding ketones and primary or secondary alcohols. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956484

LETTER
3489
Catalytic Reductive Etherification of Ketones with Alcohols at Ambient Hy-
drogen Pressure: A Practical, Waste-Minimized Synthesis of Dialkyl Ethers
Catalytic
R
educ
u
tive Etherific
k
ation of
K
et
a
ones with
A
s
lcohols at
A
mb
J
ient
H
ydr
.
n
Pressur
G
e
ooßen,* Christophe Linder
Institut für Chemie – Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-Straße, Geb. 54, 67663 Kaiserslautern
Fax +49(631)2053921; E-mail: goossen@chemie.uni-kl.de
Received 2 August 2006
substrate, thus sacrificing the atom economy of the overall
process.
Abstract: A heterogeneous platinum catalyst was found to effi-
ciently mediate the reductive etherification of ketones at ambient
hydrogen pressure. In this environmentally benign transformation,
water is released as the only by-product, and this is trapped with
molecular sieves. The preparative utility of the new reaction proto-
col is demonstrated by the synthesis of ten unsymmetrical ethers
from the corresponding ketones and primary or secondary alcohols.
A protocol that allows the coupling of carbonyl com-
pounds with a wider range of alcohols in the presence of
hydrogen as the reducing agent, under conditions suitable
for everyday laboratory use, would be of high synthetic
interest. In order to develop such a method, we chose the
coupling of cyclohexanone (1a) with 1-butanol (2a) as a
model to investigate the catalysts and conditions required
for the desired conversion to cyclohexyl 1-butyl ether
(3a). In order to ensure the practicability of our protocol,
we restricted our efforts to the use of ambient hydrogen
pressure, as achievable by a gas burette or balloon. We
soon realized that several side reactions need to be con-
trolled, most importantly the reduction of cyclohexanone
(1a) to cyclohexanol (5a) leading also to follow-up prod-
ucts such as dicyclohexyl ether (6a). Moreover, a redox
Key words: ethers, reductive etherification, platinum, catalysis,
hydrogenation
The dialkyl ether moiety is one of the most abundant sub-
structures in organic molecules. Traditionally, unsymmet-
rical ethers are prepared via the Williamson ether
synthesis, despite the need for strong bases and the inevi-
table formation of stoichiometric amounts of salts as by-
products.1,2
In contrast to the widely used reductive amination,3 an equilibration of 1a with 1-butanol (2a), yielding cyclo-
analogous ether synthesis from carbonyl compounds and hexanol (5a) and butanal, and the formation of the ketal
alcohols under reductive conditions has never become es- 4a was sometimes observed (Scheme 2).
tablished as a standard tool for ether synthesis. This can be
attributed to the fact that previously reported reductive
etherification procedures have a narrow substrate scope
and are impractical for laboratory use: in the original pro-
tocol, the carbonyl compound and excess alcohol are hy-
drogenated using PtO in strong acids or with zeolites,
which facilitates the formation of enol ether intermedi-
ates.4,5 Alternatively, the reaction can be performed with-
out acids using Pd/C albeit at high hydrogen pressure,6 or
in a continuous stream of hydrogen gas with an elaborate
apparatus for azeotropic water removal.7 All of these pro-
cesses call for a large excess of one of the substrates, usu-
ally as a solvent for the other, and most of them are limited
to short-chain primary alcohols (Scheme 1).
O
OR
RO OR
H2, cat.
+
+
ROH
1a
2a–c
3a–c
4a–c
OH
R = n-butyl, iso-propyl
or tert-butyl
O
+
+
5a
6a
Scheme 2 Model reaction with main product and major side
products
We started our catalyst development with a 1:2 mixture of
the ketone 1a and the alcohol 2a in a chloroform solution
at a temperature of 50 °C using Pt/C as a catalyst. These
initial experiments gave only low yields until we discov-
ered the detrimental effect of water on the transformation:
adding molecular sieves to the reaction mixture to remove
the water by-product increased the yields to a preparative-
ly useful level (Table 1, entries 1 and 2). Under these con-
ditions, palladium, rhodium and most other metals on
solid supports tested displayed almost no catalytic activity
(entries 2–5), but we were pleased to find that a specific
type of 5% platinum on charcoal catalyst (Degussa R-
type: F 105 R/D) resulted in a high conversion (entry 6).
Our attempt to facilitate intermediate enol ether formation
As a consequence, related procedures were favored by
synthetic chemists, in which the reductant is either a si-
lane,8 or an alkoxysilane9 pre-formed with the alcohol
O
OR''
H2
+
R'' OH
– H2O
R
R'
R
R'
1
3
2
Scheme 1 Reductive etherification with hydrogen as reducing agent
SYNLETT 2006, No. 20, pp 3489–3491
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956484; Art ID: G21906ST
© Georg Thieme Verlag Stuttgart · New York

3490
L. J. Gooßen, C. Linder
LETTER
by the addition of Lewis acids such as bismuth triflate of the amount of alcohol beyond two equivalents did not
only led to lower overall yields (entry 7). A temperature lead to any further improvement (entries 6, 11–13).
of 50 °C was found to be decisive for the selectivity of the
In order to investigate whether the new protocol could
transformation: below this temperature, the reduction of
also be extended to more sterically crowded alcohols and
the ketone to cyclohexanol dominates over formation of
thus address a problem that most previous processes en-
the desired ether 3a. Interestingly, an increase of the
countered, we tested the optimized catalyst system in the
temperature to 60 °C resulted in lower yields (entries 6,
reaction of isopropanol with cyclohexanone and were
8–10).
pleased to find that appreciable amounts of the isopropyl
Chloroform was found to be the best solvent, while coor- ether were produced (entries 16–19). The competing re-
dinating solvents, e.g. tetrahydrofuran, or plain hydrocar- dox reaction of the secondary alcohol with the ketone,
bons were less effective (entries 14 and 15). We also however, gave rise to the formation of several by-prod-
optimized the reaction stoichiometry and found that al- ucts, such as both the symmetrical ethers. Nevertheless,
ready with a 1:1 ratio of the substrates, reasonable yields when increasing the amount of isopropanol to four equiv-
were obtained. A small excess of the alcohol component alents, a high product yield was obtained even for this
(1.5–2 equiv) gave slightly better yields, while an increase difficult substrate class. A further extension to tertiary
alcohols was not yet achieved (entry 20).
Table 1 Catalytic Reductive Etherification of Ketones 1 with Alcohols 2a
Entry
Catalyst
R
Ratio 1:2
Temp (°C)
Conv. (%)
Yield of 3 (%) Main side
product (%)
1b
2
Pt/Cc
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
i-Pr
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:4
1:1.5
1:1
1:2
1:2
1:1
1:2
1:4
1:6
1:4
50
50
50
50
50
50
50
30
40
60
50
50
50
50
50
50
50
50
50
50
64
100
83
22
68
34
2
5 (35)
5 (12)
4 (14)
4 (30)
5 (2)
Pt/Cc
3
Pd/C
4
Rh/C
76
5
Pt/Al2O3
Pt/Cd
34
0
6
97
84
49
6
5 (3)
7
Pt/Cd/Bi(OTf)3
Pt/Cd
86
5 (5)
8
100
100
86
5 (63)
5 (45)
5 (2)
9
Pt/Cd
28
46
87
79
72
0
10
11
12
13
14e
15f
16
17
18
19
20
Pt/Cd
Pt/Cd
100
100
100
40
5 (4)
Pt/Cd
5 (4)
Pt/Cd
5 (5)
Pt/Cd
5 (5)
Pt/Cd
94
3
5 (53)
5 (8)
Pt/Cd
56
21
48
70
60
0
Pt/Cd
i-Pr
56
5 (13)
5 (10)
5 (8)
Pt/Cd
i-Pr
94
Pt/Cd
i-Pr
94
Pt/Cd
t-Bu
100
6 (19)
a Conditions: 1.00 mmol cyclohexanone, given amount of butan-1-ol, 0.03 mmol cat., H2 (1 bar), 500 mg MS, 4.00 mL CHCl3, 50 °C, 2 h, yields
determined by GC using n-tetradecane as internal standard.
b Without molecular sieves.
c 10% Pt/C: Acros.
d Pt/C: Degussa R-type: 5% F 105 R/D.
e In THF.
f In toluene.
Synlett 2006, No. 20, 3489–3491 © Thieme Stuttgart · New York

LETTER
Catalytic Reductive Etherification of Ketones with Alcohols at Ambient Hydrogen Pressure
Synthesis of n-Butyl Cyclohexyl Ether (3a)
3491
In order to investigate the scope of the optimized protocol,
we applied it to a number of alcohols and ketones. A rea-
sonably wide range of both substrates could be obtained in
good yields. Selected examples are shown in Table 2.
Since it had been our initial aim to increase the reducing
power of the catalyst system to a maximum achievable, it
is not surprising that only those functionalities were toler-
ated which are inert towards reducing conditions, and do
not react with carbonyl compounds. Interestingly, sub-
strates bearing an aromatic ring such as 4-phenyl-2-bu-
tanone, were reduced all the way to the corresponding
cyclohexanes. In order to make this protocol accessible to
an even larger range of compounds, future work will be
directed at tuning the hydrogenation catalyst to improve
substrate tolerance while retaining its high reactivity to-
wards the reductive etherification.
A flask was charged with platinum on charcoal (117 mg, 0.03
mmol) and molecular sieves (500 mg), evacuated and heated to
200 °C to remove residual moisture. The reaction vessel was al-
lowed to cool to 50 °C, flushed with nitrogen, and dry CHCl3 (4
mL), 1-BuOH (183 mL, 2.00 mmol) and cyclohexanone (103 mL,
1.00 mmol) were added via syringe. The reaction mixture was then
purged with hydrogen, and stirred for 2 h at 50 °C at ambient hydro-
gen pressure. For work-up, the catalyst was removed by filtration
through Celite®, the volatiles were removed in vacuo and the resi-
due was purified by column chromatography (silica gel, EtOAc–
hexane 3:7) to afford the title product (144 mg, 92%) as a clear
colorless liquid.
Acknowledgment
We thank Degussa AG and Umicore AG for generous donations of
transition metal catalysts and the FCI for financial support.
Table 2 Further Products of the Catalytic Reductive Etherification
of Ketones with Alcoholsa
References
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Product
Yield
(%)
Product
Yield
(%)
OnC4H9
OnC8H17
92
92
3g
3h
3a
3b
73b
91
83
89
OnO8H17
O
OnC8H17
OnC8H17
(5) Verhoef, M. J.; Creyghton, E. J.; Peters, J. A.; van Bekkum,
H. Chem. Commun. 1997, 1989.
(6) Bethmont, V.; Fache, F.; Lemaire, M. Tetrahedron Lett.
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(c) Wada, M.; Nagayama, S.; Mitzutani, K.; Hiroi, R.;
Miyoshi, N. Chem. Lett. 2002, 248. (d) Suzuki, T.; Ohashi,
K.; Oriyama, T. Synthesis 1999, 1561.
3i
3d
92
85
90
OnC8H17
O
3j
3e
3f
91b
OnC8H17
O
3k
(9) (a) Kato, J.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1985,
743. (b) Sassaman, M. B.; Kotian, K. D.; Prakash, G. K. S.;
Olah, G. A. J. Org. Chem. 1987, 4314. (c) Hatakeyama, S.;
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a Conditions: 1.00 mmol ketone, 2.00 mmol alcohol, 0.03 mmol plat-
inum on charcoal (5%, Degussa R-type: F 105 R/D), 1 bar H2, 500 mg
MS, 4 mL CHCl3, 50 °C, 2 h, isolated yields.
b Using 4.00 mmol alcohol.
In summary, a practical protocol for the reductive etheri-
fication of ketones and alcohols was developed, providing
a convenient entry to unsymmetrical dialkyl ethers. It is
applicable to both primary and secondary alcohols in
combination with a wide range of ketones. Key features of
the new process are the use of a special Pt/C catalyst, am-
bient hydrogen pressure, and the addition of molecular
sieves.
Synlett 2006, No. 20, 3489–3491 © Thieme Stuttgart · New York