A convenient catalytic method for the synthesis of ethers from alcohols and carbonyl compounds

Article abstract of DOI:10.1246/cl.2000.926

Unsymmetrical ethers are obtained in excellent yields by the catalytic etherification of alcohols with ketones or aldehydes in the presence of Pd/C under an atmospheric pressure of hydrogen when water produced by the reaction is continuously removed by bubbling hydrogen through the reaction mixture.

Full text of DOI:10.1246/cl.2000.926

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Chemistry Letters 2000
A Convenient Catalytic Method for the Synthesis of Ethers
from Alcohols and Carbonyl Compounds
Yasuyuki Fujii, Hisakazu Furugaki, Shinji Yano, and Katsumi Kita*
Materials Development Research Laboratories, Kao Corporation, 1334 Minato Wakayama 640-8580
(Received May 23, 2000; CL-000499)
Unsymmetrical ethers are obtained in excellent yields by
the catalytic etherification of alcohols with ketones or aldehy-
des in the presence of Pd/C under an atmospheric pressure of
hydrogen when water produced by the reaction is continuously
removed by bubbling hydrogen through the reaction mixture.
1
The Williamson synthesis has been used for the synthesis
of unsymmetrical ethers, in spite of requiring strongly basic
conditions and generating a stoichiometric amount of waste
salts. In view of the environmentally benign organic chemistry,
2-4
an alternative catalytic method with minimal waste is desired.
The catalytic methods for the synthesis of unsymmetrical ethers
reported previously5 may be unavailable for the alternative
because of their various limitations as pointed out by Lemaire
–7
et al.8 Recently, Lemaire et al. and we have independently
found that unsymmetrical ethers can be obtained from alcohols
and carbonyl compounds in good yields (> 80%) by use of Pd/C
as a catalyst under hydrogen atmosphere. The proposed meth-
ods, however, require a relatively high pressure of hydrogen (>
8
9
4
0 atm, where use of an autoclave is unavoidable) and a dilute
–
3
solution of substrates (~ 0.2 mol dm ). Under lower hydrogen
pressure, the ratio of side reactions increase and the yields
decrease remarkably; 1-butanol reacted with octanal to give
only 39% of butyl octyl ether at 10 atm of hydrogen. These
limitations are disadvantageous not only in laboratories but
especially in industries. In this paper we report a useful catalyt-
ic method that can be successfully employed even under an
atmospheric pressure of hydrogen for the synthesis of unsym-
metrical ethers (Scheme 1).
1
0
Under an atmospheric pressure of hydrogen, ethers were
scarcely formed from primary alcohols and ketones using Pd/C
as a catalyst,11 in contrast to moderate to high yields of ethers at
8
,9
relatively high hydrogen pressure (> 40 atm).
On the other
hol also reacted with aldehyde in high yields by the hydrogen-
bubbling (entry 10), whereas the corresponding ether was not
obtained with ketone (entry 11). The reduction of the carbonyl
compounds to corresponding alcohols was minimal in our
etherification process.
hand, when a stream of hydrogen was bubbled through the reac-
1
2
tion mixture during the reaction, primary alcohols reacted
with either ketones or aldehydes to give the corresponding
ethers excellent yields even under an atmospheric pressure of
hydrogen (Table 1, entries 1–8), except for diisopropyl ketone
entry 9). Paracetaldehyde, which could generate acetaldehyde,
can be used as a reactant to synthesize ethyl ether (entry 7).
Symmetrical ether was also obtained (entry 4). Secondary alco-
In the “hydrogen-bubbling method” described here, the
effusion of water with a stream of hydrogen was observed dur-
ing the reaction, and a corresponding amount of water to that of
(
1
3
ethers formed was obtained. This result suggests that the
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
927
dehydration with hydrogen-bubbling accelerates Pd/C-cat-
alyzed etherification to give good yields even under an atmos-
pheric pressure of hydrogen. The removal of water may shift
the equilibrium toward the enol ether (followed by the hydro-
genation into the corresponding ether) from hemiketal or hemi-
acetal,10 which could not be hydrogenolyzed into the ethers
4
5
R. A. Sheldon, Chem. Ind. (London), 1997, 12.
M. Verzele, M. Acke, and M. Anteunis, J. Chem. Soc.,
1963, 5598.
6
7
8
9
S. Nishimura, T. Itaya, and M. Shiota, J. Chem. Soc.,
Chem. Commun, 1967, 422 .
W. L. Howard and J. H. Brown, J. Org. Chem., 26, 1026
(1961).
V. Bethmont, F. Fache, and M. Lemaire, Tetrahedron Lett.,
36, 4235 (1995).
Y. Fujii, H. Furugaki, Y. Kajihara, K. Kita, H. Morimoto,
and M. Uno, U. S. Patent 6011071 (2000) (Priority
Application: Jpn. Patent JP 95118309, 17 May 1995);
Chem. Abstr., 126, 61873 (1997).
directly under these conditions. The use of MgSO as a dehy-
4
drating agent instead of the hydrogen-bubbling did not give sat-
1
4
isfactory results under an atmospheric pressure. It seems that
MgSO did not have enough dehydrating ability to promote the
4
reaction under our condition (1 atm, 105 °C for ketones or 160
°
C for aldehydes). Lower levels of reactivity of diisopropyl
ketone (entry 9) may be attributed to the steric hindrance.
From the viewpoint of the industrial applications, several
advantages in the proposed method are noted as follows;
employing ether synthesis (i) under an atmospheric pressure of
hydrogen, (ii) without using an autoclave, (iii) without generat-
ing any waste salts, (iv) by using 2-fold of carbonyl compounds
without using any co-solvents (in contrast to the “autoclave
method”8 requiring very dilute conditions). Further, the
amount of hydrogen used could be reduced to less than that in
the autoclave method by circulating hydrogen to reuse it during
the reaction. On the other hand, it should be pointed out as a
limitation that water-soluble and/or low boiling point sub-
strates, e.g., acetone, methanol etc., may not be applied without
an alternative procedure for separating water, instead of the
10 F. Fache, V. Bethmont, L. Jacquot, and M. Lemaire, Recl.
Trav. Chim. Pays-Bas, 115 , 231 (1996).
11 The conversion of alcohol was 12% after 8 h when 1-
octanol and 4-methyl-2-pentanone were used as substrates.
12 A typical procedure follows: A mixture of 1-octanol (39 g,
0.3 mol), 4-methyl-2-pentanone (60 g, 0.6 mol) and Pd/C
(5% palladium-on-carbon 3.1 g, 0.16 g as Pd) was placed
in a flask equipped with a tube for introducing hydrogen
and a Dean–Stark trap, and was stirred vigorously under a
stream of hydrogen (180 mL/min, at atmospheric pressure)
at 105 °C. During the reaction, water produced was elimi-
nated from the effluent and substrates effused were
returned continuously to the reaction mixture by the
“Dean-Stark trap technique”. The reaction was monitored
by GLC and after completion of reaction (8 h), the reaction
mixture was filtered. The product was purified by flash
chromatography on silica gel (hexane / ethyl acetate 20 : 1)
to afford 1,3-dimethylbutyl octyl ether (3a) (62 g, 97%).
The structure was characterized by IR, NMR and Mass
,10
“Dean–Stark trap technique” used here.
In conclusion, the Pd/C-catalyzed etherification assisted by
the hydrogen-bubbling dehydration (which can be successfully
employed even under an atmospheric pressure) may be useful
for the synthesis of ethers from alcohols and carbonyl com-
pounds, especially for the environmentally benign industrial
production as an alternative method to the Williamson synthe-
sis.
–
1
spectra. 3a: IR (Neat, cm ): 1095 (C–O–C),1371, 1468,
1
2856, 2927. H-NMR (CDCl ): 0.89 (t, 3H), 0.92 (d, 6H),
3
1
.11 (d, 3H), 1.2–1.4 (m, 10H), 1.4–1.7 (m, 4H), 1.7–1.9
1
3
We are grateful to Dr. A. Kawamata and Dr. Y. Sassa for
helpful discussions, and to Mr. M. Uno, Mr. H. Matsumoto and
Ms. E. Tamura for their assistance.
(m, 1H), 3.2–3.6 (m, 3H). C-NMR (CDCl ): 14.11,
3
20.02, 22.60, 22.72, 23.11, 24.71, 26.36, 29.37, 29.54,
30.32, 31.93, 46.48, 68.51, 73.52. HRMS (CI): Found m/z
+
2
15.2366 (M+H) . Calcd for C H O: M+H, 215.2297.
1
4
30
References and Notes
13 In the case of entry 1, 5.0 g of water (93% of theoretical
amount) was obtained.
14 The conversion of alcohol was 17% after 8 h when 1-
octanol and 4-methyl-2-pentanone were used as substrates.
1
2
3
A. W. Williamson, J. Chem. Soc. , 4, 229 (1851).
B. M. Trost, Science, 245, 1471 (1991).
R. A. Sheldon, Chem. Ind. (London), 1992, 903.