A general method for the preparation of ethers using water-resistant solid lewis acids

Article abstract of DOI:10.1002/anie.200604018

(Chemical Equation Presented) This most ethereal of cascades: Water-resistant single isolated Lewis acids within the framework of molecular sieves act as excellent general catalysts for the synthesis of ethers (see scheme). On this basis, an environmentally friendly process has been developed for the preparation of fine chemicals that involves a one-pot Meerwein-Ponndorf-Verley reduction/etherification cascade.

Full text of DOI:10.1002/anie.200604018

Communications
DOI: 10.1002/anie.200604018
Etherification
A General Method for the Preparation of Ethers Using Water-
Resistant Solid Lewis Acids**
Avelino Corma* and Michael Renz*
Ethers are fundamental compounds in organic chemistry, and
the search for simple efficient preparation methods is a matter
of general interest. The Williamson reaction, discovered in
1850, is still the best general method for the preparation of
symmetrical and unsymmetrical ethers.[1,2] This method
involves the treatment of a halide with an alkoxide or
aryloxide ion prepared from an alcohol or phenol. However,
the Williamson reaction is not applied industrially in many
cases because the starting halide compounds are not easily
available or they are too expensive. Furthermore, it should
also be considered that the use of the starting halides together
with the production of waste products is environmentally less
desirable than producing the ethers from the corresponding
alcohols, provided that a general and efficient procedure is
found.
Brønsted acids can catalyze the formation of ethers when
starting from two alcohol molecules, and this synthetic
strategy is particularly useful for the preparation of sym-
metrical lower alkyl ethers. For instance, diethyl ether can be
prepared by vapor-phase dehydration of ethanol in a fixed-
bed reactor using alumina catalyst.[3,4] Many studies in
homogeneous phases have been carried out with sulfuric
acid.[5] In these cases, the hydroxy group is converted into a
better leaving group, namely ROH2+ or ROSO2OH,[6] and the
formation of the ether may occur by a SN1 or SN2 pathway.
Both types of procedures to prepare ether, that is, the
Williamson reaction and alcohol dehydration, are limited to
primary ethers. Low yields are observed with secondary
alcohols, and especially tertiary alcohols and halides tend to
give elimination reactions.[7,8] Recently, a very efficient and
comprehensive method for the synthesis of ethers was
developed by Shintou and Mukaiyama,[9,10] involving a new
type of oxidation–reduction condensation, wherein one
alcohol is mixed successively with nBuLi, Ph2PCl, and
tetrafluoro-1,4-benzoquinone (fluoranil) and then treated
with the second alcohol. The reaction proceeds smoothly to
afford the corresponding symmetrical and unsymmetrical
ethers in good to high yields and has been demonstrated for a
broad scope of substrates. Despite the procedure being an
elegant one from an organic chemistꢀs point of view, the
reactants used can restrict its use in practice. Therefore, the
search for new efficient etherification methods is still an
interesting and current research topic.
In contrast to Brønsted acids, little is known about the
possibilities of Lewis acids as etherification catalysts,[11]
probably due to the sensibility of conventional Lewis acids
such as BF3 or AlCl3 to the water produced in the reaction
that deactivates or decomposes them.
Herein, we show that by introducing single, isolated Lewis
acid sites in the framework of molecular sieves, water-stable
Lewis acid catalysts are attained that are active and selective
for the production of a large number of ethers. We then show
that these Lewis acid catalysts can be used in cascade-type
reactions to produce ethers of interest as fragrances, starting
from commercial aldehydes and alcohols with remarkably
high yields and selectivities. We prepared Sn-, Ti-, and Zr-
containing catalysts in which the metal is located in frame-
work positions of Beta zeolite and mesoporous MCM-41
following published procedures.[12–18]
When the etherification of a lower alkyl alcohol such as 1-
butanol (2, Table 1) with para-methoxybenzyl alcohol (1a) is
carried out using para-toluenesulfonic acid as catalyst,
benzene has to be introduced as solvent to carry on the
azeotropic distillation of the water formed and allow the
reaction to proceed further.[19] However, in our case working
with an excess of 1-butanol and using Sn-Beta or Sn-MCM-41
catalysts, the removal of the water formed was not necessary
for the reaction to be completed.[20] Furthermore, owing to the
nature of the catalyst, the workup is very simple and 1-butanol
(2) can be easily recovered and recycled. Therefore, the
catalyst is collected by filtration and the excess of alcohol 2 is
distilled off (see Experimental Section). In Table 2, it can be
seen that this method provides the desired ether 3a in high
Table 1: Etherification of 1-butanol (2) with para-methoxybenzyl alcohols
(1).
[*] Prof. Dr. A. Corma, Dr. M. Renz
Instituto de Tecnología Química (UPV-CSIC)
Universidad PolitØcnica de Valencia
Avenida de los Naranjos s/n, 46022 Valencia (Spain)
Fax: ( +34)96-387-7809
E-mail: acorma@itq.upv.es
R1
R2
R3
Alcohol
Ether
mrenz@itq.upv.es
OMe
OMe
OH
OH
OMe
H
H
OMe
OEt
OMe
H
Me
H
H
H
1a
1b
1c
1d
1e
3a
3b
3c
3d
3e
[**] Financial support from the CICYT (MAT-2006-3798164) is gratefully
acknowledged. M.R. thanks the Spanish Ministry of Science and
Technology for a “Ramón y Cajal” fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
298
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Angew. Chem. Int. Ed. 2007, 46, 298 –300

Angewandte
Chemie
yield and with high selectivity (Table 2, entry 1), with the
dimer 4a (formed from two molecules of alcohol 1a) being
produced in very low amounts. Two blank experiments were
performed with 1) an all-silica Beta zeolite and 2) a silica Beta
starting with alcohol 1d in methanol as solvent in the presence
Table 2: Etherification of different alcohols with 1-butanol (2) employing
of sodium hydrogen sulfate, with ether 3d isolated in 56%
yield. It was further stated that the other ethers were also
obtained by this procedure, however, the yields obtained were
not reported.
Sn-Beta or Sn-MCM-41 as catalysts.
Entry Alcohol Catalyst
t
Conv.
[%][a]
Selectivity [%]
ether 3 dimer 4
[h]
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
Sn-Beta
Sn-MCM-41
Sn-Beta
Sn-MCM-41 0.5
Sn-Beta
Sn-MCM-41
Sn-Beta
Sn-MCM-41
Sn-Beta
4
4
0.5
97 (71)
92 (60)
99
99
23 (5)
100 (90) 100
64 (14) 100
98 (58)
64 (20) 100
85 (44) 96
98
95
97
99
100
2
5
2
1
0
0
0
0
0
3
The synthesis of this series of ethers was an interesting
challenge for our mild etherification method, as in the case of
fragrance compounds the formation of by-products even in
small amounts can condition the overall olfactory perfor-
mance. Results show that for many of these ethers, by
optimizing the reaction conditions no by-products could be
detected by gas chromatography, with 100% yield of the
desired product observed (see Supporting Information).
After a simple workup, that is, removal of the catalyst by
filtration and evaporation of the remaining alkyl alcohol, all
products were obtained in pure, solvent-free form and were
characterized by 1H and 13C NMR spectroscopy (see Support-
ing Information).
7
4
6
6
6
6
98
10
Sn-MCM-41
[a] Values in parentheses indicate the conversions after a reaction time of
1 h.
The Sn-Beta catalyst can also be employed with less-
activated substrates. However, in these cases the reaction
conditions have to be adjusted with, for example, the reaction
temperature raised to 1508C. At this temperature, 80% of
2,5-hexanediol (5) is converted into 2,5-dimethyltetrahydro-
furan (6) with excellent selectivity within 45 min [Eq. (2)].
The only products observed were the two possible diastereo-
mers of the furan 6.
zeolite impregnated with SnO2. Ether formation was not
observed in either case, confirming that the catalytic activity
must be related to the isolated Sn Lewis acid sites present
within the zeolite framework. Similar results were obtained
with Sn- and Zr-Beta catalysts, while Ti-Beta gave much lower
yields.
Alcohols with additional substituents at the aromatic ring
(see Table 1) can be more difficult to react with Sn-Beta as the
diffusion of the reactant alcohol and ether within the channels
of the Beta structure (6.5–7.6 Š) can be hindered. In such a
case, a catalyst with a mesoporous structure (pore diameter
ꢀ 35 Š), namely Sn-MCM-41,[21] can be successfully used
instead. When alcohol 1a, which can diffuse in the channels of
both Sn-MCM-41 and Sn-Beta, is treated with the former
catalyst, the reaction proceeds slower than with Sn-Beta
although full conversion is still achieved (see Table 2,
entries 1 and 2). These results show a lower intrinsic activity
of Sn-MCM-41 with respect to Sn-Beta for etherification, as
also occurs with other Lewis acid catalyzed reactions.[22,23]
Thus, by selecting the appropriate Sn-molecular sieve catalyst
a large variety of alcohols can be etherified with excellent
conversions and selectivities (see Table 2).
From an industrial point of view, alcohol 1d is an
important precursor for fragrance ethers. When it is reacted
with methanol, the corresponding ether is formed, that is, 3-
ethoxy-4-hydroxybenzyl methyl ether, commercialized as
Methyl Diantilis [Eq. (1)].[24] Methyl Diantilis is a substitute
for isoeugenol and has found use in shampoos and fine
fragrances. Interestingly, in the original patent the ethyl, n-
propyl, and isopropyl ethers of alcohol 1d have also been
described, all of which have different odor notes with good
tenacity.[25] The patent reported a synthesis of the ether
Ether 9 (Table 3) has a fruity pear odor and is a potential
fragrance compound.[26] However, for the commercial success
of a fragrance, besides an attractive odor, the cost of the
product is an important variable. The starting alcohol 1a is
obtained industrially from the corresponding aldehyde 7.[27]
Thus, the commercial process involves a first step in which the
aldehyde is reduced to the corresponding alcohol, which leads
to some loss of product and produces undesired products that
have to be distilled off. Therefore, we thought that it would be
conceptually interesting and industrially relevant if the global
process could be performed in one pot through a cascade
reaction, starting from the aldehyde 7 and ending up with the
desired product 9 with high yields and selectivities.
The idea was to convert aldehyde 7 into alcohol 1a
through a Meerwein–Ponndorf–Verley reaction with 2-buta-
nol (8) and to etherify the intermediary alcohol 1a with 2-
butanol (8) present in excess, all in a cascade reaction. Again,
the workup was very simple, as the catalyst (either Sn- or Zr-
Beta) was removed at the end by filtration and the solvent
(including butanone) was evaporated. The selectivity for the
one-pot process is very high, and the desired ether 9 was the
Angew. Chem. Int. Ed. 2007, 46, 298 –300
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www.angewandte.org
299

Communications
Table 3: Cascade reaction for the synthesis of ether 9.[a]
was added to a solution of para-methoxybenzaldehyde (7; 1.1 mmol)
in 2-butanol (8; 3 g), and the reaction mixture was heated to 1008C.
Received: September 29, 2006
Published online: November 30, 2006
Keywords: cascade reactions · etherification · Lewis acids ·
.
tin · zeolites
Catalyst
(mass [mg])
t [h]
Total
conversion [%]
Overall
selectivity [%]
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Sn-Beta (50)
Sn-Beta (100)
Zr-Beta (50)
8
24
8
71
99
100
100
99
100
[a] Alcohol 1a is produced in the first step by a Meerwein–Ponndorf–
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[4]F. Figueras Roca, L. De Mourgues, Y. Trambouze, J. Catal. 1969,
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only product observed (see Table 3). In this case, the dimer 4a
could not be detected owing to the low concentration of the
intermediary alcohol 1a during the reaction, as it rapidly
reacts on the catalyst to give the corresponding ether 9 (see
Supporting Information). With both catalysts, that is, Zr- and
Sn-Beta, the desired fragrance was obtained in 98% yield,
with the Zr catalyst being more active for the global process.
In conclusion, Sn- and Zr-containing silicate molecular
sieves are very active and selective catalysts for synthesizing a
large variety of ethers from the corresponding alcohols
without requiring the removal of water. As a result, a new
process for producing ethers of interest in the fine chemicals
industry has been developed with these catalysts, starting
from one commercial aldehyde and one alcohol, through a
cascade reaction that involves a Meerwein–Ponndorf–Verley
reduction of the aldehyde followed by etherification of the
alcohol.
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Sn-Beta,[15] Zr-Beta,[15] and Sn-MCM-41[21] were prepared following
published procedures. X-ray diffraction studies and N2 adsorption
isotherms confirmed the good quality of the samples. Atomic
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[20]In general, when Brønsted acid catalysis is employed for the
ether synthesis from two alcohols, water has to be removed to
achieve complete conversion, because also the back reaction,
that is, the conversion of an ether into two alcohols in the
presence of water, is catalyzed by Brønsted acids. In the case of
the solid Lewis acids, this back reaction is not facilitated by the
catalyst. The ether may coordinate to the Lewis acid center,
however, it will not be activated for the ether hydrolysis as the
alcoholate is not converted into a better leaving group.
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General procedure for the etherification reaction starting from
two alcohols: Sn-Beta zeolite catalyst (50 mg) was added to a solution
of para-methoxybenzyl alcohol 1a (4 mmol) in 1-butanol (2; 3 g), and
the reaction mixture was heated to 1008C. Aliquots were withdrawn
periodically, and the progress of the reaction was monitored by gas
chromatography (HP5 column, 15 m ” 0.32 mm, 5-mm film, using a
suitable temperature program). The products were identified and
characterized by GC-MS and 1H NMR spectroscopy (see Supporting
Information).
2,5-Dimethyltetrahydrofurane (6): 2,5-Hexanediol (5; 1.00 g,
8.53 mmol) and Sn-Beta (100 mg) were introduced into a 25-mL
flask, and the flask was placed in a Kugelrohr distillation apparatus.
The reaction mixture was heated for 45 min at 1508C, during which
time almost all the liquid distilled. A mainly solid material (zeolite
Beta catalyst, 134 mg) was recovered from the flask, as well as a
distillate (938 mg), which was analyzed by GC and GC-MS. The only
compounds detected were 2,5-hexanediol (5) and 2,5-dimethyltetra-
hydrofuran (6, two diastereomers) in 20:80 ratio.
General procedure for the cascade etherification reaction starting
from an aldehyde: Sn- or Zr-Beta zeolite catalyst (50 mg or 100 mg)
300
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Angew. Chem. Int. Ed. 2007, 46, 298 –300