CO2(CO)8-assisted synthesis of propargylic unsymmetrical ethers by reaction of alcohols with propargylic alcohols

Article abstract of DOI:10.1016/S0040-4039(00)01756-1

Lewis acid treatment of alcohols with CO₂(CO)₆-propargylic alcohols yielded propargylic ethers after cobalt demetallation. The procedure is highly effective for the preparation of symmetrical and unsymmetrical ethers derived from primary alcohols and primary and secondary propargylic alcohols. The method permits the use of a wide range of alcohols including those having halogens in their structures. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01756-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9993–9996
CO2(CO)8-Assisted synthesis of propargylic unsymmetrical
ethers by reaction of alcohols with propargylic alcohols
David D. D´ıaz and Victor S. Mart´ın*
Instituto Universitario de Bio-Orga´nica ‘‘Antonio Gonza´lez’’, Universidad de La Laguna,
C/Astrofisico Francisco Sa´nchez, 2, 38206 La Laguna, Tenerife, Spain
Received 5 September 2000
Abstract
Lewis acid treatment of alcohols with CO2(CO)6-propargylic alcohols yielded propargylic ethers after
cobalt demetallation. The procedure is highly effective for the preparation of symmetrical and unsymmet-
rical ethers derived from primary alcohols and primary and secondary propargylic alcohols. The method
permits the use of a wide range of alcohols including those having halogens in their structures. © 2000
Published by Elsevier Science Ltd.
Keywords: propargylic ether; Nicholas reaction; cobalt complexes.
Access to linear ethers containing two different alkyl groups is difficult starting from alcohols
and mineral acids, since the mixture of two alcohols in the presence of an acid usually leads to
a mixture of the three possible products.1 The Williamson reaction is the best-known and most
widely used method for the preparation of unsymmetrical ethers.2 The procedure involves
treatment of a halide or a sulfonate ester with alkoxide or aryl oxide anions prepared from an
alcohol or phenol under SN2 conditions.3 However, the reaction is not useful when the ethers are
sensitive to the basic conditions, such as for instance halogenated ethers due to collateral
elimination reactions.
Propargylic ethers are particularly important regarding the wide range of functional group
interconversions that the triple bond permits.4 In this communication we describe a simple
method for the preparation of such ethers by reaction of alcohols with CO2(CO)6-complexed
propargylic alcohols under acidic conditions (Scheme 1).5 The method is based on the alcoholic
quenching of the extraordinarily stable CO2(CO)6-complexed propargylic cations generated
under Nicholas reaction conditions.6
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01756-1

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Scheme 1.
A typical experiment for the preparation of these propargylic ethers is illustrated for the
preparation of 6: to a solution of 5 (100 mg, 0.29 mmol) was added dicobalt octadicarbonile
(121 mg, 0.35 mmol) in CH2Cl2 (3 mL) at rt. The reaction was stirred for 1 h, concentrated and
dissolved again in CHCl2 (15 mL) under argon atmosphere at rt. To this mixture was added
propargylic alcohol (49 mL, 0.81 mmol) and the flask was cooled to −20°C. Then, BF3·OEt2 (35
mL, 0.27 mmol) was slowly added and the reaction mixture stirred for 1 h at −20°C. The mixture
was poured with vigorous stirring into a saturated solution of NaHCO3 (15 mL) and extracted
with CH2Cl2 (2×15 mL). The organic layers were dried, concentrated and purified by silica gel
column chromatography to obtain the CO2(CO)6-propargylic ether of 5 as a reddish oil. This
complex was dissolved in acetone (2 mL) and the mixture cooled to 0°C. Then, Ce(NO3)6(NH4)2
(480 mg, 0.88 mmol) was added in one portion and the mixture stirred for 5 min. The reaction
mixture was concentrated and the resulting residue dissolved in water and extracted with ether
(3×10 mL). The combined organic phases were dried with MgSO4, concentrated and purified by
silica gel column chromatography to yield 6 (79 mg, 72%) as a colourless oil.
In order to minimize the formation of the dimer 4, resulting from the nucleophilic attack of
the propargylic alcohol itself to the generated cation, high dilution conditions (ca. 0.05 M) must
be used and the Lewis acid should be added slowly to the reaction flask, followed by an excess
(ca. 3 equiv.) of the nucleophilic alcohol (ROH in Scheme 1). When the Lewis acid was added
to a solution of complex 2, the corresponding dimer 4 was obtained in good yield (Table 1).
In preceding studies carried out in our group, we have shown the compatibility of many
functional groups with the reaction conditions.7 In order to determine the scope and synthetic
limitations of the presented procedure, different nucleophilic and propargylic alcohols were used
for experiments (Table 2).
Table 1
Representative examples of symmetrical propargylic ethers (path b)

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Table 2
Representative examples of the formation of propargylic ethers (path a)
The method is general to obtain mixed ethers when primary alcohols are used. However, when
the propargylic alcohol is secondary, only primary alcohols can be used as nucleophiles (entry
10). The use of secondary or tertiary nucleophilic alcohols provides a very low or null yield of
ethers (entries 11 and 12), probably due to competitive elimination reactions. When two
differently substituted propargylic alcohols are combined the better yields are achieved for
secondary CO2(CO)6-complexed propargylic alcohols with a primary nucleophilic alcohol
(entries 3 and 10 for the preparation of 6). One interesting feature of our method is the
compatibility with halogenated substrates (entries 6 and 7), providing a very convenient method
to obtain halide–ethers in good yields that are difficult to obtain by other methodologies.8
In summary, we describe a new procedure to obtain highly functionalized linear propargylic
ethers. These molecules are currently being used as substrates in cyclization reactions and the
results will be published in due course.

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Acknowledgements
This research was supported by the DGES-PB98-0443-C02-01 of Spain, FEDER-1FD97-
0747-C04-01 and the Consejer´ıa de Educacio´n, Cultura y Deportes del Gobierno de Canarias.
D.D. thanks the MEC of Spain for an FPI fellowship.
References
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8. Satisfactory spectroscopic data and combustion analyses were obtained for all new compounds.
.
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