2008 Short Articles
Bull. Chem. Soc. Jpn. Vol. 80, No. 10, 2008–2010 (2007)
Table 1. Debenzylation of Phenyl Benzyl Ethersa)
Facile Cleavage of Ethers
in Ionic Liquid
Entry
Heating
methodb)
T/ꢂC
Time
Yieldc)
/%
1
Thermal
Thermal
Thermal
Microwave
Microwave
Microwave
Microwave
Microwave
115
115
115
115
200
200
200
200
10 h
7 h
7 h
100 min
20 min
15 min
40 min
25 min
95
97
<5
97
93
93
93
97
2d)
3e)
4d)
5
Lili Cheng, Carlin Aw,
ꢀ
Siew Siang Ong, and Yixin Lu
6f)
7g)
8h)
Department of Chemistry, National University of Singapore,
3 Science Drive 3, 117543, Singapore
The Medicinal Chemistry Program, Office of Life Sciences,
National University of Singapore, Singapore
a) Unless otherwise indicated, all the reactions were carried
out on 0.5 mmol reaction scale of ether in 0.6 mL ionic liquid
using 5 mmol of pyridinium chloride in (bmim)þ[BF4]ꢁ.
b) Microwave-assisted reactions were carried out in sealed
vessels with a Biotage Initiator Microwave reactor; thermal
refers to thermal heating, which was performed in an oil bath.
c) Isolated yield. d) (PyH)þBrꢁ was used. e) Reaction was car-
ried out in DMF and (PyH)þBrꢁ was used. f) (Bmim)þ[PF6]ꢁ
was used. g) Equimolar amount of pyridinium chloride was
used. h) Recovered ionic liquid was used.
Received April 23, 2007; E-mail: chmlyx@nus.edu.sg
Various alkyl ethers were efficiently cleaved by treat-
ing them with pyridinium halides in ionic liquid, and the
desired products were obtained in excellent yields.
The use of alkyl ethers as protecting groups for the hydroxy
group is of fundamental importance in organic synthesis, and
such protections are crucial in the preparation of many phar-
maceutical agents and fine agrochemicals.1 Alkyl ether cleav-
ages are typically carried out under strong acidic conditions or
by catalytic hydrogenolysis. Ether cleavages can also be real-
ized through electron-transfer reactions,2 or using photochem-
ical, electrochemical, and enzymatic methods.3 However, there
still exists a need to develop efficient and convenient methods
for the removal of the alkyl ethers.
Ionic liquids have recently attracted much attention as reac-
tion media for green chemical synthesis mainly due to their
very low vapor pressure, excellent thermal stability and ease
of handling.4 The use of ionic liquid as a solvent for nucleo-
philic displacement has been well studied.5 There have been
a number of reports on the increased nucleophilicity of
the nucleophiles in ionic liquids, thus facilitating various
chemical transformations.6 Chi and co-workers have elegantly
demonstrated that 1-butyl-3-methylimidazolium bromide
(bmim)þBrꢁ in (bmim)þ[BF4]ꢁ in the presence of protic acids
can cleave the ethers.6c Johnson and co-workers have dis-
covered that the novel 3-methylimidazolium bromohydrogen-
ates(I) ionic liquid can cleave a range of methyl ethers.7 In a
recent study carried out by Kemperman et al., chloroaluminate
ionic liquid has been shown to be an excellent ether-cleaving
agent.8
the efficiency of the reactions. Since the dielectric properties
of ionic liquids make them absorb microwave irradiation very
efficiently, they are highly suitable for the microwave-assisted
organic synthesis. Herein, we report that pyridinium halides in
ionic liquids are effective reagents for the cleavage of various
aryl and alkyl ethers.
We initially performed a feasibility study with phenyl ben-
zyl ethers, and the results are summarized in Table 1. When
a mixture of phenyl benzyl ether and ten molar amounts of
pyridinium chloride in ionic liquid were heated in an oil bath
for ten hours, the debenzylated product was isolated12 in excel-
lent yield (Entry 1). The reaction proceeded faster when pyri-
dinium bromide was used (Entry 2). Ionic liquids are essential
for the cleavage, and the reaction in normal solvents such
as DMF, yielded only trace amount of dealkylated product
(Entry 3). Microwave irradiation is more efficient than thermal
heating. The rate of reaction was substantially improved
when microwave irradiation was employed (Entries 4 and 5).
In addition, the reaction worked equally well in the presence
of different ionic liquids (Entry 6). We typically used ten
molar amounts of pyridinium halide to expedite the reaction.
It should be noted that the debenzylation also went to comple-
tion in the presence of only equimolar amount of pyridinium
salt, although a longer reaction time was required (Entry 7).
When we carried out reaction with the recovered ionic liquid,13
the reaction proceeded equally well (Entry 8).
At the outset of this work, we aimed to develop a facile and
efficient method for the cleavage of alkyl ethers. Pyridinium
halide in an ionic liquid seems to be a good choice,9 because
both a proton donor and a nucleophile are present in the same
molecule. In the cleavage reaction, pyridinium cation can
serve as a mild proton donor to protonate ether substrates,
and the enhanced nucleophilicity of halide in an ionic liquid10
will then be utilized to cleave the protonated ethers. The avail-
ability, low cost and mild nature of pyridinium halides made
this method especially appealing. Moreover, we envision that
the use of the microwave irradiation11 could further improve
The deprotections of various benzyl ethers are illustrated in
Table 2. The efficiency of our method and the observed rate
enhancement can be attributed to microwave effects.11 The re-
action under thermal heating in an ionic liquid at 200 ꢂC only
afforded a moderate yield of the desired product (Entry 1).
However, the reaction under microwave irradiation at the same
temperature was quantitative (Entry 2). In the absence of an
ionic liquid, when pyridinium halide was used as both reagent
and solvent, the reaction was less effective (Entry 3). Under
the microwave irradiation conditions in an ionic liquid, the
debenzylations of various substrates were typically completed