Cleavage of Aromatic Methyl Ethers by Chloroaluminate Ionic Liquid Reagents
FULL PAPER
ane, followed by evaporation of the solvent to obtain the cooled with an ice bath. Aluminium chloride was added in small
portions to the stirred powder. A highly exothermic reaction took
ionic liquid in a pure form. The ionic liquid solution can
place. After all the aluminium chloride (7.1 g, 53.2 mmol) had been
also be used as such for the demethylation reaction.
added, the cooling was removed and the reaction mixture was
Surprisingly, selective methyl ether cleavage was observed
warmed to ambient temperature. This process yielded a yellow
when 4,5-dimethoxyindanone was treated with [TMAH]-
liquid (12.1 g, 99%). The density of the liquid was determined by
accurately measuring the weight of a 10 mL sample, and was found
to be 1.15 g/mL.
[
Al Cl ] in dichloromethane giving a 96:4 mixture of the
2 7
pharmaceutically interesting intermediate, 4-hydroxy-5-
methoxy-indanone, and its regioisomer. On the contrary,
aluminum chloride displayed a very poor regioselectivity in
this reaction, resulting in a 7:3 mixture of regioisomers.
[
BMIM][Al
2
Cl
7
] could also be prepared using dichloromethane as
Cl ].
a solvent, as described above for [TMAH][Al
2
7
Ether cleavage by [TMAH][Al Cl ] was elaborated using
2
7
2 6
[EMIM][Al Cl I] (3): Powdered N-ethyl-N-methylimidazolium iod-
several heterocyclic aromatic compounds bearing a variety ide (50 g, 0.21 mol) was stirred and cooled with an ice bath under
of functional groups. We have demonstrated that the ionic a flow of nitrogen gas and then powdered aluminium chloride
liquid-mediated ether cleavage is widely applicable. Besides (53.2 g, 0.4 mol) was added in small portions. The cooling bath
was removed and after stirring for 1 h, a brown liquid had formed.
Yield: 103 g (99%).
methyl ethers, the ionic liquid reagent also cleaves allyl and
benzyl ethers effectively.
In summary, the ionic liquid [TMAH][Al Cl ] can be em-
2
7
The density of the liquid was determined by accurately measuring
ployed both on laboratory scale and on large scale as an the weight of 10 mL of sample, and was found to be 1.41 g/mL.
ether-cleaving agent that, with regard to reactivity, is
[
2 6
EMIM][Al Cl I] could also be prepared by using dichloromethane
superior to its conventional solid counterpart, aluminum
chloride.
as a solvent according to the method described for [TMAH]-
Al Cl ].
[
2
7
Robot Experiments
Experimental Section
The solvent for the system was dichloromethane. Reactions were
carried out in septum-sealed reactor tubes under a flow of nitrogen.
Tubes were dried before use by heating to 150 °C and then cooling
under nitrogen. Generally, the starting material (200 mg) was dis-
solved in dichloromethane such that the total volume including the
ionic liquid was 8 mL. To this solution, ionic liquid (1, 2, or 3) was
General Remarks: Reactions were monitored on an HP 6890 Series
GC and TLC (silica gel). The NMR spectra were recorded on a
Bruker DPX-400. Mass spectrometry was performed on a PE Sciex
API 165. An Anachem Sk233 Workstation equipped with a Stem
RS1000 10 position reactor block was used for the High Speed
Experimentation (HSE).
3
added dropwise and AlCl (3 equiv.) was added manually in
portions. The reaction mixture was warmed to 38 °C. Samples were
taken after 8, 16, 24, and 48 h. Samples (10 µL) were taken by
aspiration of the reaction mixture, and were quenched in 50%
saturated NaCl solution/1 HCl and extracted with ethyl acetate
N-Butyl-N-methylimidazolium Chloride: A mixture of N-methylimi-
dazole (100 g, 1.22 mol) and n-butyl chloride (113 g, 1.22 mol) was
stirred and heated at 70 °C for 96 h. The reaction mixture was
cooled to ambient temperature. The viscous oil was washed three
times with ethyl acetate and then the ethyl acetate remaining was
removed in vacuo. The resulting oil crystallized as a white solid.
(
800 µL). The samples were analyzed off-line by GC.
Laboratory Experiments. General Procedure for Entries 1؊20 of
Table 2: The substrate was dissolved in dichloromethane (1 g/
40 mL). To the stirred solution, ionic liquid (3 equiv. of [TMAH]-
Yield: 210 g (98%). NMR (D
2
O): δ ϭ 8.6 (s, 1 H), 7.3 (d, 2 H), 4.1
(t, 2 H), 3.8 (s, 3 H), 1.8 (m, 2 H), 1.2 (m, 2 H), 0.8 (t, 3 H) ppm.
[
2 7
Al Cl ]) was added dropwise. The reaction mixture was warmed
N-Ethyl-N-methylimidazolium Iodide: N-Methylimidazole (32.9 g,
.4 mol) and ethyl iodide (38.4 mL, 0.48 mol) were dissolved in
dichloromethane (100 mL) and heated under reflux for 18 h. The
remaining dichloromethane and ethyl iodide were evaporated. The
crude product was stirred in diethyl ether and the white crystals
that formed were collected by filtration. Yield: 93.3 g (98%). NMR
to reflux. The reactions were monitored by GC and TLC. After the
reaction was complete, the mixture was poured into dilute hydro-
chloric acid (1 ). The aqueous layer was extracted three times with
ethyl acetate. The ethyl acetate was washed with saturated NaHCO
and brine, and then the ethyl acetate was dried with MgSO
the solvents were evaporated.
0
3
4
and
(D
2
O): δ ϭ 8.6 (s, 1 H), 7.3 (s, 2 H), 4.1 (q, 2 H), 3.8 (s, 3 H), 1.4
(
t, 3 H) ppm.
In cases where the substrate had basic functional groups, the reac-
tion mixture was poured into water. The aqueous layer was neu-
tralized with a NaOH solution (1 ). The aqueous layer was ex-
tracted three times with ethyl acetate, and then the ethyl acetate
2 7
[TMAH][Al Cl ] (1): Aluminum chloride (173 g, 1.3 mol) was sus-
pended in dichloromethane. The suspension was cooled with an ice
bath, and trimethylammonium chloride (62 g, 0.65 mol) was added
with stirring. After the addition, the reaction mixture was warmed
to ambient temperature and was stirred for 2 h. The clear yellow
solution of ionic liquid could be used as such. To obtain the ionic
liquid in a pure form, the dichloromethane was evaporated. Yield:
was washed with brine, dried with MgSO
evaporated.
4
, and the solvents were
4-Hydroxy-5-methoxyindanone. Large-Scale Procedure: A solution
of [BMIM][Al Cl ] (250 mL, 2.5 equiv.) in dichloromethane (1 L)
2
7
2
35 g (99%).
was added dropwise to a solution of 4,5-dimethoxyindanone (50 g,
.26 mol) in dichloromethane (500 mL). The reaction mixture was
stirred for 23 h at 40 °C. The reaction mixture was poured into a
mixture of water (4 L) and concentrated hydrochloric acid (0.6 L).
The aqueous layer was extracted three times with dichloromethane.
0
The density of the liquid was determined by accurately measuring
the weight of 10 mL of sample, and was found to be 1.23 g/mL.
[BMIM][Al
2 7
Cl ] (2): N-Butyl-N-methylimidazolium chloride (5 g,
28.6 mmol) was stirred under a stream of nitrogen gas while being
The organic layer was subsequently dried with MgSO
4
and the sol-
Eur. J. Org. Chem. 2003, 1681Ϫ1686
www.eurjoc.org
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1685
Kemperman, Gerardus J.
