Application of Ionic Liquid Halide Nucleophilicity for the Cleavage of Ethers: A Green Protocol for the Regeneration of Phenols from Ethers

Article abstract of DOI:10.1021/jo035886e

We have used the high nucleophilicity of bromide ion in the form of the ionic liquid, 1-n-butyl-3-methylimidazolium bromide ([bmim][Br]), for the nucleophilic displacement of an alkyl group to regenerate a phenol from the corresponding aryl alkyl ether. Using 2-methoxynaphthalene (1) as a model compound, we found that the combination of ionic liquid [bmim][Br] and p-toluenesulfonic acid with warming effected demethylation in 14 h, affording the desired product 2-naphthol (2) in good yield (97%). Various other protic acids (MsOH, hydrochloric acid (35%), dilute sulfuric acid (50%)) could be used as a proton source in this demethylation reaction. Under the same conditions, cleavage of alkyl alkyl ether 2-(3-methoxypropyl)naphthalene yielded mixture of corresponding 2-(3-bromopropyl)naphthalene and 2-(3-hydroxypropyl)naphthalene. Dealkylation of various aryl alkyl ethers could also be achieved using significantly reduced (i.e., stoichiometric) amounts of concentrated hydrobromic acid (47%) in the ionic liquid. Both procedures afforded the desired products in moderate to good yield; however, cleavage of aryl alkyl cyclic ether, 2,3-dihydrobenzofuran, resulted in low yield of the desired product o-2-bromoethylphenol. The convenience of this method for ether cleavage and its effectiveness using only a moderate excess of hydrobromic acid make it attractive as a green chemical method.

Full text of DOI:10.1021/jo035886e

Ap p lica tion of Ion ic Liqu id Ha lid e Nu cleop h ilicity for th e
Clea va ge of Eth er s: A Gr een P r otocol for th e Regen er a tion of
P h en ols fr om Eth er s
Shanthaveerappa K. Boovanahalli, Dong Wook Kim, and Dae Yoon Chi*
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Korea
dychi@inha.ac.kr
Received December 30, 2003
We have used the high nucleophilicity of bromide ion in the form of the ionic liquid, 1-n-butyl-3-
methylimidazolium bromide ([bmim][Br]), for the nucleophilic displacement of an alkyl group to
regenerate a phenol from the corresponding aryl alkyl ether. Using 2-methoxynaphthalene (1) as
a model compound, we found that the combination of ionic liquid [bmim][Br] and p-toluenesulfonic
acid with warming effected demethylation in 14 h, affording the desired product 2-naphthol (2) in
good yield (97%). Various other protic acids (MsOH, hydrochloric acid (35%), dilute sulfuric acid
(50%)) could be used as a proton source in this demethylation reaction. Under the same conditions,
cleavage of alkyl alkyl ether 2-(3-methoxypropyl)naphthalene yielded mixture of corresponding 2-(3-
bromopropyl)naphthalene and 2-(3-hydroxypropyl)naphthalene. Dealkylation of various aryl alkyl
ethers could also be achieved using significantly reduced (i.e., stoichiometric) amounts of
concentrated hydrobromic acid (47%) in the ionic liquid. Both procedures afforded the desired
products in moderate to good yield; however, cleavage of aryl alkyl cyclic ether, 2,3-dihydroben-
zofuran, resulted in low yield of the desired product o-2-bromoethylphenol. The convenience of this
method for ether cleavage and its effectiveness using only a moderate excess of hydrobromic acid
make it attractive as a green chemical method.
In tr od u ction
Ionic liquids (Figure 1) are a fascinating group of
chemicals, composed of anions and cations, either of
which may interact with solutes and therefore signifi-
cantly affect the outcome of reactions. Numerous nucleo-
philic displacement reactions have been reported in these
new media.5 In this respect, ionic liquids are attracting
growing interest as alternative reaction media.6 Their
properties, low vapor pressure, recyclability, high thermal
stability, and ease of handling, and the fact that ionic
liquids can often act as catalysts as well as reaction
media, make these systems very attractive for developing
environmentally benign chemical processes.
The cleavage of ethers is a nearly ubiquitous trans-
formation in organic synthesis for the production of many
of pharmaceuticals and other fine chemicals.1 Although
a variety of reagents is capable of cleaving ethers, most
conventional methods involve harsh reagents and/or
drastic conditions.2 Consequently, methods that effect
ether cleavage under milder conditions have been the
focus of much attention.
Nucleophilic substitution reactions are solvent depend-
ent, and the outcome of these reactions in terms of both
equilibrium and rate can be altered by the microenvi-
ronment created by the solvent.3 In our recent reports,
we have successfully developed novel methodologies for
various nucleophilic substitution reactions performed in
the presence of ionic liquids, and the results we have
obtained are superior compared with those of earlier
reported methods.4
Ford et al.7 reported that the relative nucleophilicities
of Cl-, Br-, and I- in triethylhexylammonium triethyl-
(4) (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J . Am. Chem. Soc. 2002,
124, 10278-10279. (b) Kim, D. W.; Song, C. E.; Chi, D. Y. J . Org. Chem.
2003, 68, 4281-4285. (c) Kim, D. W.; Choe, Y. S.; Chi, D. Y. Nucl.
Med. Biol. 2003, 30, 345-350.
(5) (a) Wheeler, C.; West, K. N.; Liotta, C. L.; Eckert, C. A. Chem.
Commun. 2001, 887-888. (b) Badri, M.; Brunet, J .-J . Tetrahedron Lett.
1992, 33, 4435-4438. (c) J udeh, Z. M. A.; Shen, H.-Y.; Chi, B. C.; Feng,
L.-C.; Selvasothi, S. Tetrahedron Lett. 2002, 43, 9381-9384. (d)
Chiappe, C.; Pieraccini, D.; Saullo, P. J . Org. Chem. 2003, 68, 6710-
6715. (e) Lourenco, N. M. T.; Afonso, C. A. M. Tetrahedron 2003, 59,
789-794.
* Phone: +82-32-860-7686. Fax: +82-32-867-5604.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 246-276.
(2) For reviews on cleavage of ethers, see: (a) Bhatt, M. V.; Kulkarni,
S. U. Synthesis 1983, 249-282. (b) Tiecco, M. Synthesis 1988, 749-
759. (c) Maercker, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 972-
989. (d) Ranu, B. C.; Bhar, S. Org. Prep. Proced. Int. 1996, 28, 371-
409.
(6) For recent reviews on ionic liquids, see: (a) Sheldon, R. Chem.
Commun. 2001, 2399-2407. (b) Wasserscheid, P.; Keim, W. Angew.
Chem., Int. Ed. 2000, 39, 3772-3789. (c) Welton, T. Chem. Rev. 1999,
99, 2071-2083. (d) Baudequin, C.; Baudoux, J .; Levillain, J .; Cahard,
D.; Gaumont, A.-C.; Plaquevent, J .-C. Tetrahedron: Asymmetry 2003,
14, 3081-3093. (e) Rogers, R. D.; Seddon, K. R. Science 2003, 302,
792-793.
(3) (a) Reichardt, C. Solvents and Solvent Effects in Organic
Chemistry, 2nd ed.; VCH (UK), Ltd.: Cambridge, UK, 1998. (b) Martin,
D.; Weise, A.; Niclas, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 318-
334. (c) Normant, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 1046-
1067. (d) Parker, A. J . Chem. Rev. 1969, 69, 1-32. (e) Sowinski, A. F.;
Whitesides, G. M. J . Org. Chem. 1979, 44, 2369-2376. (f) Hutchins,
R. O.; Taffer, I. M. J . Org. Chem. 1983, 48, 1360-1362.
(7) Ford, W. T.; Hauri, R. J .; Smith, S. G. J . Am. Chem. Soc. 1974,
96, 4316-4318.
10.1021/jo035886e CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/10/2004
3340
J . Org. Chem. 2004, 69, 3340-3344

Demethylation of Methyl Phenyl Ethers
TABLE 1. Dem eth yla tion of 2-Meth oxyn a p h th a len e
w ith Va r iou s P r otic Acid s in [Bm im ][BF 4]a
F IGURE 1. Ionic liquids.
hexylboride ionic liquid were in agreement with the
known gas-phase nucleophilicities of the halide ions.8
Recently, a few investigations on the nucleophilicity of
an ionic liquid anion itself such as chloride, bromide, and
iodide salts of the 1-n-butyl-3-methylimidazolium cation,
i.e., [bmim][X] (X ) Cl-, Br-, and I-), have also been
reported. In these studies, the nucleophilicities of Cl- and
I-, compared with Br-, were found to be approximately
constant; iodide showed a little variation, but chloride
showed more.9
It is well-known that a strong bond is present between
the halide anions and the complex [bmim]+ cation;10 this
“hydrogen bond” is formed via the hydrogen atom on a
carbon R to a quaternary nitrogen.11 Moreover, there have
been speculations on the effect of this ionic liquid
hydrogen bonding on organic reactions.12,13 Thus, we
anticipated that the dissociation of the [bmim]+ cation
from the halide counterion, in reaction media in the
presence of substrate, would give rise to a high concen-
tration of available halide ion, which might effectively
catalyze certain reactions. In view of these consider-
ations, we have explored the cleavage of ethers by uti-
lizing as a catalyst the enhanced halide anion nucleo-
philicity of the ionic salt [bmim][Br] in ionic liquid [bmim]-
[BF4] as a solvent media.
Recently, Kemperman et al. reported the use of chlo-
roaluminate ionic liquids for the cleavage of aromatic
methyl ethers.14 Acylative cleavage of ethers using
1-ethyl-3-methylimidazolium halogenoaluminate ionic
liquids has also been reported,15 as has cleavage of ether
using anhydrous hydrobromic acid in 1-methylimida-
zole.16 However, to our knowledge, there has been no
report on the dealkylation of ethers using the enhanced
halide nucleophilicity of an ionic liquid anion in the
presence of a proton source in ionic liquid media.
Herein, we report the application of the enhanced
nucleophilicity of the ionic liquid salt [bmim][Br] for the
[bmim][Br]
(equiv)
time
(h)
yield
(%)b
entry
protic acid
equiv
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
HBr (47%)
HBr (47%)
HBr (47%)
5
2
1
7
9
96
97
94
32
22
22
22
14
22
14
22
22
22
22
22
22
22
3
p-TsOH
p-TsOH
p-TsOH
MsOH
MsOH
AcOH
3
2
3
3
3
3
3
3
3
3
3
3
30
97
97
27
97
2
3
3
3
3
AcOH
HCl (35%)
HCl (35%)
H2SO4 (50%)
H2SO4 (50%)
H2O
25
93
29
93
3
3
a
All reactions were carried out on a 1.0 mmol reaction scale of
2-methoxynaphthalene 1 in 1.0 mL of [bmim][BF4] at 115 °C.
b
Isolated yield.
nucleophilic displacement of the alkyl group in aryl-
alkyl, alkyl-alkyl, and aryl-alkyl cyclic ethers to obtain
the corresponding phenol or alcohol in an ionic liquid as
the medium and in the presence of a proton source. We
also report the regeneration of the phenol in this system
using only stoichiometric amounts of concentrated hy-
drobromic acid in the ionic liquid, a procedure that could
be used to significantly reduce the amount of concen-
trated hydrobromic acid used in such conversions, as
typically performed by conventional methods.
Resu lts a n d Discu ssion
To investigate the relative nucleophilic reactivity of
various ionic liquid salts, we carried out the demethyla-
tion of 2-methoxynaphthalene (1) in the ionic liquid
[bmim][BF4] in the presence of various protic acids. Table
1 illustrates the nucleophilic demethylation of this com-
pound with the Bro¨nsted acids, concentrated hydrobromic
acid (47%), p-toluenesulfonic acid (p-TsOH), methane-
sulfonic acid (MsOH), acetic acid, concentrated hydro-
chloric acid (35%), and dilute sulfuric acid (50%), as well
as a combination of these protic acids as proton donors
with [bmim][Br] as a nucleophile source; initial investi-
gations were done using [bmim][BF4] as the reaction
medium. Reactions were performed on a 1 mmol reaction
scale of methyl ether 1, along with protic acid alone, and
with the combination of protic acid and ionic liquid
[bmim][Br] on different mmol scales in 1 mL of [bmim]-
[BF4].
The reaction with concentrated hydrobromic acid alone
with 5 or 2 mmol equiv in [bmim][BF4] was completed
in 7 and 9 h, respectively, affording 2-naphthol 2 in
excellent yields (96 and 97%, entries 1 and 2, respec-
tively). The same reaction with a lower mole ratio (1.1
mmol equiv) also furnished the desired product in good
yield but was significantly slower and required longer
reaction times (32 h, 94%, entry 3). This difference can
(8) (a) Brauman, J . I.; Olmstead, W. N.; Lieder, C. A. J . Am. Chem.
Soc. 1974, 96, 4030-4031. (b) Olmstead, W. N.; Brauman, J . I. J . Am.
Chem. Soc. 1977, 99, 4219-4228. (c) Tanaka, K.; Mackay, G. I.;
Payzant, J . D.; Bohme, D. K. Can. J . Chem. 1976, 54, 1643-1659.
(9) (a) Lancaster, N. L.; Welton, T.; Young, G. B. J . Chem. Soc.,
Perkin Trans. 2 2001, 2267-2270. (b) Lancaster, N. L.; Salter, P. A.;
Welton, T.; Young, G. B. J . Org. Chem. 2002, 67, 8855-8861.
(10) (a) Avent, A. G.; Chaloner, P. A.; Day, M. P.; Seddon, K. R.;
Welton, T. J . Chem. Soc., Dalton Trans. 1994, 3405-3413. (b) Abdul-
Sada, A. K.; Al-J uaid, S.; Greenway, A. M.; Hitchcock, P. B.; Howells,
M. J .; Seddon, K. R.; Welton, T. Struct. Chem. 1990, 1, 391-394. (c)
Elaiwi, A.; Hitchcock, P. B.; Seddon, K. R.; Srinivasan, N.; Tan, Y.-M.;
Welton, T.; Zora, J . A. J . Chem. Soc., Dalton Trans. 1995, 3467-3472.
(11) Cannizzaro, C. E.; Houk, K. N. J . Am. Chem. Soc. 2002, 124,
7163-7169.
(12) (a) Sethi, A. R.; Welton, T. In Ionic Liquids: Industrial
Applications to Green Chemistry; Rogers, R. D., Seddon, K. R., Eds.;
ACS Symposium Series 818; American Chemical Society: Washington,
DC, 2002; pp 241-246. (b) Aggarwal, A.; Lancaster, N. L.; Sethi, A.
R.; Welton, T. Green Chem. 2002, 4, 517-520.
(13) Dzyuba, S. V.; Bartsch, R. A. Tetrahedron Lett. 2002, 43, 4657-
4659.
(14) Kemperman, G. J .; Roeters, T. A.; Hilberink, P. W. Eur. J . Org.
Chem. 2003, 1681-1686.
(15) Green, L.; Hemeon, I.; Singer, R. D. Tetrahedron Lett. 2000,
41, 1343-1346.
(16) Driver, G.; J ohnson, K. E. Green Chem. 2003, 5, 163-169.
J . Org. Chem, Vol. 69, No. 10, 2004 3341

Boovanahalli et al.
TABLE 2. Con ver sion of 2-Meth oxyn a p h th a len e to
2-Na p h th ol in Va r iou s Ion ic Liqu id s a n d Solven tsa
be attributed to the catalytic influence of bromide ion
concentration on the rate of ether cleavage, and it
suggests that a minimum of ca. 2 equiv of hydrobromic
acid is required for achieving an optimal conversion rate.
[bmim][X] or
solvent
protic acid
(equiv)
[bmim][Br] time yield
entry
(equiv)
(h)
(%)b
1
2
3
4
5
6
7
8
9
[bmim][PF6]
HBr (47%) (2)
12
16
12
22
48
48
48
48
20
16
22
22
90
92
95
37
37
34
19
35
90
93
93
-
Use of other protic acids such as p-TsOH, MsOH,
hydrochloric acid, and sulfuric acid alone resulted in poor
conversion (30, 27, 25, and 29%, entries 5, 8, 12, and 14,
respectively); moreover, the reaction using acetic acid did
not proceeded at all (entry 10). We presume that these
differences are due to the lower nucleophilicity of the
counterions of these acids relative to hydrobromic acid.
However, the efficiency of p-TsOH, MsOH, concentrated
hydrochloric acid (35%), and dilute sulfuric acid (50%)
in cleaving the methyl ether was significantly increased
when these were employed together with the ionic liquid
[bmim][Br] as a source of additional nucleophile.
[bmim][NTf2] HBr (47%) (2)
[bmim][OTf] HBr (47%) (2)
[bmim][OAc] HBr (47%) (2)
ClCH2CH2Cl HBr (47%) (2)
benzene
CH3CN
H2O
HBr (47%) (2)
HBr (47%) (2)
HBr (47%) (2)
p-TsOH (3)
[bmim][PF6]
3
3
3
3
10
11
12
[bmim][NTf2] p-TsOH (3)
[bmim][OTf] p-TsOH (3)
[bmim][OAc] p-TsOH (3)
a
All reactions were carried out on a 1.0 mmol reaction scale of
2-methoxynaphthalene 1 in 1.0 mL of ionic liquid or solvent at
115 °C. Isolated yield.
b
The reaction using the combination of p-TsOH as
proton donor on a 2 mmol scale in conjunction with
[bmim][Br] on a 2 mmol scale as a nucleophile source
was complete in 22 h, furnishing the desired product
2-naphthol 2 in very good yield (97%, entry 6). Conse-
quently, the duration of reaction could be reduced further
by employing p-TsOH and [bmim][Br], each on a 3 mmol
scale, complete conversion being achieved within 14 h
(97%, entry 7). As expected, similar results were obtained
using the combination of ionic liquid [bmim][Br] along
with protic acids, MsOH, concentrated hydrochloric acid
(35%) and dilute sulfuric acid (50%), each on a 3 mmol
ratio, giving the desired product in 14, 22, and 22 h,
respectively, in good yields (97, 93, and 93%, entries 9,
13, and 15, respectively). However, under the same
conditions, the reaction using acetic acid and water as a
proton source along with [bmim][Br] as nucleophile did
not proceed at all, even after 22 h (entries 11 and 16).
Accordingly, it was found that [bmim][Br] alone also is
not sufficiently effective for dealkylation of the ether,
with no detectable transformation being noted when the
reaction was performed with this reagent alone in [bmim]-
[BF4], despite heating for 22 h (entry 4).
and solvents such as 1,2-dichloroethane, benzene, aceto-
nitrile (Table 2).
A comparison of entries 3 and 4 in Table 2 demon-
strates that demethylation in the ionic liquid [bmim][OTf]
not only proceeded remarkably faster but also provided
2-naphthol 2 in higher yield (95%) (12 h, entry 3). In
contrast to this, the same reaction in [bmim][OAc]
converted only 37% of 2-methoxynaphthalene 1 to 2-naph-
thol 2 in 22 h (entry 4). It is noteworthy that both the
ionic liquids [bmim][PF6] and [bmim][NTf2] were also
found to be equally good for this conversion, affording
the desired product 2-naphthol 2 in good yield (90 and
92% in 12 and 16 h, entries 1 and 2, respectively).
Interestingly, by employing ionic liquids [bmim][PF6],
[bmim][NTf2], and [bmim][OTf] as reaction media in the
presence of [bmim][Br] and p-TsOH, the expected prod-
uct, 2-naphthol 2, was also obtained in good yield (90,
93, and 93%, respectively; 20, 16, and 22 h, entries 9-11,
respectively), whereas the same reaction in [bmim][OAc]
did not proceed at all, even after 22 h (entry 12). All four
solvents, 1,2-dichloroethane, benzene, acetonitrile, and
water, afforded the desired compound in low yield,
despite having the reaction heated for 48 h (entries 5-8,
yields of 37, 34, 19, and 35%, respectively), indicating that
the specific ionic liquid used plays a pivotal role in
providing the enhanced nucleophilicity of HBr in this
displacement reaction, and that certain solvents can
moderate the effectiveness of the ether cleavage reagent.
From these results, it is evident that both an efficient
nucleophile as well as an effective proton source are
required to achieve a smooth transformation of ether to
phenol, with the reaction failing when either of the two
components is omitted. Notably, hydrobromic acid ex-
hibits dual character, being a proton donor as well as an
effective nucleophile in the ionic liquid.
The initial reaction is obviously formation of the
protonated ether. Cleavage then involves nucleophilic
attack by the halide ion on the alkyl carbon adjacent to
this protonated ether. In the cases where p-TsOH donates
a proton, the ionic liquid [bmim][Br] acts as a halide
nucleophile source, with the resulting ionic liquid stabi-
lized as [bmim]+[OTs]-.
These results reveal that the ionic liquids [bmim][PF6],
[bmim][NTf2], and [bmim][OTf] enhance the reactivity of
HBr, as does the combination of [bmim][Br] and p-TsOH,
resulting in the facile demethylation of 2-methoxynaph-
thalene 1. Thus, considerable selectivity in ether cleavage
can also be achieved by using [bmim][PF6], [bmim][NTf2],
and [bmim][OTf] as a solvent medium. On the other
hand, a significant decline in yield or no reaction is noted
when using [bmim][OAc], indicating that this ionic liquid
diminishes not only the activity of HBr but also the
combination of [bmim][Br] and p-TsOH, thereby giving
poor conversion.
To enlarge the scope of both of these dealkylation
methods, we have subjected a series of aryl methyl ethers,
as well as aryl benzyl and propyl ethers, to the same
conditions as done for entries 2 and 7 in Table 1; the
results are shown in Table 3. Interestingly, entries 1 and
As with organic solvents, all ionic liquids will not be
suitable for a particular reaction, and any one ionic liquid
will not always be best for every reaction. However, by
varying the structure of the ionic liquid, one can optimize
both the rates and the selectivity for each reaction. As a
further study of the reactions shown in entry 2 and 7 in
Table 1 and to establish the generality of reaction media,
we have performed demethylation of 2-methoxynaphtha-
lene 1 employing various other ionic liquids such as
[bmim][PF6], [bmim][NTf2], [bmim][OTf], [bmim][OAc],
3342 J . Org. Chem., Vol. 69, No. 10, 2004

Demethylation of Methyl Phenyl Ethers
TABLE 3. Clea va ge of Va r iou s Eth er s in [Bm im ][BF 4]a
thol in 12 h (89%)]. The same reaction using a combina-
tion of [bmim][Br] and p-TsOH in [bmim][BF4] was
accomplished in identical yield (89%), but it required
longer reaction time (20 h). Similarly, in the demethy-
lation of 2-methoxydibenzofuran (entry 4), complete
transformation was achieved in 5 h (94%) with concen-
trated hydrobromic acid in [bmim][BF4], whereas the
combination of [bmim][Br] and p-TsOH in [bmim][BF4]
afforded the expected product in 10 h in good yield (95%).
Furthermore, in entries 5-7, demethylation of 2-bromo-
6-methoxynaphthalene (10 h, 95% and 12 h, 92%),
4-methoxybenzophenone (13 h, 93% and 13 h, 91%), and
4-methoxybiphenyl (20 h, 94% and 20 h, 95%), respec-
tively, gave identical results with both procedures.
A few steroids and coumarins are known to be sensitive
to high concentrations of protic and Lewis acids at higher
temperatures. Therefore, methods for the efficient dem-
ethylation of these methoxy aromatic compounds would
be useful. Remarkably, estrone-3-methyl ether and 17â-
estradiol-3-methyl ether underwent demethylation with
both the procedures in 5 h, providing the desired products
estrone (entry 8, 86 and 85%, respectively) and â-estra-
diol (entry 9, 87 and 87%, respectively) in good yields.
Consequently, virtually complete demethylation of 7-meth-
oxycoumarin was accomplished in 13 h, under both the
conditions, giving 7-hydroxycoumarin in moderate yield
(entry 10, 75 and 80%, respectively).17
We have also investigated the reactivity of an alkyl
alkyl ether and an aryl alkyl cyclic ether toward both
the reagents. 2-(3-Methoxypropyl)naphthalene gave a
mixture of 2-(3-bromopropyl)naphthalene and 2-(3-hy-
droxypropyl)naphthalene under both procedures, in 12
h (45, 46% and 46, 47%, entry 11). Informatively, 2,3-
dihydrobenzofuran underwent ring cleavage to give cor-
responding o-2-bromoethylphenol with both the proce-
dures, but in low yield (40 and 40%, entry 12). Unfortu-
nately, with this reactant, we were unable to effect an
improvement in yield even upon prolonged heating, with
byproducts being formed in preference to additional
product. It is evident from these results that both the
procedures for the dealkylation of ethers furnished the
desired products in good to excellent yield.
Con clu sion
From the results described in this report, it is apparent
that one can often anticipate the conditions required to
achieve a particular conversion efficiently and effectively
by making use of an ionic liquid having a suitable
combination of cation and anion. Here, we have demon-
strated one useful application of enhanced halide anion
nucleophilicity, in the form of ionic liquid [bmim][Br], in
conjunction with a proton source for the regeneration of
phenols from various ethers. In this work, the halide
anion of the ionic liquid [bmim][Br] exhibits a pivotal role
as an efficient nucleophile acting in the presence of an
effective proton donor to achieve this important and
general transformation. There are some limitations, as
cleavage of an alkyl alkyl ether under the same condi-
tions resulted in the mixture of corresponding alcohol and
haloalkane, and efforts to cleave an aryl alkyl cyclic ether,
a
All reactions were carried out on a 1.0 mmol reaction scale of
ether in 1.0 mL of [bmim][BF4] at 115 °C using a 2.0 mmol ratio
of concentrated hydrobromic acid (47%). All reactions were
carried out on a 1.0 mmol reaction scale of ether in 1.0 mL of
[bmim][BF4] at 115 °C using a combination of p-TsOH and
b
d
[bmim][Br] each in
a
3.0 mmol ratio. c Isolated yield. 2-(3-
Bromopropyl)naphthalene was also obtained in 45 and 46% yield
for method A and method B, respectively. e 2-(2-Bromoethyl)phenol
was obtained, and starting material was recovered.
2 show that both of the dealkylation procedures are
widely applicable, besides 2-methoxynaphthalene (entries
2 and 7 in Table 1), 2-n-propoxynaphthalene (13 h, 95%
and 20 h, 91%, entry 1) and 2-benzyloxynaphthalene (4
h, 93% and 4 h, 90%, entry 2) can also be cleaved
efficiently in good yield. In entry 3, demethylation of
1-methoxynaphthalene with concentrated hydrobromic
acid in [bmim][BF4] yielded the desired product 1-naph-
(17) Moderate isolated yield can be attributed to the poor solubility
of 7-hydroxycoumarin in ether at room temperature; hence, product
was isolated with warm ether.
J . Org. Chem, Vol. 69, No. 10, 2004 3343

Boovanahalli et al.
2,3-dihydrobenzofuran, resulted in a low yield of the
desired product, o-2-bromoethylphenol, by both proce-
dures.
ethers can also be cleaved efficiently. Both the procedures
are expected to contribute significantly to the develop-
ment of green chemistry strategies for the regeneration
of phenols from ethers.
Cleavage of aryl alkyl and alkyl alkyl ethers depends
on three factors: halide anion nucleophilicity, proton
source, and temperature. Among the proton sources
employed, p-TsOH was found to be preferable in terms
of yield and ease of handling; moreover, sulfonate ion is
a very weak base and thus is a very good leaving group.
Other proton sources (MsOH, concentrated hydrochloric
acid (35%), dilute sulfuric acid (50%)) in the presence of
[bmim][Br] also afforded the desired products in good
yield. However, the use of acetic acid and water as a
proton source under the same conditions did not proceed
at all. Out of the several ionic liquids employed as
reaction media, [bmim][BF4] most reliably enhanced the
reactivity of the combination of [bmim][Br] and p-TsOH,
furnishing the desired products in high yield.
Exp er im en ta l Section
Typ ica l P r oced u r e for Clea va ge of Eth er : Meth od A.
Ether (1 mmol) and concentrated hydrobromic acid (47%, 2
mmol) in 1-n-butyl-3-methylimidazolium tetrafluoroborate (1.0
mL) were stirred at 115 °C for an appropriate time (see Table
3). The reaction time was determined by TLC analysis. The
reaction mixture was extracted with diethyl ether (4 × 10 mL).
The combined ether extracts were concentrated under reduced
pressure, and the resulting product was purified by flash
column chromatography (10% EtOAc/hexane) to furnish phe-
nol. The products were characterized by comparison of their
1H NMR, 13C NMR, and TLC data with authentic samples.
The spectral data of all products were identical with those of
authentic samples.
Meth od B. Ether (1 mmol), 1-n-butyl-3-methylimidazolium
bromide (657 mg, 3 mmol), and p-TsOH (3 mmol) in 1-n-butyl-
3-methylimidazolium tetrafluoroborate (1.0 mL) were stirred
at 115 °C for an appropriate time (see Table 3). The reaction
mixture was worked up as in method A to obtain the phenol
product.
Our alternative approach for the facile cleavage of
ethers offers a promising tool, as it involves only near
stoichiometric amounts of hydrobromic acid, which is
significantly less than the amount of this acid typically
used in conventional ether cleavage methods. Thus, the
use of ionic liquids as reaction media for this transforma-
tion avoids the use of excessive amounts of hydrobromic
acid in acetic acid or acetic anhydride, by functioning in
a dual role, as the solvent as well as the catalyst.
Moreover, the products can be obtained in good yield by
a simple isolation procedure. The scope and generality
of both of the procedures are illustrated with some
oxygen-containing heterocyclic aromatic compounds. We
have also demonstrated that both methods are widely
applicable: besides methyl ethers, benzyl and propyl
Ack n ow led gm en t. This work was supported by
National Research Laboratory Program. We are grateful
to Professor J ohn A. Katzenellenbogen for his comments
on this manuscript.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectral data of compounds in this manuscript. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035886E
3344 J . Org. Chem., Vol. 69, No. 10, 2004