Demethylation of aromatic methyl ethers using ionic liquids under microwave irradiation

Article abstract of DOI:10.2174/157017811794557741

An efficient demethylation reaction for aromatic methyl ethers has been developed. Deprotection reactions give high yields with butylpyridinium bromide under microwave irradiation. Basic and acidic functional groups are tolerated if the reaction is performed under acidic conditions.

Full text of DOI:10.2174/157017811794557741

48
Letters in Organic Chemistry, 2011, 8, 48-52
Demethylation of Aromatic Methyl Ethers Using Ionic Liquids under
Microwave Irradiation
Mikko Passiniemi, Mikko J. Myllymäki, Juha Vuokko and Ari M.P. Koskinen*
Department of Chemistry, Aalto University School of Science and Technology, P.O. Box 16100, FI-00076 Aalto,
Finland
Received April 28, 2010: Revised July 16, 2010: Accepted December 09, 2010
Abstract: An efficient demethylation reaction for aromatic methyl ethers has been developed. Deprotection reactions give
high yields with butylpyridinium bromide under microwave irradiation. Basic and acidic functional groups are tolerated if
the reaction is performed under acidic conditions.
Keywords: Aromatic ether, demethylation, ionic liquid, microwave irradiation, solvent free.
INTRODUCTION
aromatic methyl ethers, being 78% for p-anisaldehyde.
Chauhan and Jain broadened the scope by changing the ionic
liquid to butylpyridinium bromide [bpy][Br] and 1-butyl-3-
methyl imidazolium bromide [bmim][Br] [9]. Dealkylation
was more facile in [bpy][Br] than in [bmim][Br] and
reactions also gave slightly higher yields. Demethylations
were conducted in 1 mmol scale both in the substrate and the
IL. With [bpy][Br] the yields varied between 71% and 90%,
being 86% for p-anisaldehyde.
The nucleophilic (Lewis basic) or electrophilic (Lewis
acidic) character of functional groups can be modified by
modulating their specific character through the use of
protective groups [1]. Ethers are useful protective groups for
alcohols in synthetic chemistry. Methyl ether is considered
to be the most effective protective group because of its high
stability under a variety of reaction conditions. This stability
towards reagents sometimes leads to harsh deprotection
conditions, which in many cases give rise to side reactions
and lower yields [2]. For the deprotection of alkyl aryl ethers
a wide variety of reagents have been developed, including
Lewis acids (e.g. BBr3 [3], AlCl3 [4]), Brønsted acids (e.g.
Pyr•HCl [5]) and nucleophilic reagents (e.g. NaSEt in DMF
[6]). These methods are often quite drastic and require high
reaction temperatures, which often lead to decomposition of
the substrate or unwanted side reactions. Consequently ether
cleavage methods under milder conditions have been the
focus of much attention.
Dealkylation of aryl alkyl ethers using ionic liquids is
reported to be efficient also without microwave irradiation.
Driver and Johnson have shown 3-methylimidazolium
bromohalogenates(I) [HmimBr-HBr] demethylate anisole
and other ethers at room temperature [10]. Kemperman et al.
have expanded the scope of this methodology to
chloroaluminate ionic liquids ([TMAH][Al2Cl7]) [11].
RESULTS AND DISCUSSION
Encouraged by the results of Desai [8] and Chauhan [9]
we examined the use of ionic liquids in the cleavage of an
aromatic benzyl ether when hydrogenation was not a choice
[12]. Debenzylation proceeded smoothly under microwave
irradiation, albeit in our hands the reaction required more
ionic liquid (200 mol-%) compared to previous results by
Chauhan. We therefore decided to have a closer look at the
demethylation reaction of aromatic ethers especially since
detailed demethylation conditions have not been reported.
Ionic liquids (IL) have attracted scientists for years [7].
Their properties (low vapour pressure, recyclability, high
thermal stability, ease of handling, functions as catalyst as
well as reaction media) make them attractive for
environmentally benign chemical processes. Ionic liquids
have especially good response to microwave irradiation: they
absorb energy very rapidly and at high temperatures they can
function as reagents, thus making them attractive reactive
solvents for chemical synthesis.
To investigate and find the best conditions, we carried
out demethylations in four different IL’s (Fig. 1); N-Bu4NBr,
IL have been used successfully in demethylation
reactions of aromatic methyl ethers under microwave
irradiation. Kulkarni et al. demethylated various aryl methyl
ethers in pyridine hydrochloride under microwave irradiation
[8]. They performed demethylations in 10 mmol scale in a
closed round-bottomed flask with a five-fold excess of ionic
liquid. Isolated yields varied between 74-95% for
N,N-BuMeIm
([bmim][Br]),
N,N-BuMe2ImBr
([bmmim][Br]) and N-BuPyBr ([bpy][Br]). p-Anisaldehyde
was chosen as the model compound (Scheme 1). The
substrate and the IL were mixed together and irradiated in a
CEM Discovery microwave reactor in short cycles [13]. GC
samples were taken after each irradiation cycle to determine
the progress of the reaction. Conversions after five
irradiation cycles varied between <20% (N-Bu4NBr) to 60-
70% ([bpy][Br] and [bmmim][Br]) based on GC analysis.
With all four ionic liquids used, there was substantial
formation of O-butylated phenol ether as a side product (by
*Address correspondence to this author at the Department of Chemistry,
Aalto University School of Science and Technology, P.O. Box 16100, FI-
00076 Aalto, Finland; Tel: +358 9 470 22526; Fax: +358 9 470 22538;
E-mail: Ari.Koskinen@tkk.fi
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Demethylation of Aromatic Methyl Ethers Using Ionic Liquids
Br-
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
49
Br-
N
N
N+
Br-
Br-
N
N
N
N-BuPyBr
N-Bu4NBr
N,N-BuMe2ImBr
N,N-BuMeImBr
[bpy][Br]
[bmmim][Br]
[bmim][Br]
Fig. (1). Structures of ionic liquids used in this study.
1H NMR), which has not been reported in the previous
studies. [bpy][Br] was chosen for further investigation over
N,N-BuMe2ImBr since the amount of by product was
substantially lower (less than 15% compared to 30% with
N,N-BuMe2ImBr). Also imidazolium based ionic liquids
decomposed (burnt-like material was recovered) more easily
under microwave irradiation and therefore isolation of
products required more tedious workup procedures. This
decomposition could be reduced by lowering the irradiation
power to 100 W or less, but unfortunately that decreased the
yield of the reaction.
In order to dampen the side reaction, the effect of a
Brønsted acid was studied (Table 1). This idea was backed
by the results of Chi who had studied the effect of an acid
with ionic liquids using conventional heating as the energy
source [14].
Most acids have an effect on the outcome. The formation
of p-butoxybenzaldehyde was diminished to almost non-
detectable amounts (by GC analysis) as it did with excess of
IL used. The presence of acids lowers the reactivity of the
bromide anion, thus decreasing the yield of the reaction.
Since the addition of an acid did not seem to improve the
reaction as much as the excess of IL (Table 1, entry 3), the
substrate scope study was performed without the acid
additive. Even though MsOH (Table 1, entry 4) gave slightly
better yield than HBr (Table 1, entry 9) the latter was used as
Brønsted acid for the practical reason to avoid
multicomponent systems and competing anions in such
reactions where separately noted.
CHO
CHO
Ionic liquid,
MW irradiation
HO
MeO
Scheme 1. Model reaction. Deprotection of p-anisaldehyde into p-
hydroxybenzaldehyde.
We next studied the influence of the amount of ionic
liquid on the conversion of substrate (Fig. 2). With 100 mol-
% of [bpy][Br] the isolated yield of p-hydroxybenzaldehyde
The substrate scope was explored next, and as can be
seen from the results in Table 2, the demethylation reaction
gave fair to good yields to a wide variety of aromatic methyl
ethers. Surprisingly p-bromoanisole gave phenol as a by-
product in a 40% yield (Table 2, entry 4). Similar results
have been reported by others in dealkylation reactions with
AlCl3 [15]. m-Bromoanisole gave only the demethylated 4-
bromophenol in an excellent 87% yield (entry 6) and phenol
after
8
irradiation cycles was 72% and p-
butoxybenzaldehyde was 12%. With 150 mol-% of IL
maximum conversion of 92% was reached in seven, with
200 mol-% in six (95%) and with 300 mol-% in three
irradiation cycles (97%). Using 200 mol-% or more of
[bpy][Br] the amount of side product was negligible.
Fig. (2). GC-conversions with different amounts of [bpy][Br]. Line, p-anisaldehyde; Dashed line, p-hydroxybenzaldehyde; Dotted line, p-
butoxybenzaldehyde. The amount of IL: ꢀ, 100 mol-%; ꢁ, 150 mol-%; ꢂ, 200 mol-%; ꢃ, 300 mol-%.

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Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Passiniemi et al.
Table 1. The Effect of Brønsted acid to the Demethylation Reactiona
Entry
Acid
Yield (%)
Entry
Acid
Yield (%)
1
2
3
4
5
- (closed vessel)
- (open vessel)
72
46
80
81
31
6
7
BzOH
AcOH
63
52
(71) impure
73
- (closed vessel, 300 mol-% of IL)b
8
CF3CO2H
HBr (48-%)
NH4Br
MsOH
9
p-TsOH
10
16
aProcedure: 1.0 mmol of the substrate, 1.0 mmol of the corresponding acid and 1.0 mmol of [bpy][Br] were placed in a sealed CEM 10 mL reaction tube. After each irradiation cycle
1.0 mmol more of the IL was added. The mixture was irradiated in cycles until no more progress was detected with GC analysis. Method: P = 300 W , Tmax = 100 ºC, Ramp 30 sec,
Hold 10 sec, PowerMax (full air cooling) ON, Stirring ON. bThe 10 mL reaction tube was loaded with 1.0 mmol of the substrate and 3.0. mmol of [bpy][Br]. The mixture was
irradiated in cycles until reaction ceased to progress.
Table 2. Substrate Screena
Yield (%)b
Entry
Nr. of cycles
Yield (%)b
Substrate
Substrate
Entry
Nr. of cycles
1
MeO
5
50
14
MeO
CN
6
92
CN
2
3
4
MeO
8
4
4
62
77
49
15
16
17
1
3
2
84
MeO
MeO
MeO
MeO
OH
CO2Me
90 d
MeO
Br
CO2H
95 e, g
35 e
CO2H
5
6
MeO
CHO
3
5
80
87
18
19
1
4
N
H
MeO
Br
MeO
CONH2
30
MeO
CHO
7
8
5
2
72
20
21
MeO
NH2
5
4
56 e(15)f
MeO
O
O
65 c
66 e
MeO
N
MeO
OHC
MeO
N
9
4
2
70
70
22
23
5
1
54 e
MeO
NH
MeO
CHO
OH
N
O
10
72
MeO

Demethylation of Aromatic Methyl Ethers Using Ionic Liquids
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
51
(Table 2). Contd…..
Substrate
Yield (%)b
Entry
Nr. of cycles
Yield (%)b
Substrate
Entry
Nr. of cycles
O
N
OH
11
3
85
24
1
86
MeO
O
BnO
31e (13)f
25
26
3
2
0
MeO
12
13
MeO
NHMe
6
2
OH
O
Trace e
MeO
94
MeO
NH2
aProcedure: 1.0 mmol of the substrate 3.0 mmol of [bpy][Br] were placed in a sealed CEM 10 mL reaction tube. The mixture was irradiated in cycles until no more progress was
detected with GC analysis. Method: P = 300 W, Tmax = 100 ºC, Ramp 30 sec, Hold 10 sec, PowerMax (full air cooling) ON, Stirring ON. bIsolated yields; c4-Hydroxybenzaldehyde as
e
f
product; d4-Hydroxybenzoic acid as product; 100 mol-% of HBr (48%) was used as an additive; Isolated yield without HBr in parentheses; gDecarboxylation was detected when
reaction was performed without HBr.
by-product could not be detected by GC analysis. Acetal
protecting group (2-(4-methoxyphenyl)1,3-dioxane, entry 8)
did not withstand the reaction conditions at all. Most of the
acetal protecting groups were cleaved off already after the
first irradiation cycle and the reaction followed the
deprotection reaction of p-anisaldehyde. With basic
(nucleophilic) amino groups 100 mol-% of 48% aq. HBr was
required for the reaction to proceed (entries 12, 18, 20, 21,
22). Presumably, the acid protonated the amine, thus making
it less prone to interfere with the ionic liquid. Also
carboxylic acids required 100 mol-% of 48% HBr (entries
17, 18). Without the acid, after one irradiation cycle p-anisic
acid had decarboxylated and also demethylated to phenol in
50% when a three-fold excess of the IL was used. The
reaction is fast, reliable and easy to perform. Amine and
carboxylic acid functionalities are tolerated when an
equimolar amount of HBr is added. This method can also be
used for the deprotection of aryl benzyl ethers (Table 2, entry
24).
ACKNOWLEDGEMENTS
The National Technology Agency of Finland (TEKES)
and Finnish Cultural Foundation are gratefully
acknowledged for financial support.
a
conversion of 83% (entry 17). The desired p-
REFERENCES AND NOTES
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desired 4-hydroxybenzoic acid in almost quantitative yield
(95%). Methyl ester also reacted with the [bpy][Br] and 4-
hydroxybenzoic acid was the sole product from the reaction
(entry 16). Decarboxylation of the acid was not detected.
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