O-Methylation of phenolic compounds with dimethyl carbonate under solid/liquid phase transfer system

Article abstract of DOI:10.1016/S0040-4039(02)00201-0

The industrially important alkyl aryl ethers, of which anisole is the simplest form, can be synthesized by reacting the corresponding phenols with the environmentally benign dimethyl carbonate (DMC). The reaction is carried out under mild conditions of temperature and pressure. Excellent yields and selectivity of product were obtained after a few hours of reaction.

Full text of DOI:10.1016/S0040-4039(02)00201-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2661–2663
O-Methylation of phenolic compounds with dimethyl carbonate
under solid/liquid phase transfer system
Samedy Ouk,a Sophie Thiebaud,a,* Elisabeth Borredon,a Pierre Legarsb and Lo¨ıc Lecomteb
aLaboratoire de Chimie Agro-industrielle, UMR 31010 INRA/INP-ENCIACET, 118 route de Narbonne,
31077 Toulouse cedex 4, France
bSNPE-Toulouse, Chemin de la loge, 31078 Toulouse cedex, France
Received 12 December 2001; revised 22 January 2002; accepted 25 January 2002
Abstract—The industrially important alkyl aryl ethers, of which anisole is the simplest form, can be synthesized by reacting the
corresponding phenols with the environmentally benign dimethyl carbonate (DMC). The reaction is carried out under mild
conditions of temperature and pressure. Excellent yields and selectivity of product were obtained after a few hours of reaction.
© 2002 Elsevier Science Ltd. All rights reserved.
In organic synthesis, dimethyl carbonate (DMC) is
considered as an alternative methylating reagent to
replace hazardous compounds such as methyl halides or
dimethyl sulfate.1–4
mono-methylation of 2,4-dihydroxybenzophenone in an
autoclave at the temperature ranges between 140 and
180°C in the presence of alkaline base.11
Recently, alkyl methyl carbonate was used to accom-
plish the O-methylation of phenols in the presence of
potassium carbonate and a polar solvent. Due to the
high boiling point of carbonate, the reaction can be
conducted under atmospheric pressure.12 The reaction
of hydroquinone with alkyl carbonates in the presence
of an alkaline base takes place in a soxhlet extractor at
170–200°C; the presence of a solvent such as pyridine
or an alkyl formamide is vital.13
The O-methylation of phenols leads to alkyl aryl ethers,
useful as starting materials for the preparation of fra-
grances, dyes and pesticides, as antioxidants in oils and
fats or as stabilisers of plastics.5
It has been found that the reaction of methylation of
phenols with DMC can be carried out in an autoclave
at 160°C with a catalyst system composed of an alka-
line base or a tertiary amine in association with an
iodide.6 Tertiary amines or phosphines,7 or nitrogen-
containing heterocyclic catalysts (4-[dimethylamino]-
pyridine),8 penta-alkylguanidines,9 cesium carbonate,10
have been used as catalysts to prepare phenolic ethers
by reaction of phenols with a dialkyl carbonate at a
temperature between 120 and 200°C under autogenous
pressure. Notari et al. described how 2-hydroxy-4-
alkoxybenzophenone was synthesised by selective
Basic zeolites, alumina or alumina-silica, were also
described as good catalysts in a continuous flow pro-
cess. The reaction was conducted in the vapour phase
at high temperature range from 180 to 300°C. High
yields of aryl methyl ether were obtained but by-prod-
ucts of C-methylation were observed.14,15 Fu et al.
described the vapour-phase O-methylation of catechol
with DMC over alumina. The alumina loaded with
Scheme 1.
Keywords: alkyl aryl ether; anisole; dimethyl carbonate; phase transfer catalyst; environmentally safe.
* Corresponding author. Tel.: 33(0)5 62 88 57 19; fax: 33(0)5 62 88 57 30; e-mail: sthiebaud@ensct.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00201-0

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S. Ouk et al. / Tetrahedron Letters 43 (2002) 2661–2663
lithium hydroxide was found to provide an excellent
selectivity toward guaiacol, whereas alumina loaded with
potassium nitrate is selective for the synthesis of vera-
trole.16–18
respectively, obtained. Under the same conditions, the
O-methylation of 2-naphthol yielded 82% of 2-methoxy-
naphtalene.25 It should be noted that crown ethers are
very expensive and toxic.
To overcome these problems, we have studied the reaction
of phenol derivatives with DMC under solid/liquid phase
transfer conditions (Scheme 1). The reaction was carried
out at 90–100°C under atmospheric pressure in a reactor
equippedwithastirrerandarefluxcondensatorforDMC.
At the end of the reaction, the base (K2CO3) was simply
recovered by filtration and the PTC was separated from
the reaction medium by liquid/liquid extraction with an
aqueous hydrochloric acid (pH 1) and tert-butyl methyl
ether (MTBE). The organic phase, containing methylated
products, was analysed by gas chromatography. The PTC
recovered in the aqueous phase can be regenerated.26
Gas/solid phase transfer methods using polyethylene
glycol (PEG) as phase transfer catalyst (PTC) and
potassium carbonate as base have been widely
reported.19–24 The reaction was conducted at high tem-
perature (180°C). The authors described that the
reaction is O-selective and resulted in good yields of
phenolic ethers. For some phenols, this procedure
seems to be restrictive due to their high boiling point
that creates difficulties in feeding the reactor.
Lissel et al. have reported the O-methylation of p-cresol,
t-butyl-phenol and phenol with DMC using crown ether
(18 crown 6) as PTC and potassium carbonate as base.
After 8 h at 100°C only 23, 36 and 40% yields were,
Among various catalyst systems tested, the couple of
K2CO3 (base)/tetrabutylammonium bromide (PTC) was
shown to be the most effective catalyst for the O-methyl-
ation of 2,4-dihydroxybenzophenone (2,4-DHB) (Table
1). Under such conditions, the reaction is regioselective
as 2-hydroxy-4-methoxybenzophenone (2-H-4-MB) is
exclusively obtained.
Table 1. Effect of catalyst system on the yield of the reac-
tion of 2,4-DHB (R=C6H5(CO)−; n=2) with DMCa
No
Base
PTC
Yieldb (%)
1
2
K2CO3
’’
(Et)4NBr
(Bu)4NBr
8.5
12
In order to improve the yield of the reaction, the
PTC/2,4-DHB ratio was modified. Increasing this ratio
from 0.05 (entry 2, Table 1) to 0.5 and 1.0 (entries 12 and
13, Table 2) resulted in a good yield. We have observed
that the mono-methylation on the OH group at position
4 took place first. The hydroxy group at position 2 may
be protected by a hydrogen bond with a carbonyl group
(Scheme 2).
3
4
5
6
’’
’’
’’
’’
(Octyl)4NBr
(Bu)4NOH
Ph3(CH2CH2OH)PCl
CHBG, HClc
(Bu)4PCl
4
11
1.5
8.5
11
7
’’
8
9
10
11
KHCO3
Cs2CO3
’’
(Bu)4NBr
(Et)4NBr
(Et)3BzNBr
(Bu)4NBr
2.5
5.5
4.5
1
KOH
a T: 93°C; molar ratio DMC/base/PTC/2,4-DHB: 16/1.5/0.05/1; time:
9 h.
b Yield of 2-H-4-MB; no trace of 2,4-dimethoxybenzophenone (2,4-
DMB) was observed.
c Hydrochloride of hexabutylguanidinium chloride.
Scheme 2.
Table 2.
No
Substrate (S)
PTCa/Sb
DMC/Sb
K2CO3/Sb
Time (h)
Yield (%)
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2,4-DHB
’’
Phenol
’’
’’
’’
’’
0.5
1
0.2
’’
’’
0.6
’’
0.3
0.4
0.5
0.6
0.5
’’
16
’’
’’
’’
’’
1.5
’’
0.75
’’
’’
’’
’’
1.5
’’
’’
’’
9
’’
5
10
13
5
’’
4
’’
5
34/3c
6/72c
31
64
80
96
99
25
48
99
97
95
99
45
0
’’
30
16
’’
’’
’’
8
10
’’
p-Cresol
’’
’’
’’
’’
’’
’’
’’
4
5
’’
’’
0.75
’’
0
1
0
’’
1
’’
All reactions were conducted at 93°C.
a PTC=Bu4NBr.
b mol/mol.
c Yield 2-H-4MB/yield 2,4-DMB.

S. Ouk et al. / Tetrahedron Letters 43 (2002) 2661–2663
2663
When this catalyst system (K2CO3/Bu4NBr) was used
with phenol and p-cresol, 100% conversion and selectiv-
ity to O-methylated products was achieved only after a
few hours (entries 17–18 and 21–24, Table 2). The
attempt to reduce the PTC amount led to a poor yield
(entries 14–16 and 19–20, Table 2), but longer reaction
times can improve the reaction yield (entries 15–16,
Table 2).
5. Dorothea, G. Phenol derivatives. Ullmann’s Encyclopedia
of Industrial Chemistry; Barbara, E.; Stephen, H.; Gail,
S., Eds.; VCH: Weinheim, 1991; Vol. A19.
6. Iori, G.; Romano, U. Patent GB 2,026,484 A, 1981, CAS
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7. Merger, F.; Tovae, F.; Schroff, L. Patent US 4,192,949,
1980, CAS No 92:6229c.
8. Thompson, R. B. Patent EP 0,104,598, 1984, CAS No
101:151578z.
The different reactivity between phenols can be
explained by the negative inductive effect (I− effect) of
the (C6H5)CO group of 2,4-DHB, which creates
difficulty in the reaction between the phenoxy ion with
DMC. The negative charge on the oxygen atom of the
phenoxy ion formed in situ by the reaction of the base
with 2,4-DHB is weakened by the attraction of this
effect. On the contrary, the I+ effect of the methyl
group of p-cresol accelerates the reaction kinetics.
9. Barcelo, G.; Grenouillat, D.; Senet, J. P.; Sennyey, G.
Tetrahedron 1990, 46, 1839–1848.
10. Lee, Y.; Shimizu, I. Synlett 1998, 1063–1064.
11. Notari, N.; Mizia, F.; Rivetti, F. Patent US 5,849,955,
1998, CAS No 129:54182m.
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425–430.
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Although we note that tetrabutylammonium bromide
alone can act as a catalyst (entry 25, Table 2), the yield
of the reaction is reduced to 45%, even if the molar
ratio is doubled. Moreover, the base alone is unable to
make the reaction take place (entry 26, Table 2).
In conclusion, we have presented an efficient method to
synthesise aryl methyl ethers by using the environmen-
tal safe, DMC as reagent. The reaction takes place
under mild conditions of temperature and pressure,
while good to excellent yields (95–99%) are obtained.
Furthermore, the catalysts (base and PTC) can be easily
recovered and regenerated.
23. Tundo, P.; Moraglio, G.; Trotta, F. Ind. Eng. Chem. Res.
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