Convenient O-methylation of phenols with dimethyl carbonate

Article abstract of DOI:10.1055/s-1998-1893

Reaction of phenols in dimethyl carbonate in the presence of cesium carbonate at 120-160° C gave aryl methyl ethers in good yields, whereas the reaction of aliphatic alcohols gave the corresponding alkyl carbonates. This method provides a useful synthetic method for preparation of various aryl methyl ethers without using toxic methyl iodide or dimethyl sulfate. O-Methylation of the aromatic hydroxy group of estradiol was carried out in 2 steps without protection of the alcoholic hydroxy group in the same molecule.

Full text of DOI:10.1055/s-1998-1893

October 1998
SYNLETT
1063
Convenient O-Methylation of Phenols with Dimethyl Carbonate
Youngmin Lee and Isao Shimizu*
Department of Applied Chemistry, Waseda University
Okubo 3-4-1, Shinjuku-ku, Tokyo 169-8555, Japan
Received 7 July 1998
Abstract: Reaction of phenols in dimethyl carbonate in the presence of
cesium carbonate at 120-160° C gave aryl methyl ethers in good yields,
whereas the reaction of aliphatic alcohols gave the corresponding alkyl
carbonates. This method provides a useful synthetic method for
preparation of various aryl methyl ethers without using toxic methyl
iodide or dimethyl sulfate. O-Methylation of the aromatic hydroxy
group of estradiol was carried out in 2 steps without protection of the
alcoholic hydroxy group in the same molecule.
phenyl ether by the reaction of the phenol anion with dimethyl
carbonate, works as a base again as shown in Scheme 2 [7, 8].
Carboxylic acids can be also methylated to their methyl esters, thus,
both the phenolic hydroxide and the carboxylic acid of mycophenolic
o
acid were methylated at 160 C to give 4 in 69% yield (Scheme 1).
Replacement of chemical processes using toxic materials by those with
safes materials is an urgent issue in organic synthesis. The O-
methylation reaction of phenols is important in organic synthesis,
however, toxic dimethyl sulfate or methyl iodide is used generally as a
methylation agent. Dimethyl carbonate is produced cheaply on an
industrial scale by the catalytic oxidative carbonylation of methanol as a
non-phosgene process [1-3]. Although dimethyl carbonate is recognized
as a useful methoxycarbonylating reagent, its synthetic use as a
methylating agent is rare [4, 5]. In this paper we describe that
methylation of phenols can be carried out using dimethyl carbonate in
good yields in the presence of a catalytic amount of base.
Scheme 1
As shown in Table 1 the reactions using sodium carbonate or potassium
carbonate were very slow. The use of Cs CO gave the best result and
2
3
the reaction of 1-naphthol (1) in the presence of Cs CO (0.25 eq.) in
2
3
dimethyl carbonate at 120° C for 4 h gave O-methyl-1-naphthol (2) in
00% yield [6].
1
Scheme 2
Selective methylation of estradiol is possible by applying this method.
o
Thus, methylation of estradiol in dimethyl carbonate at 120 C for 4 h
gave 3O-methyl-17O-methoxycarbonylestradiol (5) in 87% yield.
Treatment of the carbonate (5) with K CO3 in methanol gave 3O-
2
methylestradiol (6) in 74% yield (Scheme 3).
Various aromatic hydroxy compounds were converted to the
corresponding O-methyl ethers but the reaction of geraniol gave methyl
geranyl carbonate as the sole product (Scheme 1). These results indicate
that the phenol anion attacks the methyl group of dimethyl carbonate
directly, whereas the alcoholic anion attacks the carbonyl groups.
Furthermore, the reaction proceeded with a catalytic amount of Cs CO ;
2
3
cesium methyl carbonate, which is generated after formation of a methyl
Scheme 3

1
064
LETTERS
SYNLETT
In addition to the advantage that this reaction is clean, isolation of the
products is carried out with ease by concentration before purification.
(3) Y. Ono, Pure & Appl. Chem., Vol. 68, No 2, pp 367-375, 1996.
(4) P. Tundo, F. Trotta, G. Moraglio and F. Ligorati, Ind. Eng. Chem.
Therefore this method provides
a useful synthetic method for
Res., 27 (1988) 1565.
methylation of phenols, especially in a large scale.
(5) M. Lissel, S. Schmidt. B. Neumann. Synthesis (1986) 382.
(
6) Typical experiment for Table 1. Methylation of 1- naphthol (1)
(36.2 mg), cesium carbonate (20.4 mg), and dimethyl carbonate (2
ml) were placed in a test tube equipped with a sealed cap. The test
Acknowledgment: This research was supported by the Materials
Characterization Central Laboratory, Waseda University, for NMR and
HRMS measurement. This research was carried out as a part of the
research program in a Grant-in-Aid for Scientific Research on Priority
Areas (No 10132261) of Education, Science, Sports, and Culture of
Japan and the Materials Research Laboratory for Bioscience and
Photonics, Waseda University. YL thanks Iwaki Foundation for Foreign
Students for financial support.
o
tube was heated at 120 C for 4 h. After the mixture was cooled
to room temperature, the volatile materials were evaporated in
vacuo. The residue was chromatographed on SiO2 with 5%
EtOAc - Hexane to give O-methyl-1-naphthol (2) (40 mg, 100%
1
yield). H NMR (300 MHz, CDCl ) : δ 3.9 ( 3H, s), 6.72 ( 1H, dd,
3
J = 1.1 Hz, J = 2.2 Hz), 7.27 -7.35 ( 4H, m), 7.65 - 7.75 (1H, m),
8
.13 - 8.22 ( 1H, m)
-1
IR (ν, cm ) : 3053 - 3000, 2950 - 2810, 1650, 1580, 1510, 1465,
450, 1440, 1390, 1265, 1240.
References and notes
1
(
1) D. Delledonne, F. Rivetti and U. Romano, J. Organometal. Chem.,
88 (1995) C15.
(7) Review, Y. Ono, Applied Catalysis A: General 155 (1997) 133-
4
166.
(2) Chem. Eng. News, 4 May (1992) 25.
(8) P. Tundo, M. Selva, ChemTech 25 (5) (1995) 31.