Bis(chloromethyl) Ether

[542-88-1]  · C2H4Cl2O  · Bis(chloromethyl) Ether  · (MW 114.96)

(useful reagent for the chloromethylation of aromatic moieties1 and for the preparation of oxygen-containing heterocycles2)

Alternate Names: BCME; a,a-dichloromethyl ether; 1,1-dichloromethyl ether; chloromethyl ether; oxybis(chloromethane); sym-dichloromethyl ether.

Physical Data: bp 106 °C; mp -41.5 °C; d 1.315 g cm-3.

Preparative Method: the large-scale preparation of bis(chloromethyl) ether using paraformaldehyde, hydrogen chloride, and chlorosulfonic acid has been reported by Buc as an Organic Synthesis preparation.3

Handling, Storage, and Precautions: this agent is a strong irritant to the eyes and respiratory tract and is a known carcinogen.4 All procedures using this reagent should be carried out in a fume hood.

Aromatic Chloromethylation.

Bis(chloromethyl) ether is an effective reagent for the direct chloromethylation of a variety of aromatic substrates. The reaction occurs via electrophilic aromatic substitution of the oxonium ion generated upon treatment of the reagent with acid catalyst. For example, chloromethylation of p-nitroanisole using BCME and Zinc Chloride in dimethyl sulfide afforded 4-nitro-2-chloromethylanisole in 74% yield (eq 1).1 The procedure was reported to be superior to chloromethylation using paraformaldehyde and hydrogen chloride, which afforded only poor yields of the desired anisole. A variation of this process using Chlorosulfonic Acid as the catalyst chloromethylated p-nitrotoluene to give 2-chloromethyl-4-nitrotoluene in quantitative yield (eq 2).5

The chloromethylation of aromatic heterocycles has also been reported. For example, 3,5-dimethylisoxazole was chloromethylated to give 4-chloromethyl-3,5-dimethylisoxazole (eq 3).6 The synthesis of 5-(halomethyl)-2-pyranones for use as a-chymotrypsin inhibitors have also employed this chloromethylation procedure. Thus treatment of 5-(trifluoromethyl)-2-pyranone with BCME and sulfuric acid gave 3-(chloromethyl)-5-(trifluoromethyl)-2-pyranone in 50% yield (eq 4).7

Alkylation and Heterocycle Formation.

Oxygen-containing heterocycles have also been prepared using BCME. For example, tetrahydrofurans have been prepared via cyclocondensation of simple alkenes with chloromethoxymethyllithium (eq 5), an agent derived from BCME.2 Other examples include the preparation of macrocyclic heterocycles. For example, 18-crown-6 coronands have been prepared for use as ionophores via condensation of a bipyrazole with BCME (eq 6).8

BCME has also been employed in the preparation of symmetrical and unsymmetrical dimethyl ether derivatives (eq 7). Bis(pyridinium and imidazolium) quaternary salts, useful as reversible acetylcholinesterase inhibitors, were prepared via stepwise condensation of the requisite pyridine or imidazole with BCME followed by a second equivalent of amine heterocycle.9 Likewise, symmetrical dineopentyl ethers have been prepared by Refomatsky reaction using ethyl a-bromo esters, BCME, and zinc (eq 8).10

Phenols, thiols, phosphines, and pyridines have also been used as nucleophiles with BCME for the synthesis of symmetrical ethers. For example, 4-chlorophenol,11 2,5-dimethylbenzenethiol,12 pyridine,13 and triphenylphosphine14 gave, respectively, 90%, 72%, 48%, and 69% yields of the corresponding bis-alkylation products.

1. Bendz, G.; Culvenor, C. J.; Goldsworthy, L. J.; Kirby, K. S.; Robinson, R. JCS 1950, 1130.
2. Groen, M. B.; Jacobs, E. H. TL 1972, 4029.
3. Buc, S. R. OSC 1963, 4, 101.
4. Merck Index, 11th edn.; Merck: Rahway, NJ, 1989; p 3058. Carcinogenicity studies: IARC Monographs 1974, 4, 231. Fourth Annual Report on Carcinogens, 1985, 46.
5. Berezovskii, V. M.; Kurdyukova, V. A.; Preobrazhenskii, N. A. Zur. Russ. Fiz-Chim. 1951, 1163.
6. Gainer, J.; Howarth, G. A.; Hoyle, W.; Roberts, S. M.; Suschitzky, H. JCS(P1) 1976, 994.
7. Boulanger, W. A.; Katzenellenbogen, J. A. JMC 1986, 29, 1483.
8. Lupo, B.; Tarrago, G. BSF(2) 1984, 473.
9. Bedford, C. D.; Harris, R. N.; Howd, R. A.; Goff, D. A.; Koope, G. A.; Petesch, M.; Miller, A.; Nolen, H. W.; Musallam, H. A.; Pick, R. O.; Jones, D. E.; Koplovitz, I.; Sultan, W. E. JMC 1989, 32, 493.
10. Johnson, P. Y.; Zitsman, J. JOC 1973, 38, 2346.
11. Fujita, H.; Ohara, Y. NKK 1976, 1648 (CA 1977, 86, 29 454n).
12. Iovu, M.; Badau, E. Rev. Chim. (Bucharest) 1983, 34, 795 (CA 1984, 100, 138 684r).
13. Taylor, L. D.; McLaughlin, P. J. Appl. Polym. Sci. 1976, 20, 2225.
14. Ojima, J.; Kimura, A.; Ikeguchi, M. BCJ 1976, 49, 3709.

Gregory H. Merriman

Hoechst-Roussel Pharmaceuticals, Somerville, NJ, USA

Shinichi Itsuno

Toyohashi University of Technology, Japan

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