Methoxyacetyl Chloride

[38870-89-2]  · C3H5ClO2  · Methoxyacetyl Chloride  · (MW 108.53)

(acylating reagent;1 precursor to methoxyketene;4 in combination with Lewis acids is a reagent for aromatic chloromethylation12)

Physical Data: bp 112-113 °C; nD20 1.4190; d 1.87 g cm-3.

Solubility: miscible with most nonprotic organic solvents.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: reacts readily with water, alcohols, and other protic solvents. Stable to storage at rt for long periods if kept moisture-free in closed bottles.

Acylation: Generation of Methoxyketene.

Methoxyacetyl chloride has been used for the preparation of esters and amides by reaction with alcohols and amines.1,2 Schotten-Baumann conditions or tertiary amine catalysis (eq 1)3 gives excellent yields. Use of Triethylamine, most commonly at rt, results in smooth generation of methoxyketene, [2 + 2] cycloaddition of which with both cyclic and acyclic imines (eq 2)4 gives stereopure b-lactams in good to excellent yield.5-8

Aromatic Chloromethylation.

Although commercially available in bulk quantities, methoxyacetyl chloride can also be readily prepared in excellent yield by simple reaction of methoxyacetic acid with Thionyl Chloride.9 It is important, however, that the reagent be prepared and distilled fairly rapidly, and that it not be exposed for prolonged periods to acids as, like other alkoxyacetic acids, it undergoes decarbonylative decomposition to produce chloromethyl methyl ether. Both protic and Lewis acids catalyze the decarbonylation, and the procedure has been recommended as a convenient means of generating Chloromethyl Methyl Ether free of Bis(chloromethyl) Ether (eq 3).9-11

Aluminum Chloride-catalyzed decarbonylation is relatively slow at 0-5 °C in nitromethane, and it has been suggested that MeO+=CH2 AlCl4- is formed under these conditions. When the reaction is carried out in the presence of certain types of aromatic substrates, smooth chloromethylation is observed (eq 4).12,13 The procedure is especially useful for anisoles which contain a powerful electron-withdrawing substituent in the ortho or para position (eqs 5 and 6). With aromatic substrates highly activated to electrophilic substitution, use of the same conditions leads either to formation of diarylmethanes (eq 7) or to polymerization.

Related Reagents.

Chloromethyl Methyl Ether.

1. Reese, C. B.; Stewart, J. C. M. TL 1968, 4273.
2. Bowden, B. F.; Picker, K.; Ritchie, E.; Taylor, W. C. AJC 1975, 28, 2681.
3. Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. JOC 1983, 48, 5221.
4. Palomo, C.; Cossio, F. P.; Cuevas, C. TL 1991, 32, 3109.
5. Bose, A. K.; Fahey, J. L.; Manhas, M. S. JHC 1973, 10, 791.
6. Bose, A. K.; Manhas, M. S.; Chib, J. S.; Chawla, H. P. S. JOC 1974, 39, 2877.
7. Foxton, M. W.; Mearman, R. C.; Newall, C. E.; Ward, P. TL 1981, 22, 2497.
8. Nagao, Y.; Kumagai, T.; Takao, S.; Abe, T.; Ochiai, M.; Inoue, Y.; Taga, T.; Fujita, E. JOC 1986, 51, 4737.
9. Stadlwieser, J. S 1985, 490.
10. Jones, M. S 1984, 727.
11. Basavaiah, D.; Dharma Rao, P.; Gowriswari, V. V. L. SC 1988, 18, 1411.
12. McKillop, A.; Madjdabadi, F. A.; Long, D. A. TL 1983, 24, 1933.
13. Abassi, F.; Hodge, P.; Khoshdel, E. Polym. Commun. 1988, 29, 368.

Alexander McKillop

University of East Anglia, Norwich, UK

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