Methyl Chloroacetate

(1; R = Me)

[96-34-4]  · C3H5ClO2  · Methyl Chloroacetate  · (MW 108.53) (2; R = Et)

[105-39-5]  · C4H7ClO2  · Ethyl Chloroacetate  · (MW 122.56)

(alkylating agent;1 undergoes Michael2,3 and Darzens4 condensations; effects two-carbon homologation of alkenes;5 widely used in heterocyclic synthesis)

Physical Data: (1) mp -33 °C; bp 130-132 °C; d 1.238 g cm-3.6 (2) mp -26 °C; bp 144-146 °C; d 1.1498 g cm-3.6

Solubility: insol water; sol alcohol, ether.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: store in a cool dry place. Toxic, corrosive lachrymator. Avoid contact and inhalation. Use in a fume hood.

Alkylation.

Methyl chloroacetate has been widely used as an alkylating agent for sulfur,1,7-9 nitrogen,1,10,11 and oxygen1,12,13 nucleophiles under standard conditions. Reaction with phosphide anions affords o-phosphinocarboxylic acids.14 Malonates are alkylated to form the 1,1,1-trialkoxycarbonyl derivatives,15 which are easily monodecarboxylated and may function as masked 1,1-diesters in a synthetic sequence. C-Alkylation of ketones is accomplished by their reaction with Grignard reagents in HMPA to form magnesium enolates which are readily and selectively C-alkylated with methyl chloroacetate.16

Michael Reaction.

Reaction of a-halo esters, such as methyl chloroacetate, with a,b-unsaturated esters in the presence of base furnishes cyclopropane derivatives (eq 1).

The effects of leaving group, base catalyst, and solvent polarity and solvating ability on the ratio of cis:trans isomer formation have been investigated.2,3

Darzens Condensation.

Methyl chloroacetate reacts with aldehydes and ketones in the presence of base to afford glycidic esters (eq 2).4

Subsequent hydrolysis to the corresponding glycidic acids and decomposition furnishes aldehydes or ketones, efficiently accomplishing one-carbon homologation. Mechanistic studies have investigated the effects of various esters (R2)17 and reaction temperature18 on cis:trans isomer ratios obtained. In homologation sequences, dianions of a-halocarboxylic acids have often been employed to circumvent premature epoxide cleavage during ester hydrolysis.19 A procedure involving reaction of ethyl chloroacetate with benzalaniline broadens the scope of the Darzens synthesis to include preparation of aziridine esters (eq 3).20 The trans-aziridine is formed preferentially.

Two-Carbon Alkene Homologation.

Methyl chloroacetate adds to alkenes and dienes under redox catalysis by Copper(I) Chloride in the presence of 2,2-bipyridyl or 1,10-phenanthroline, affording a-chloro esters or unsaturated esters.21 Alkenes which have been converted to the corresponding trialkylboranes react with ethyl chloroacetate to effect two-carbon homologation of the alkene and furnish the corresponding esters (eq 4).5 The reaction is widely applicable and yields are generally high. Reactions with ethyl bromoacetate proceed at a slightly faster rate, with somewhat higher yields.

Heterocycles.

A wide variety of heterocycles has been synthesized employing ethyl or methyl chloroacetate. Among the precursor nucleophiles, thiourea, salicylonitriles, mercaptobenzaldehydes, and cyanopyridinethiones furnish triazines,22 benzofurans,23 benzothiophenes,24 and thienopyridines,25 respectively.

Related Reagents.

Chloroacetonitrile; Iodoacetonitrile; Methyl Bromoacetate; Methyl Dichloroacetate.


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2. Akabori, S.; Yoshii T. TL 1978, 4523.
3. Nishiyama, K.; Inouye, Y. ABC 1982, 46, 1027.
4. Rosen, T. COS 1991, 2, 409.
5. Brown, H. C.; Rogíc, M. M.; Rathke, M. W.; Kabalka, G. W. JACS 1968, 90, 818.
6. Budavari, S. The Merck Index, 11th ed.; Merck: Rahway, NJ, 1989.
7. Tanikaga, R.; Nozaki, Y.; Tamura, T.; Kaji, A. S 1983, 134.
8. Petrosyan, V. A.; Niyazymbetov, M. E.; Konyushkin, L. D.; Litvinov, V. P. S 1990, 841.
9. Briel, D.; Dumke, S.; Wagner, G.; Olk, B. JCR(S) 1991, 178.
10. Shiozaki, M.; Ishida, N.; Hiraoka, T.; Maruyama, H. T 1984, 40, 1795.
11. Ohtaka, H.; Yoshida, K.; Suzuki, K.; Shimohara, K.; Tajima, S.; Ito, K. CPB 1988, 36, 4825.
12. Yazawa, H.; Tujiuti, M.; Kawai, N.; Kagara, K. Chem. Express 1991, 6, 519.
13. Rao, S. J.; Bhalerao, U. T.; Tilak, B. D. IJC(B) 1988, 27B, 277.
14. Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G.; Kabachnik, M. I. S 1986, 198.
15. Brillon, D. SC 1986, 16, 291.
16. Fauvarque, J.; Fauvarque, J. F. BSF 1969, 1, 160 (CA 1969, 70, 96 109m).
17. Bachelor, F. W.; Bansal, R. K. JOC 1969, 34, 3600.
18. Villieras, J.; Combret, J. C. CR(C) 1971, 272, 236.
19. Johnson, C. R.; Bade, T. R. JOC 1982, 47, 1205.
20. Deyrup, J. A. JOC 1969, 34, 2724.
21. Julia, M.; Saussine, L.; Le Thuillier, G. JOM 1979, 174, 359 (CA 1980, 92, 41 507p).
22. Overberger, C. G.; Michelotti, F. W. OSC 1963, 4, 29.
23. Trofimov, F. A.; Lelyak, G. F.; Shevchenko, L. I.; Grinev, A. N. KGS 1974, 9, 1171 (CA 1974, 82, 16 634p).
24. Rahman, L. K. A.; Schrowston, R. M. JCS(P1) 1983, 12, 2973.
25. Paniagua, E.; Rubio, M. J.; Seoane, C.; Soto, J. L. RTC 1987, 106, 554.

Karen J. Guarino

Pfizer Central Research, Groton, CT, USA



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