t-Butyl Chloroacetate

[107-59-5]  · C6H11ClO2  · t-Butyl Chloroacetate  · (MW 150.60)

(reagent used in glycidic ester condensations1 and as a two-carbon alkylating agent2)

Physical Data: bp 48-49 °C/11 mmHg.

Form Supplied in: colorless liquid; widely available.

Preparative Method: prepared by treatment of chloroacetyl chloride with t-butyl alcohol.3

Handling, Storage, and Precautions: is a lachrymator and should be used in a well-ventilated fume hood.

t-Butyl chloroacetate has been used extensively in the formation of glycidic esters via the Darzens reaction4 since the reagent minimizes metal enolate self-condensation.1,5 Darzens reaction of t-butyl chloroacetate (1) and chiral h6-Cr(CO)3 complexed aromatic aldehydes (2) leads to a mixture of cis and trans glycidic esters of high optical purity (eq 1).6 A related chloroacetate has been used in an asymmetric Darzens glycidic ester condensation for the synthesis of the calcium channel blocker diltiazem.7 a-Halo ketones undergo a novel Darzens-type reaction in the presence of N-tri-n-butylstannylcarbamates.8 Condensation of enolates of t-butyl chloroacetate with chiral imines leads to 3-haloazetidinones or aziridines, depending on the metal enolate.9 The triisopropoxytitanium enolate of (1) gives (3R,4R)-chloroazetidinone (4) (eq 2), while lithium (eq 3) and zinc enolates (eq 4) give only (2R,3S) (5) and (2S,3R) (6) aziridines, respectively.

t-Butyl chloroacetate is the reagent of choice for the vicarious nucleophilic substitution of hydrogen in nitroarenes.10 This reaction has been applied to the formal total synthesis of eupolauramine (eq 5).11

Although less reactive than the corresponding bromide, t-butyl chloroacetate has been used as a two-carbon alkylating agent. For example, N-formylglycine is formed by the reaction of (1) and sodium diformylamide.2 The synthesis of dialkyl alkoxycarbonylmethanephosphonates,12 rhenium enolate complexes,13 and t-butyl (triphenylphosphoranylidine)acetate14 also rely upon the electrophilic nature of (1).

The limitations of t-butyl chloroacetate as an electrophile is illustrated in the synthesis of (-)-8-azaestrone by Meyers (eq 6).15 Reaction of the lithium anion of (7) with (1) gives a 2:1 ratio of (8) to (9). The undesired lactam (9) is formed by nucleophilic attack of (10) on the chlorine atom of (1), presumably due to the steric bulk of the alkylating agent (eq 7).

Related Reagents.

Methyl Bromoacetate; Methyl Chloroacetate.

1. Johnson, W. S.; Belew, J. S.; Chinn, L. J.; Hunt, R. H. JACS 1953, 75, 4995.
2. Meduna, V.; Sawlewicz, P.; Vogt, R. SC 1989, 19, 1487.
3. Baker, R. H. OSC 1955, 3, 144.
4. Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 39, 1.
5. Bansal, R. K.; Sharma, V. K. IJC(B) 1992, 31B, 521.
6. Baldoli, C.; Del Buttero, P.; Maiorana, S. T 1990, 46, 7823.
7. Schwartz, A.; Madan, P. B.; Mohacsi, E.; O'Brien, J. P.; Todaro, L. J.; Coffen, D. L. JOC 1992, 57, 851.
8. Fujisawa, T.; Hayakawa, R.; Shimizu, M. TL 1992, 33, 7903.
9. Shibata, I.; Yamasaki, H.; Baba, A.; Matsuda, H. JOC 1992, 57, 6909.
10. Mudryk, B.; Makosza, M. S 1988, 1007.
11. Makosza, M.; Wrobel, Z. H 1992, 33, 585.
12. Ye, W.; Liao, X. S 1985, 986.
13. Stack, J. G.; Doney, J. J.; Bergman, R. G.; Heathcock, C. H. OM 1990, 9, 453.
14. Wasserman, H. H.; Kuo, G. T 1992, 48, 7071.
15. Meyers, A. I.; Elworthy, T. R. JOC 1992, 57, 4732.

Steven K. Davidsen

Abbott Laboratories, Abbott Park, IL, USA

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