Methyl 2-Bromocrotonate

(1; R = Me)

[17642-18-1]  · C5H7BrO2  · Methyl 2-Bromocrotonate  · (MW 179.02) (E)-(1)

[36297-23-1] (Z)-(1)

[22966-48-9] (2; R = Et)

[59065-89-3]  · C6H9BrO2  · Ethyl 2-Bromocrotonate  · (MW 193.05) (E)-(2)

[51263-38-8] (Z)-(2)


(vinyl cyclopropanation/oxiranation reagent;1,2 bisannulating agent3a)

Alternate Names: methyl 2-bromo-2-butenoate; methyl a-bromocrotonate.

Physical Data: (1) bp 61 °C/9 mmHg; d 1.5064 g cm-3 (17 °C); n17D 1.48700. (2) bp 69-70 °C/12 mmHg; d 1.3952 g cm-3 (18.4 °C); n18D 1.47660.

Solubility: sol most organic solvents.

Form Supplied in: light yellow liquid as a mixture of (E) and (Z) isomers. The methyl ester is available commercially.

Analysis of Reagent Purity: NMR, GC.

Preparative Methods: ethyl or methyl crotonate is treated with Br2/CCl4 or Br2/AcOH followed by dehydrobromination with quinoline2 or DBU.1

Handling, Storage, and Precautions: handle under nitrogen in a fume hood; these reagents are moisture sensitive. Store refrigerated and in brown bottles to avoid polymerization. Caution: lachrymator and irritant; may be harmful.

Vinylcyclopropanation/Oxiranation Reagents.

The lithium dienolate of ethyl 2-bromocrotonate, formed upon low temperature addition to Lithium Diisopropylamide, was reacted with enones to yield vinylcyclopropanes as endo and exo isomer mixtures (eq 1).1,4 The endo/exo ratio was variable, and independent of the (E/Z) ratio of the starting ethyl bromocrotonate.

Yields of isolated products varied from 30 to 90%, depending on the enone. Thermal rearrangement of these vinylcyclopropanes afforded cyclopentene annulated systems (eq 2).1,4,5

This method was successfully applied to the synthesis of a number of natural products, including pentalenene (3)6 (nonlinear sesquiterpene) and retigeranic acid (4)1,7 (sesterterpene).

Reaction of the lithium dienolate of ethyl 2-bromocrotonate, with aldehydes as the electrophiles, furnished vinyloxiranes2 in yields ranging from 47 to 70%. Only one stereoisomer (anti) was formed (eq 3). Aldehydes were, in general, more reactive than ketones. The vinyloxiranes were subjected to pyrolysis to afford the corresponding dihydrofurans in 7-95% yield (eq 3).2 This method was applied to the synthesis of the natural product ipomeamarone (5).8

Bisannulation Reactions.9

Addition of a cross-conjugated dienolate to methyl 2-bromocrotonate resulted in double Michael addition, followed by alkylation. In the case of 2-cyclohexenone, the formation of the tricyclic system shown in eq 4 was accomplished in a one-step synthesis.3 Yields ranged between 25 and 55%.

Natural products ishwarane (6)10 and helminthosporal (7)11 were prepared using this methodology.

Use of acetylcyclohexenes as the enone component furnished the tricycle shown in eq 5.12 Yields varied between 20 and 61%.

Substitution of Bromine.

Methyl 2-bromocrotonate is a substrate for halogen-metal exchange with Lithium Dimethylcuprate; organocopper reagent (8) is the product.13

Reaction of methyl 2-bromocrotonate with ethanethiol produces the 2-ethylthiocrotonate (9).14 When (9) is subjected to the bisannulation protocol of eq 4, the reaction stops at the point of the double Michael addition (eq 6).15 The sulfide product lends itself to further modification (oxidation/elimination).

Related Reagents.

Methyl 4-Bromocrotonate.

1. Hudlicky, T.; Fleming, A.; Radesca, L. JACS 1989, 111, 6691.
2. Hudlicky, T.; Fleming, A.; Lovelace, T. C. T 1989, 45, 3021.
3. (a) Hagiwara, H.; Kodama, T.; Kosugi, H.; Uda, H. CC 1976, 413. (b) This reaction is similar to the one reported by Cory, where vinyltriphosphonium bromide is treated with the enolate of cyclohexenone: Cory, R. M.; Chan, D. M. T. TL 1975, 4441.
4. Hudlicky, T.; Radesca, L.; Luna, H.; Anderson, F. E., III JOC 1986, 51, 4746.
5. Hudlicky, T.; Sheth, J. P.; Gee, V.; Barnvos, D. TL 1979, 4889.
6. Hudlicky, T.; Natchus, M. G.; Sinai-Zindge, G. JOC 1987, 52, 4641.
7. Hudlicky, T.; Radesca-Kwart, L.; Li, L.-q., Bryant, T. TL 1988, 29, 3283.
8. Hudlicky, T.; Lovelace, T. C. SC 1990, 20, 1721.
9. For a review of double Michael annulation reactions, see: Ihara, M.; Fukumoto, K. AG(E) 1993, 32, 1010.
10. Hagiwara, H.; Uda, H.; Kodama, T. JSC(P1) 1980, 963.
11. Nagaoka, H.; Baba, A.; Yamada, Y. TL 1991, 32, 6741.
12. Hagiwara, H.; Abe, F.; Uda, H. CC 1991, 1070.
13. (a) Klein, J.; Levene, R. JCS(P2) 1973, 1971. (b) Klein, J.; Levene, R. JACS 1972, 94, 2520.
14. Gundermann, K.-D.; Schulze, H. CB 1961, 94, 3254.
15. Hagiwara, H.; Uda, H. JCS(P1) 1986, 629.

Lilian A. Radesca

The DuPont Merck Pharmaceutical Company, Deepwater, NJ, USA

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