Methyl 4-Bromocrotonate

(1; R = Me)

[1117-71-1]  · C5H7BrO2  · Methyl 4-Bromocrotonate  · (MW 179.02) (E)-(1)

[6000-00-6] (Z)-(1)

[56699-18-4] (2; R = Et)

[6065-32-3]  · C6H9BrO2  · Ethyl 4-Bromocrotonate  · (MW 193.05) (E)-(2)

[37746-78-4] (Z)-(2)


(precursor for Reformatsky reagents;1-9 alkylating agent;22-41 1,4-addition electrophile42-45)

Alternate Names: methyl 4-bromo-2-butenoate; methyl g-bromocrotonate.

Physical Data: (1) bp 83-85 °C/13 mmHg; d 1.4900 g cm-3 (19 °C); n20D 1.50210. (2) bp 99.0-99.5 °C/17 mmHg; d 1.3990 g cm-3 (23 °C); n23D 1.49050.

Solubility: sol most organic solvents.

Form Supplied in: colorless 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 N-Bromosuccinimide/CCl4 and Dibenzoyl Peroxide.18b

Handling, Storage, and Precautions: handle under nitrogen and in a fume hood. Store refrigerated and tightly closed. Caution: harmful material: allergenic, corrosive, lachrymator, and irritant.

Reformatsky and Other Anionic Reactions.

Methyl and ethyl 4-bromocrotonate have been used extensively as Reformatsky reagents. The reaction has been investigated with regard to the issue of alkylative regioselectivity of the allylic organometallic species toward simple aldehydes and ketones (eq 1).2 -8 In general, it is observed that by using ZnCu(HOAc) in ethyl ether, only a-addition occurs, and when Zn (dry) in THF or cyclohexane is used, g-addition is favored.3,6,8,9 Yields range between 90-95%.6 Additional investigations lead to the development of conditions which furnish either the a-1,2 (3) (ZnCu(HOAc), Et2O, 3 min) or the g-1,4 (6) (Zn, THF, 4 h) adducts of a,b-enones.8 The structure of the electrophile may affect the stereochemical outcome of the reaction as well.10,11

Other variations in the formation of the organo-Zn compound include the addition of Diethylaluminum Chloride,12 Silver,13 Boron Trifluoride Etherate,14 and Dichlorobis(cyclopentadienyl)titanium.15 In all cases, the a- or g-regioselectivity of addition can be controlled, and yields range between 44-99%.

Zn has been replaced by other metallic reagents in the formation of the allylic carbanion. These include Cerium/Mercury(II) Chloride16 and Bu3SnAlEt2.17 The reagents derived from these sources produce a-adducts in 51 and 74% yields, respectively, when treated with methyl 4-bromocrotonate and benzaldehyde, but the conjugated product is isolated from the cerium-mediated reaction. Electrolysis of methyl 4-bromocrotonate and treatment with a,b-unsaturated esters afford exclusively the a-adduct (in a Michael type addition) in 39% yield.18 When mixtures of an imonium salt and methyl 4-bromocrotonate are subjected to electroreduction, Reformatsky-type products are obtained, in which only the g-adducts form (93% yield).19 The same results are obtained when the Reformatsky reaction is performed with Zn and imonium salts in acetonitrile (90% yield).20

When treated with the hindered base potassium 2,6-di-t-butylphenoxide, ethyl 4-bromocrotonate yields the a-bromo anion, which, in the presence of trialkylboranes, results in alkyl transfer and (upon workup) deconjugation of the alkene in 72-89% yields.21

Bromide Replacement.

Many examples of the direct replacement of the bromide from ethyl or methyl 4-bromocrotonate have been reported. Thus the 4-bromocrotonate esters undergo substitution at C-4 with aryltributylstannanes (catalyzed by palladium, 71-91% yield),22 arenetricarbonylchromium anions (58% yield),23 organomanganese derivatives of 3-sulfolenes (82% yield),24 diphenylamine or N-methylaniline (catalyzed by copper(II) perchlorate and copper metal, 76-94% yield),25 thiols under basic conditions (71% yield),26a and a variety of alcohols with Potassium Carbonate (83-87% yield).26b

Displacement of the bromide in methyl 4-bromocrotonate with allylic inversion (i.e. at C-2) can be achieved with organocopper reagents in 49-61% yields.27 Mixtures of direct and allylic displacements (27:73, 91% yield) were obtained when alkylzirconium derivatives were used in the presence of Copper(I) Cyanide as catalyst.28

Triethyl phosphite reacts with methyl 4-bromocrotonate via C-4 alkylation. The resulting phosphonate, after deprotonation, serves as a typical Wadsworth-Emmons reagent (with aldehydes), furnishing the extended dienes in 84% yield (initial g-addition).29a Triphenylarsine reacted with ethyl 4-bromocrotonate to yield, under basic conditions, an ylide which displayed Wittig-like reactivity toward ketones and aldehydes (45-95% yields).29b

The presence of the a,b-unsaturated ester moiety in ethyl and methyl 4-bromocrotonates makes them attractive as bifunctional electrophiles. In these cases, a cyclization follows the direct alkylation. Thus carbocyclic compounds have been obtained by palladium-catalyzed cyclizations30 or [4 + 2] cycloadditions.31 Indoles, isoquinolines, and other nitrogen heterocycles can be formed by palladium-catalyzed cyclizations,32 oxidative electrocyclizations,33 [4 + 2] cycloadditions,34 or Michael additions.35 Oxygen heterocycles are formed by radical cyclizations,36 intramolecular 1,4-condensations,37 palladium-catalyzed cyclizations,38 [4 + 2] cycloadditions,34 or Claisen rearrangements.39 Sulfur heterocycles were formed through a variety of intramolecular cyclizations, all following initial sulfur alkylation at C-4.40 Morpholines were prepared by intramolecular 1,4-cycloadditions.41

1,4-Additions and Subsequent Cyclopropane Formation.

When nucleophiles such as lithium alkylthiolates,42 lithium ester enolates,43 sulfur-containing carbanions,44 or cross-conjugated lithium enolates45 react with ethyl or methyl 4-bromocrotonate in a conjugate fashion, a ring closure by attack of the resulting enolate on C-4 follows to form the corresponding cyclopropanes. In some cases the direct substitution of the bromide is a competitive reaction.42,43a

Related Reagents.

Methyl 2-Bromocrotonate.

1. (a) Fuson, R. C.; Arnold, R. T.; Cooke, Jr. H. G. JACS 1938, 60, 2272: (b) von Ziegler, K.; Schumann, W.; Winkelman, E. LA 1943, 551, 120: (c) Cook, J. W.; Schoental, R. JCS 1945, 288.
2. Jones, E. R. H.; O'Sullivan, D. G.; Whiting, M. C. JCS 1949, 1415.
3. Dreiding, A. S.; Pratt, R. J. JACS 1953, 75, 3717.
4. (a) Cologne, J.; Varagnat, J. BSF 1961, 234: (b) Daviaud, G.; Miginiac, P. BSF 1971, 2325: (c) Couffignal, R.; Gaudemar, M. JOM 1973, 60, 209.
5. Short, R. P.; Revol, J.-M.; Ranu, B. C.; Hudlicky, T. JOC 1983, 48, 4453.
6. Rice, L. E.; Boston, M. C.; Finklea, H. O.; Suder, B. J.; Frazier, J. O.; Hudlicky, T. JOC 1984, 49, 1845.
7. (a) Hudlicky, T.; Frazier, J. O.; Kwart, L. D. TL 1985, 26, 3523: (b) Hudlicky, T.; Frazier, J. O.; Seoane, G.; Tiedje, M.; Seoane, A.; Kwart, L. D.; Beal, C. JACS 1986, 108, 3755.
8. Hudlicky, T.; Natchus, M. G.; Kwart, L. D.; Colwell, B. L. JOC 1985, 50, 4300.
9. Snider, B. B.; Allentoff, A. J. JOC 1991, 56, 321.
10. Robinson, C. Y.; Brouillette, W. J.; Muccio, D. D. JOC 1989, 54, 1992.
11. Lei, B.; Fallis, A. G. CJC 1991, 69, 1450.
12. (a) Maruoka, K.; Hashimoto, S.; Kitagawa, Y.; Yamamoto, H.; Nozaki, H. JACS 1977, 99, 7705: (b) Maruoka, K.; Hashimoto, S.; Kitagawa, Y.; Yamamoto, H.; Nozaki, H. BCJ 1980, 53, 3301.
13. Bortolussi, M.; Seyden-Penne, J. SC 1989, 19, 2355.
14. Basile, T.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. S 1990, 305.
15. Ding, Y.; Zhao, G. CC 1992, 941.
16. Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.; Yokoyama, M. JOC 1984, 49, 3904.
17. Tsuboniwa, S.; Matsubara, S.; Morizawa, Y.; Oshima, K.; Nozaki, H. TL 1984, 25, 2569.
18. (a) Satoh, S.; Suginome, H.; Tokuda, M. TL 1981, 22, 1895: (b) Satoh, S.; Suginome, H.; Tokuda, M. BCJ 1981, 54, 3456.
19. Shono, T.; Usui, Y.; Mizutani, T.; Hamaguchi, H. TL 1980, 21, 3073.
20. (a) Hirai, Y.; Hagiwara, A.; Yamazaki, T. H 1986, 24, 571: (b) Hirai, Y.; Terada, T.; Hagiwara, A.; Yamazaki, T. CPB 1988, 36, 1343.
21. Brown, H. C.; Nambu, H. JACS 1970, 92, 1761.
22. Owton, W. M.; Brunavs, M. SC 1991, 21, 981.
23. Beswick, P. J.; Greenwood, C. S.; Mowlem, T. J.; Nechvatal, G.; Widdowson, D. A. T 1988, 44, 7325.
24. Kasatkin, A. N.; Prokopenko, Y. A.; Khabibov, A. M.; Tolstikov, G. A. Mendeleev Commun. 1993, 17.
25. Baruah, J. B.; Samuelson, A. G. T 1991, 47, 9449.
26. (a) Birkofer, L.; Hartwig, I. CB 1954, 87, 1189; (b) Harding, K. E.; Clement, B. A.; Moreno, L.; Peter-Katalinic, J. JOC 1981, 46, 940.
27. (a) Dunn, M. J.; Jackson, R. F. W. CC 1992, 319; (b) Girard, C.; Romain, I.; Ahmar, M.; Bloch, R. TL 1989, 30, 7399.
28. Venanzi, L. M.; Lehmann, R.; Keil, R.; Lipshutz, B. H. TL 1992, 33, 5857.
29. (a) Roush, W. R. JACS 1978, 100, 3599; (b) Huang, Y.; Shen, Y.; Zheng, J.; Zhang, S. S 1985, 57.
30. O'Connor, B.; Zhang, Y.; Negishi, E.-i. TL 1988, 29, 3903.
31. (a) Devine, P. N.; Oh, T. JOC 1991, 56, 1955 (Note: ethyl 4-bromocrotonate only acts as a dienophile in this reference); (b) Bérubé, G.; Fallis, A. G. TL 1989, 30, 4045.
32. (a) Mori, M.; Chiba, K.; Ban, Y. TL 1977, 1037; (b) Mori, M.; Ban, Y. TL 1979, 1133.
33. Grigg, R.; Myers, P.; Somasunderam, A.; Sridharan, V. T 1992, 48, 9735.
34. Levin, J. I. TL 1989, 30, 2355.
35. (a) Barco, A.; Benetti, S.; Casolari, A.; Pollini, G. P.; Spalluto, G.; TL 1990, 31, 3039; (b) Barco, A.; Benetti, S.; Spalluto, G.: (c) Casolari, A.; Pollini, G.; Zanirato, V. JOC 1992, 57, 6279.
36. Abeywickrema, A. N.; Beckwith, A. L. J.; Gerba, S. JOC 1987, 52, 4072.
37. (a) Hesek, D.; Rybár, A.; Bella, J. S 1991, 625; (b) Padwa, A.; Carlsen, P. H. J.; Ku, A. JACS 1978, 100, 3494; (c) Weeratunga, G.; Jaworska-Sobiesiak, A.; Horne, S. Rodrigo, R. CJC 1987, 65, 2019; (d) Kato, T.; Chiba, T.; Sato, H.; Ito, T. H 1977, 8, 417.
38. Negishi, E.-i.; Nguyen, T.; O'Connor, B. H 1989, 28, 55.
39. Sunitha, K.; Balasubramaniam, K. K. T 1987, 43, 3269.
40. (a) Datta, A.; Ila, H.; Junjappa, H. S 1988, 556; (b) Selby, T. P.; Smith, B. K. JHC 1989, 26, 1237.
41. Loftus, F. SC 1980, 10, 59.
42. Little, R. D.; Dawson, J. R. TL 1980, 21, 2609.
43. (a) Prempree, P.; Radviroongit, S.; Thebtaranonth, Y. JOC 1983, 48, 3553; (b) Yamaguchi, M.; Tsukamoto, M.; Hirao, I. TL 1985, 26, 1723.
44. Ghera, E.; Ben-David, Y. TL 1979, 4603.
45. Kanemasa, S.; Kumegawa, M.; Wada, E.; Nomura, M. BCJ 1991, 64, 2990.

Lilian A. Radesca

The DuPont Merck Pharmaceutical Company, Deepwater, NJ, USA

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