Ethyl 3-Bromo-2-(hydroxyimino)propanoate

[73472-94-3]  · C5H8BrNO3  · Ethyl 3-Bromo-2-(hydroxyimino)propanoate  · (MW 210.03)

(alkylating agent, especially useful for 3-substitution of indoles under mild conditions;1 reacts with bases to give ethyl 2-nitrosopropenoate, an electron-deficient heterodiene1,2)

Alternate Name: ethyl bromopyruvate oxime.

Physical Data: mp 78-79 °C.

Solubility: sol ether, dichloromethane, and most organic solvents.

Preparative Methods: reaction of ethyl 3-bromo-2-oxopropanoate (ethyl bromopyruvate) with hydroxylamine hydrochloride in methanol-chloroform gives the oxime (quantitative yield); it can be recrystallized from dichloromethane-hexane.3,4 The compound has also been prepared using a two-phase system (water and chloroform).5

Handling, Storage, and Precautions: can be stored for several months in a refrigerator without deterioration. No specific toxicity data are available, but as a highly reactive alkylating agent it must be handled with appropriate precautions.

Alkylation of Indoles.

Indoles unsubstituted at the 3-position are alkylated by reaction with ethyl 3-bromo-2-(hydroxyimino)propanoate (1) and anhydrous Sodium Carbonate in dichloromethane at room temperature. The reaction has been carried out with a wide range of indoles, including indole-2-carbaldehyde and others with an electron-withdrawing substituent at the 2-position.6 Adducts can usually be isolated in good yield when equimolar amounts of the indole and of the oxime are used. A side reaction which is sometimes troublesome is attack of a second mole of the alkylating agent at C-3 to give a 2:1 adduct, as in the example shown in eq 1.7 This reaction can be suppressed by using the indole in excess.8 Alkylation at other positions of the indole ring system is rare; minor products resulting from attack at the 2- and 5-positions have been observed with indoles bearing a dialkylamino substituent at C-4.9

The oximes produced in these reactions have the (E) configuration,8 as required by a mechanism involving cycloaddition of a transient nitrosoester, ethyl 2-nitrosopropenoate, to the indole followed by ring opening. The cycloadduct with 1-methoxyindole has been detected in solution; it rearranges to the oxime under mild conditions.10

With indoles bearing an alkyl or other electron-donating substituent at C-3, attack still takes place at the 3-position to give cycloadducts which can usually be isolated in high yield.5,11 3-(Alkylthio)indoles are an exception in that the products isolated result from migration of the alkylthio substituent to C-2.12

Alkylation of Other Heterocycles.

Pyrrole and 1-methylpyrrole are alkylated at C-2 by (1). 2,5-Dimethylpyrrole is also attacked at C-2, the product being a cycloadduct (eq 2).13 Furan and 2,5-dimethylfuran similarly form cycloadducts.5,14 With the nucleophilic heterocycles imidazole, pyrazole, and 1,2,4-triazole, products of N-alkylation are isolated.15

Formation of 5,6-Dihydro-4H-1,2-oxazines with Nucleophilic Alkenes.

Ethyl 2-nitosopropenoate, generated in situ from (1) and sodium carbonate, is an electron-deficient heterodiene which reacts with a wide range of electron-rich alkenes (eq 3). Cycloadducts have been formed in good yield with enamines,16,17 enol ethers,16,18 silyl enol ethers,19 and allylsilanes.20 The cycloaddition is regioselective and stereoselective; diastereoselective addition to a chiral enol ether has also been observed.21 Conjugated alkenes such as indene and cyclopentadiene also form cycloadducts, but with simple alkenes such as 1-octene the yields are low.5 Addition to methoxyallene takes place in good yield at the substituted double bond.22 An example of cycloaddition to a C=N bond, in N-methyl-N-phenylbenzamidine, has also been reported.23 The cycloadducts can be reduced to pyrroles16,18,19 and pyrrolidines17,18,24 and there are several reports of one-pot cycloadditions and in situ reductions.

One special application of the reaction with enamines has been in the construction of the skeleton of Vinca alkaloids.25


1. Gilchrist, T. L. CSR 1983, 12, 53.
2. Gilchrist, T. L.; Lingham, D. A.; Roberts, T. G. CC 1979, 1089.
3. Ottenheijm, H. C. J.; Plate, R.; Noordik, J. H.; Herscheid, J. D. M. JOC 1982, 47, 2147.
4. Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kaspar, A. M. JACS 1991, 113, 1713.
5. Gilchrist, T. L.; Roberts, T. G. JCS(P1) 1983, 1283.
6. Plate, R.; Nivard, R. J. F.; Ottenheijm, H. C. J.; Kardos, J.; Simonyi, M. H 1986, 24, 3105. Li, J. P.: Newlander, K. A.; Yellin, T. O. S 1988, 73. Examples in synthesis: Webb, R. R., II; Venuti, M. C.; Eigenbrot, C. JOC 1991, 56, 4706. Kozikowski, A. P.; Shum, P. W.; Basu, A.; Lazo, J. S. JMC 1991, 34, 2420.
7. Chung, J. Y. L.; Wasicak, J. T.; Nadzan, A. M. SC 1992, 22, 1039.
8. Plate, R.; Nivard, R. J. F.; Ottenheijm, H. C. J. JCS(P1) 1987, 2473.
9. Muratake, H.; Okabe, K.; Natsume, M. T 1991, 47, 8545. Okabe, K; Muratake, H.; Natsume, M. T 1991, 47, 8559.
10. Acheson, R. M.; Aldridge, G. N.; Choi, M. C. K.; Nwankwo, J. O.; Ruscoe, M. A.; Wallis, J. D. JCR(S) 1984, 101.
11. Davies, D. E.; Gilchrist, T. L. JCS(P1) 1983, 1479. Plate, R.; Theunisse, A. W. G.; Ottenheijm, H. C. J. JOC 1987, 52, 370.
12. Plate, R.; Ottenheijm, H. C. J.; Nivard, R. J. F. JOC 1984, 49, 540. Plate, R.; Nivard, R J. F.; Ottenheijm, H. C. J. T 1986, 42, 4503.
13. Gilchrist, T. L.; Lemos, A. JCS(P1) 1993, 1391.
14. Gilchrist, T. L.; Hughes, D.; Stretch, W.; Chrystal, E. J. T. JCS(P1) 1987, 2506.
15. Gilchrist, T. L.; Stretch, W.; Chrystal, E. J. T. JCS(P1) 1987, 2235.
16. Nakanishi, S.; Otsuji, Y.; Itoh, K.; Hayashi, N. BCJ 1990, 63, 3595.
17. Henning, R.; Lerch, U.; Urbach, H. S 1989, 265.
18. Chrystal, E. J. T.; Gilchrist, T. L.; Stretch, W. JCR(S) 1987, 180.
19. Hippeli, C.; Ressig, H.-U. LA 1990, 217. Zimmer, R.; Collas, M.; Roth, M.; Reissig, H.-U. LA 1992, 709.
20. Nakanishi, S.; Higuchi, M.; Flood, T. C. CC 1986, 30.
21. Arnold, T.; Orschel, B.; Reissig, H.-U. AG(E) 1992, 31, 1033.
22. Zimmer, R.; Reissig, H.-U. LA 1991, 553.
23. Nakanishi, S.; Nantaku, J.; Otsuji, Y. CL 1983, 341.
24. Hippeli, C.; Reissig, H.-U. LA 1990, 475.
25. Sóti, F.; Kajtár-Peredy, M.; Keresztury, G.; Incze, M.; Kardos-Balogh, Z.; Szántay, C. T 1991, 47, 271.

Thomas L. Gilchrist

University of Liverpool, UK



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