Dimethyl (E)-4-Oxo-2-pentenedioate

[78939-37-4]  · C7H8O5  · Dimethyl (E)-4-Oxo-2-pentenedioate  · (MW 172.15)

(useful reagent for Doebner-von Miller-type annulations, quinoline synthesis; a potential dienophile)

Alternate Name: dimethyl 2-oxoglutaconate.

Physical Data: mp 61-62 °C.

Preparative Methods: dimethyl 2-oxoglutaconate (1) has been known since 1946, when it was prepared in low yield by the oxidation of dimethyl glutaconate.1 Although the preparation by this route was recently improved,2 the following procedure, as previously described, has been shown to be a more efficient synthesis.3 A solution of bromine in dry methylene chloride (1.01 equiv) is added dropwise to a solution of dimethyl 2-oxoglutarate in the same solvent at reflux, followed by removal of solvent (and HBr) in vacuo. The resulting a-bromo ketone is treated with Triethylamine (TEA, 1 equiv) in ether at 25 °C for 20 min followed by filtration, passing the filtrate through a pad of silica gel, and concentration in vacuo to provide (1).

Handling, Storage, and Precautions: the enone functional group is remarkably reactive with amines at rt. Care should be exercised to avoid addition of excess TEA in its preparation. Handle in a fume hood.

Annulation Reactions.

The applications of (1) have been primarily as a synthon in the Doebner-von Miller-type synthesis of elaborated quinolines. Aryl amines with a free ortho position are excellent candidates for annulations with (1). In its original application, the reaction of (1) with aminoindole (2) provided in a one-pot preparation an advanced intermediate in the synthesis of the oxidative enzyme cofactor PQQ.3 The first step in such annulations involves the conjugate addition of the amino group, followed by cyclization to a tetrahydroquinolinol intermediate. Addition of an acid catalyst (HCl, TsOH, or BF3.Et2O) promotes dehydration and aromatization to give, in the example cited, the pyrroloquinoline (3) (eq 1).

Cyclization with substituted anilines can occur with high regioselectivity. For example, there are two available sites ortho to the amine of (4); however, no product of the cyclization to the 5-position was observed.4 The exclusive formation of (5) as a result of cyclization at the 7-position was anticipated due to the bond fixation of indoles (eq 2).

As a consequence of the facile one-step annulations with a variety of aniline derivatives, the reagent has been invaluable in the preparation of several biologically significant quinolines,5,6 benzoquinolines,7 and pyrroloquinolines.8,9 In this capacity the reagent affords easy access to the quinoline dicarboxylates. Other alkyl esters can be obtained by starting with the corresponding alkyl 2-oxoglutaconate as evidenced in an example utilizing a didecyl ester derivative.10

The potential utility of reagent (1) as a dienophile in Diels-Alder cycloadditions has been recognized in one report.2

Related Reagents.

Dimethyl 2,3-Pentadienedioate; Methyl 5-Methoxy-3-oxopentanoate; Methyl 3-Oxo-4-pentenoate.

1. Cornforth, J. W.; Cornforth, R. H. JCS 1946, 755.
2. Ananda, G. D. S.; Cremins, P. J.; Stoodley, R. J. CC 1987, 882.
3. Corey, E. J.; Tramontano, A. JACS 1981, 103, 5599.
4. MacKenzie, R. A.; Moody, C. J.; Rees, C. W. T 1986, 42, 3259.
5. Carling, R. W.; Leeson, P. D.; Moseley, A. M.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R. JMC 1992, 35, 1942.
6. Ohshiro, Y.; Ito, S. Jpn. Kokai Tokkyo Koho 04 139 171, 1992 (CA 1992, 117, 212 343y).
7. Itoh, S.; Fukui, Y.; Haranou, S.; Ogino, M.; Komatsu, M.; Ohshiro, Y. JOC 1992, 57, 452.
8. Itoh, S.; Kato, J.; Inoue, T.; Kitamura, Y.; Komatsu, M.; Ohshiro, Y. S 1987, 12, 1067.
9. Jongejan, J. A.; Bezemer, R. P.; Duine, J. A. TL 1988, 29, 3709.
10. (a) Kurobe, H.; Sugawara, T.; Matsutani, Y.; Takahashi, J.; Moriguchi, Y.; Endo, T. Jpn. Kokai Tokkyo Koho 02 262 581, 1990 (CA 1991, 114, 101 542f). (b) Kuroki, Y.; Asada, H.; Oda, H.; Setoguchi, M. Jpn. Kokai Tokkyo Koho 02 270 872, 1990 (CA 1991, 114, 121 870q).

Clifford Berkman

IGEN Research Institute, Rockville, MD, USA

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