Ethyl 2-Methyl-4-oxo-2-cyclohexene-1-carboxylate

[487-51-4]  · C10H14O3  · Ethyl 2-Methyl-4-oxo-2-cyclohexene-1-carboxylate  · (MW 182.22)

(a useful building block in natural product synthesis;1-5 often alkylated in the 3-position6)

Alternate Names: Hagemann's ester; 4-ethoxycarbonyl-3-methyl-2-cyclohexenone.

Physical Data: bp 268-272 °C; d 1.078 g cm-3.

Form Supplied in: 90% technical grade liquid commercially available.

Preparative Methods: ethyl 2-methyl-4-oxo-2-cyclohexene-1-carboxylate7 is typically prepared by the condensation of 2 equiv of ethyl acetoacetate with 1 equiv of formaldehyde in the presence of catalytic piperidine.8 Aldehydes other than formaldehyde have been used to prepare 6-substituted compounds (eq 1).9

Cyclization of diketo esters proceeds in 50-75% yield using catalytic pyrrolidine and acetic acid (eq 2).10

Natural Product Syntheses.

The title reagent (Hagemann's ester) serves, for example, as a starting material in the synthesis of (±)-a- and (±)-b-pinene,1 yohimbine congeners,2 vermiculine,3 and other natural products.4

The 6-methyl derivative was employed in a total synthesis of (±)-agarospirol (epihinesol).5 Lithium Aluminum Hydride reduction of its ethylene acetal followed by hydrolysis and concomitant dehydration afforded 3,5-dimethyl-4-methylene-2-cyclohexenone which underwent a 1,6-Michael addition with Diethyl Malonate.

Alkylation of Hagemann's ester occurs predominantly at the 3-position, with a small amount of alkylation at the 1-position (eqs 3 and 4).6

Reaction of Hagemann's ester with Michael acceptors such as Methyl Vinyl Ketone leads to C-1 and C-3 Michael adducts.11

Functionalization at C-1 is best achieved via the dienol ether or ester.12 The ethyl dienol ether was prepared by treatment of Hagemann's ester with 2 equiv of diethyl sulfate and sodium hydride (eq 5).

The ethyl dienol ether can be alkylated by a variety of electrophiles upon deprotonation with Lithium Diisopropylamide (eq 6). Other electrophiles used include Formaldehyde, Michael acceptors, and Methyl Chloroformate. All proceed in good to excellent yields.

A regiospecific synthesis of substituted 1,3-cyclohexadienes uses Hagemann's ester and its derivatives as starting material.13 Borohydride reduction or Grignard reaction of the ketone carbonyl followed by saponification and dehydrative decarboxylation with N,N-dimethylformamide dineopentyl acetal gives various substituted 1,3-cyclohexadienes.

Related Reagents.

Ethyl Acetoacetate; Formaldehyde; Iodomethane; Methyl 6-Oxo-1-cyclohexenecarboxylate; Methyl 3-Oxo-4-pentenoate; Methyl Vinyl Ketone.

1. Thomas, M. T.; Fallis, A. G. TL 1973, 4687.
2. Danishefsky, S.; Langer, M. E.; Vogel, C. TL 1985, 26, 5983.
3. Fukuyama, Y.; Kirkemo, C. L.; White, J. D. JACS 1977, 99, 646.
4. Ziegler, F. E.; Kloek, J. A. T 1977, 33, 373; Kametani, T.; Tsubuki, M.; Nemoto, H. JOC 1980, 45, 4391; Gesson, J. P.; Jacquesy, J. C.; Renoux, B. TL 1983, 24 2757; Ghosh, A. K.; Ray, C.; Ghatak, U. R. TL 1992, 33, 655.
5. Mongrain, M.; Lafontaine, J.; Belanger, A.; Deslongchamps, P. CJC 1970, 48, 3273.
6. White, J. D.; Sung, W. L. JOC 1974, 39, 2323; Nasipuri, D.; Sarkar, G.; Guha, M.; Roy, R. TL 1966, 927.
7. Hagemann, C. T. L. CB 1893, 26, 876.
8. Rabe, P.; Spence, D. LA 1905, 342, 328; Rabe, P.; Rahm, F. CB 1905, 38, 969; Smith, L. I.; Rouault, G. F. JACS 1943, 65, 631.
9. McCurry, Jr., P. M.; Singh, R. K. SC 1976, 6, 75.
10. Begbie, A. L.; Golding, B. T. JCS(P1) 1972, 602.
11. Nasipuri, D.; Mitra, K.; Venkataraman, S. JCS(P1) 1972, 1836.
12. Baker, M. V.; Ghitgas, C.; Haynes, R. K.; Hilliker, A. E.; Lynch, G. J.; Sherwod, G. V.; Yeo, H.-L. TL 1984, 25, 1625; AJC 1984, 37, 2037; Baker, M. V.; Ghitgas, C.; Dancer, R. J.; Haynes, R. K.; Sherwood, G. V. AJC 1987, 40, 1331.
13. Rüttiman, A.; Wick, A.; Eschenmoser, A. H 1975, 58, 1451.

Regina Zibuck

Wayne State University, Detroit, MI, USA

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