Methyl 6-Oxo-1-cyclohexenecarboxylate

(1; R = Me)

[52784-37-9]  · C8H10O3  · Methyl 6-Oxo-1-cyclohexenecarboxylate  · (MW 154.18) (2; R = Et)

[57205-09-1]  · C9H12O3  · Ethyl 6-Oxo-1-cyclohexenecarboxylate  · (MW 168.21)

(dienophile for Diels-Alder reactions5 and other cycloadditions;7 Michael acceptor in conjugate additions)

Alternate Name: 2-methoxycarbonyl-2-cyclohexen-1-one.

Physical Data: (2) bp 59 °C/0.1 mmHg.

Preparative Methods: the ethyl ester has been prepared by phenylselenylation of the sodium enolate of ethyl 6-oxo-1-cyclohexanecarboxylate with Benzeneselenenyl Chloride using Sodium Hydride as the base in THF, followed by oxidation with Hydrogen Peroxide in a water-dichloromethane system. Syn elimination of benzeneselenic acid occurs at rt under essentially neutral condition, allowing the isolation of the compound with an enol content of less than 2%.1,2 Kügelrohr distillation increases the enol content, which can vary from 5 to 50%. Normally, the crude product is sufficiently pure to be used. The methyl ester has been prepared in a similar way using pyridine as the base in dichloromethane, thus avoiding the use of strong base in anhydrous solvent; isolation of the phenylseleno intermediate is unnecessary.3 Mention should be made of an efficient synthesis of the methyl ester, which avoids the use of toxic selenium reagents, through Birch reduction of methyl 2-methoxybenzoate followed by acidic hydrolysis.4

Handling, Storage, and Precautions: these compounds with doubly activated double bonds are unstable and should be used as soon as possible, although they can be stored for several weeks in solution at -20 °C. Use in a fume hood.

Diels-Alder Reactions.

These reagents are very good dienophiles for different types of cycloaddition. With Tin(IV) Chloride as catalyst, methyl 6-oxo-1-cyclohexenecarboxylate undergoes Diels-Alder reaction with a variety of dienes to give directly the cis-decalin system with methoxycarbonyl group at the angular position (eq 1).5 Secondary orbital overlap of the diene with the ester carbonyl rather than the ketone carbonyl is responsible for the stereochemistry of the major isomer. On the other hand, reaction of this dienophile in refluxing benzene with a silyloxydiene derived from 1-acetylcyclopentene gives the endo adduct as the major isomer (eq 2).4 A [2 + 3] cycloaddition of the trimethylenemethane-palladium complex to methyl 6-oxo-1-cyclohexenecarboxylate readily gives the methylenecyclopentane adduct.6

Base-Catalyzed Cycloaddition.

A very closely related transformation by base-catalyzed cycloaddition (or double Michael addition) of methyl 6-oxo-1-cyclohexenecarboxylate with t-Butyl (E)-3-Oxo-4-hexenoate gives the corresponding cis-decalin, the t-butyl ester being selectively cleaved by acid with concomitant decarboxylation (eq 3).7 High stereoselectivity in favor of the exo adduct is achieved using a nonpolar solvent. Several substituted 6-oxo-1-cyclohexenecarboxylates react similarly. Reversal of the methyl group stereochemistry is surprisingly achieved by using the corresponding g,d-unsaturated b-keto sulfoxide as the diene (eq 4).7 Very good selectivity is obtained irrespective of the solvent polarity, in contrast to the reaction with the t-butyl ester. This methodology has been applied to the synthesis of 14-a-hydroxy-13a-methyl steroids8 and optically active 14b-hydroxy steroids.9

Michael Addition.

Conjugate addition of O-silylated ketene acetals to methyl 6-oxo-1-cyclohexenecarboxylate is readily achieved by using high pressure (eq 5).10 It has been shown that, in other substrates, this procedure overcomes steric and conformational requirements while maintaining conditions compatible with acid-sensitive functionalities. Conjugate addition of allyl,11 vinyl,12 tributylstannyl,13 and dimethylphenylsilyl14 groups have been reported.

Related Reagents.

t-Butyl (E)-3-Oxo-4-hexenoate; Diethyl Ethylidenemalonate; Ethyl Ethoxymethyleneacetoacetate; Ethyl 2-Methyl-4-oxo-2-cyclohexene-1-carboxylate; Methyl 5-Methoxy-3-oxopentanoate; Methyl 3-Oxo-4-pentenoate.

1. Renga J. M.; Reich H. J. OSC 1988, 6, 23.
2. Reich H. J.; Renga J. M.; Reich I. L. JACS 1975, 97, 5434.
3. Liotta D.; Barnum C.; Puleo R.; Zima G.; Bayer C.; Kezar, H. S. III JOC 1981, 46, 2920.
4. Orban J.; Turner J. V. TL 1983, 24, 2697.
5. Liu H.-J.; Ngooi, T. K.; Browne E. N. C. CJC 1988, 66, 3143.
6. Cleary D. G.; Paquette L. A. SC 1987, 17, 497.
7. Lavallée J.-F.; Spino C.; Ruel R.; Hogan K. T.; Deslongchamps P. CJC 1992, 70, 1406.
8. Lavallée J.-F.; Deslongchamps P. TL 1988, 29, 6033.
9. Ruel R.; Deslongchamps P. CJC 1992, 70, 1939.
10. Bunce R. A.; Schlecht M. F.; Dauben W. G.; Heathcock C. H. TL 1983, 24, 4943.
11. Ruel R.; Deslongchamps P. CJC 1990, 68, 1917.
12. Bruhn J.; Heimgartner H.; Schmid H. HCA 1979, 62, 2630.
13. Baldwin J. E.; Adlington R. M.; Robertson J. T 1989, 45, 909.
14. Majetich G.; Song J.-S.; Ringold C.; Nemeth G. A.; Newton M. G. JOC 1991, 56, 3973.

Gilles Berthiaume

Université de Sherbrooke, Québec, Canada

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