t-Butyl (E)-3-Oxo-4-hexenoate

(1; R = t-Bu)

[132117-94-3]  · C10H16O3  · t-Butyl (E)-3-Oxo-4-hexenoate  · (MW 184.23) (2; R = Et)

[25654-09-5]  · C8H12O3  · Ethyl (E)-3-Oxo-4-hexenoate  · (MW 156.18) (3; R = Me)

[37734-08-0]  · C7H10O3  · Methyl (E)-3-Oxo-4-hexenoate  · (MW 142.15)

(for base-catalyzed cycloaddition;1 b-keto ester with additional enone reactivity for trapping intermediates)

Alternate Name: Nazarov reagent.

Physical Data: bp (2) 101 °C/15 mmHg; (3) 95 °C/14 mmHg.

Preparative Methods: the t-butyl ester has been prepared by reacting the Reformatsky reagent derived from t-butyl bromoacetate with (E)-Crotonaldehyde, followed by oxidation with Manganese Dioxide to afford the desired t-butyl (E)-3-oxo-4-hexenoate (1) in 55% overall yield.1 In a similar way, the reaction of the lithium enolate of ethyl acetate with (E)-crotonaldehyde followed by Jones oxidation gave, after isolation by Kügelrohr distillation, a 50% overall yield of the ethyl ester.2 This synthesis is amenable to scale-up and has been submitted to Organic Syntheses.3 The enol content for this compound is 40% when neat and 60% in a CCl4 solution. Mention should be made of the reported quantitative yield of the ethyl ester by reaction of the lithium enolate of ethyl acetate with (E)-crotonyl chloride.4

Handling, Storage, and Precautions: use in a fume hood.

Base-Catalyzed Cycloaddition.

These g,d-unsaturated b-keto esters are known as Nazarov reagents since they undergo Michael addition with enolizable ketones followed by an aldol condensation, accomplishing Robinson annulation. No example using the reagent (1) (or other esters) for this specific six-membered ring formation has been found in the literature. A very closely related transformation by base-catalyzed cycloaddition (or double Michael addition) of (1) with Methyl 6-Oxo-1-cyclohexenecarboxylate gave the corresponding cis-decalin, the t-butyl ester being selectively cleaved by acid with concomitant decarboxylation (eq 1). High stereoselectivity in favor of the exo adduct is achieved using a nonpolar solvent. Several substituted 6-oxo-1-cyclohexenecarboxylates react similarly.1 This methodology was applied to the synthesis of optically active 14b-hydroxy steroids.5


3-(1-Oxo-2-propenyl)coumarins (benzopyran-2-ones) are easily prepared in one step by cyclocondensation of (2) with 2-hydroxybenzaldehyde, affording a divinyl ketone (eq 2)6 susceptible to undergo double Michael addition and to be a good substrate for the Nazarov cyclization.6 As a potential source of 3,5-bis(alkenyl)pyrazoles, 2,3-dihydropyran-4-ones were prepared by condensation of the ethoxymagnesio enolate of (2) with cinnamoyl or sorbitoyl chloride (eq 3).7 After acylation, the enolic hydroxy group originating from the acyl chloride adds exclusively to the double bond. With (E)-3-chloroacryloyl chloride it is the enolic hydroxy group originating from the b-keto ester which undergoes conjugate addition, giving the 4H-pyran-4-one (eq 4).8

Other Heterocyclic Compounds.

In the pyranone synthesis (eqs 3 and 4) this reagent reacts like other b-keto esters, with the added advantage of having an enone for further reaction. This aspect was exploited in the synthesis of 1,4,5,6-tetrahydropyridazin-4-ones. Thus the reaction of (2) with a diazonium salt affords the a-hydrazone, which cyclized on heating (eq 5).9 Also, condensation of (2) with dimethylformamide dimethyl acetal affords the enamine in almost quantitative yield. When treated with Phenylhydrazine in acetic acid, the pyrazole is obtained, while using DME instead of acetic acid resulted in the formation of the 1,4,5,6-tetrahydro-3-pyridinecarboxylate (eq 6).10

Related Reagents.

Ethyl 2-Methyl-4-oxo-2-cyclohexene-1-carboxylate; Ethyl 4-(Triphenylphosphoranylidene)acetoacetate; Methyl Dilithioacetoacetate; Methyl 5-Methoxy-3-oxopentanoate; Methyl 6-Oxo-1-cyclohexenecarboxylate; Methyl 3-Oxo-4-pentenoate; Methyl Vinyl Ketone; trans-3-Penten-2-one.

1. Lavallée, J.-F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslongchamps, P. CJC 1992, 70, 1406.
2. Zibuck, R.; Streiber, J. M. JOC 1989, 54, 4717.
3. Zibuck, R.; Streiber, J. M. OS 1993, 71, 236.
4. Andrews, J. F. P.; Regan, A. C. TL 1991, 32, 7731.
5. Ruel, R.; Deslongchamps, P. CJC 1992, 70, 1939.
6. van den Goorbergh, J. A. M.; van der Steeg, M.; van der Gen, A. S 1987, 314.
7. Chantegrel, B.; Nadi, A.-I.; Gelin, S. S 1983, 948.
8. Chantegrel, B.; Nadi, A.-I.; Gelin, S. S 1982, 1107.
9. Deshayes, C.; Gelin, S. S 1980, 623.
10. Gelin, S.; Deshayes, C. S 1983, 566.

Gilles Berthiaume

Université de Sherbrooke, Québec, Canada

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