[487-51-4] · C10H14O3 · Ethyl 2-Methyl-4-oxo-2-cyclohexene-1-carboxylate · (MW 182.22)
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
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.
Wayne State University, Detroit, MI, USA