Cyclohexenones, from dehydration reactions

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

Lee et al. have developed a simple, two-step method for the synthesis of indanone derivatives 133 and 134 using an intramolecular Heck reaction of MBH adducts 132 of 2-iodobenzaldehyde in the presence of Pd(OAc)2/ (o-ToOsP/EtsN (Scheme 3.52). Interestingly, using MBH adduct derived from cyclohexenone as the substrate afforded 1-hydroxyfluorene (135) in 32% yield, presumably via a p-hydrogen elimination, dehydration and aromatiza-tion along with proton migration (Scheme 3.52). 

Let s revisit the Wieland approach to steroids (Steroids-7). The reaction of 87 with the enone derived from in situ dehydrohalogenation of 88 gave 89. This was followed by an intramolecular aldol-dehydration to give 90. This is variation of 68 -I- 69 67 66 (followed by hydration to a cyclohexenone) as seen in Functional Groups-11. There are many more tactics that have been developed to accomplish this fundamental strategy in the laboratory. 

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