2-Cyclohexenone Grignard additions

Fig. 10.37. Preparation of cyclohexenones through addition of a Grignard- or organo-lithium compound to 3-ethoxy-2-cyclohexenone, which is inevitably followed by an El elimination—even if workup of the reaction mixture is performed with a weak acid.

In addition, Grignard addition to the lactam followed by hydrolysis of the bicyclic lactam affords either 3,4,4-or 2,6,6-trisubstituted 2-cyclohexenones, depending upon the hydrolytic conditions employed (eq 4). ... 

Ethoxy-2-cyclohexenone is a useful intermediate in the synthesis of certain cyclohexenones. The reduction of 3-ethoxy-2-cyclohexenone with lithium aluminum hydride followed by hydrolysis and dehydration of the reduction product yields 2-cyclo-hexenone. Similarly, the reaction of 3-ethoxy-2-cyclohexenone with Grignard reagents followed by hydrolysis and dehydration of the addition product affords a variety of 3-substituted 2-cyclo-hexenones. ... 

The conjugate addition of Grignard reagents to 2-cyclohexenone was promoted by catalytic amounts (2-4 mol %) of alkylcopper(I) complexes of the lithium amide prepared from N- (R)-1 -phenylethyl]-2-[(/ )-l-phenylethyliminojcycloheptatrienamine, Li[CuR(CHIRAMT)]52,11. However, 3-substituted cyclohexanones were obtained in very low ee (4-14%). 

This work was initiated in 1988 when Villacorta et al.71a reported the asymmetric conjugate addition of a Grignard reagent to 2-cyclohexenone. This study showed that 1,4-adducts with 4-14% ee were obtained in the presence of aminotroponeimine copper complex.713 Enhanced results (74% ee) were obtained by adding HMPA or silyl halides.71b Several other copper complexes were also used for inducing asymmetric conjugate addition reactions. Moderate results were obtained in most cases when THF was used as the solvent and HMPA as the additive. 

TABLE 2. Cu/NHC-catalyzed addition of Grignard reagents to 3-substituted 2-cyclohexenones... 

An improved route to the key intermediate 326 was also developed (165). Namely, 322 was converted to the monoprotected 1,4-dione 327 by sequential addition of the Grignard reagent derived from 2-(2-bromoethyl)-2-methyl-l,3-dioxolane followed by oxidation of the resulting benzylic alcohol with pyridin-ium dichromate (PDC). The ketone 327 was then smoothly transformed to the 2-azadiene 328 by olefination with BAMP. The regioselective addition of n-butyllithium to 328 as before followed by alkylation of the resulting metalloenamine with benzyl A-(2-bromoethyl)-A-methylcarbamate and acid-catalyzed hydrolysis furnished 325, which was converted to the cyclohexenone 326 by base-induced cycloaldolization and dehydration. 

The copper-catalyzed addition of butyl Grignard reagent to cyclohexenone was reported by using selenium-oxazoline-based ligand 35 which gave butylcy-clohexanone 36 in 62% ee (Scheme 4) [24]. 

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