Grignard reagent enol lactone

The addition of Grignard reagents or organolithiums (alkenyl, alkyl, alkynyl, allyl or aryl) to nitroenamines (281)213 was reported by Severin to afford P-substituted-a-nitroalkenes.214 b Similarly, ketone enolates (sodium or potassium), ester enolates (lithium) and lactone enolates (lithium) react to afford acr-nitroethylidene salts (294) which, on hydrolysis with either silica gel or dilute acid, afford 7-keto-a,(3-unsaturated esters or ketones (295)2l4c-d or acylidene lactones (296).214 Alternatively, the salts (294, X s CH2) can be converted to -y-ketoketones (297) with ascorbic acid and copper catalyst. 

Cobalt catalysts were used for substitution reactions of organic halides [442] and a small-ring enol lactone [Eq. (201) 443]. The cobalt salt seems to be the most effective one among a few transition metal salts involving copper, nickel, [see Eq. (130)], and iron. Without the catalyst, Grignard reagent attacked the carbonyl carbon of the enol lactone to give a mixture of a few ketonic compounds in a low yield. 

Fujimoto-Belleau reaction. Synthesis of cyclic a-substituted a,(3-unsaturated ketones from enol lactones and Grignard reagents prepared from primary halides. 

Synthesis of fused cyclohexenones from cyclic enol lactones with Grignard reagents (an alternative to the Robinson annulation) (see 1st edition). 

To a solution of the enol lactone 25 (1 mmol) in anhydrous tetrahydrofiiran (3 mL) was added the appropriate Grignard reagent (1.5 mmol) in ethereal solution at -60 °C over 30 min. After stirring at -60 °C for 1 h, the reaction mixture was poured onto saturated ammonium chloride solution, and the reaction product extracted with diethyl ether. The organic extract was washed and dried (sodium sulfate). After removal of the solvent, the residue was dissolved in 2 N methanolic potassium hydroxide solution (4 mL), and the resultant mixture heated under reflux for 1 h. The cooled mixture was neutralised with AcOH and evaporated under reduced pressure. The residue was then diluted with water and extracted with diethyl ether or dichloromethane. Chromatography of the crude product on silica gel (eluent 3 7 ethyl acetate/hexanes) afforded pure enones 26 in 20-50% yields. 

The total synthesis of ( + /—)-isostemonamide (38) (Scheme 21) proceeded from 213 according to the sequence described for (+ /—)-stemonamide (37) (Scheme 20) in 16 steps and in 3.5% overall yield from 207. In the Cu(I)-mediated addition of Grignard reagent 215 to the Q ,/8-unsaturated ketone 219 only or-attack was observed, and ketone 221 and the corresponding silyl enol ether 220 were formed in 32% and 57% yield, respectively. Both compounds were converted to the a -methylene lactone 222 under treatment with the Mannich reagent iV,iV-dimethylformaldimmonium trifluoroacetate, albeit under different experimental conditions (80). 

The enol acetate group has been shown to be stable to the conditions of semicarbazone formation from another ketone group in the molecule [137], and to the action of a Grignard reagent on a concomitant enol lactone group [138]. 

Treatment of enol lactone with Grignard reagent leads to cyclic a-substituted oc,P-unsaturated ketone. An alternative to the Robinson annulation. 

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