Iron-mediated and -catalyzed metalative cyclization of electron-withdrawing-group-substituted alkynes and alkenes with Grignard reagents

Treatment of ethyl (E)‐5,5‐bis(benzyloxy)methyl]‐8‐(N,N‐diethylcarbamoyl)‐2‐octen‐7‐ynoate with an iron reagent generated from FeCl₂ and tBuMgCl in a ratio of 1:4 (abbreviated as FeCl₂/4 tBuMgCl) afforded ethyl 4,4‐bis(benzyloxy)methyl]‐2‐(E)‐(N,N‐diethylcarbamoyl)methylene]cyclopent‐1‐yl]acetate in good yield. Deuteriolysis of an identical reaction mixture afforded the bis‐deuterated product ethyl 4,4‐bis(benzyloxy)methyl]‐2‐(E)‐(N,N‐diethylcarbamoyl)deuteriomethylene]cyclopent‐1‐yl]deuterioacetate, thus confirming the existence of the corresponding dimetalated intermediate. The latter intermediate can react with halogens or aldehydes to facilitate further synthetic transformations. The amount of FeCl₂ was reduced to catalytic levels (10 mol % relative to enyne), and catalytic cyclizations of this sort proceeded with yields comparable to those of the aforementioned stoichiometric reactions. The cyclization of diethyl (E,E)‐2,7‐nonadienedioate with a stoichiometric amount of FeCl₂/4 tBuMgCl, followed by the addition of sBuOH as a proton source, afforded a mixture of 2‐(ethoxycarbonyl)‐3‐bicyclo3.3.0]octanone and its enol form in good yield. The use of aldehyde or ketone in place of sBuOH afforded 2‐(ethoxycarbonyl)‐3‐bicyclo3.3.0]octanone, which has an additional hydroxyalkyl side chain. Additionally, the metalation of a carbon–carbon unsaturated bond in N,N‐diethyl‐5,5‐bis(benzyloxy)methyl]‐7,8‐epoxy‐2‐octynamide or (E)‐3,3‐dimethyl‐6‐(N,N‐diethylcarbamoyl)‐5‐hexenyl p‐toluenesulfonate with FeCl₂/4 tBuMgCl or FeCl₂/4 PhMgBr was followed by an intramolecular alkylation with an epoxide or alkyl p‐toluenesulfonate to afford 5,5‐bis(benzyloxy)methyl]‐3‐(E)‐(N,N‐diethylcarbamoyl)methylene]‐1‐cyclohexanol or N,N‐diethyl(3,3‐dimethylcyclopentyl)acetamide after hydrolysis. In both cases, the remaining metalated portion α to the amide group was confirmed by deuteriolysis and could be utilized for an alkylation with methyl iodide.