Nucleophilic, Ferrocenium-Catalyzed Ring-Opening Reactions of Propargylic Alcohols with Unactivated Cyclopropyl Substituents to Afford Enynes: Trends and Selectivity

Ferrocenium-catalyzed transformations provide a practical and sustainable approach to propargylic substitution reactions. Herein, we investigate the ring-opening of cyclopropyl-substituted propargylic alcohols with alcohol nucleophiles, catalyzed by ferrocenium tetrafluoroborate ([FeCp2][BF4]) to afford synthetically valuable enyne ethers. Mechanistic studies using GC and NMR spectroscopy reveal that the reaction proceeds via initial formation of a ring-closed propargylic ether intermediate, which subsequently undergoes ring opening to the enyne ether. Experimental evidence supports a carbocationic pathway in which the ferrocenium cation promotes ionization to a stabilized cyclopropyl ether intermediate, followed by intramolecular, ferrocenium-assisted cyclopropyl ring opening to the enyne product. Reaction rates and product distributions are strongly influenced by temperature and solvent polarity, with polar solvents and elevated temperatures favoring ring opening. At room temperature, the ring-closed substitution product predominates, whereas efficient formation of enynes occurs at 65 °C. The reaction progresses faster in a polar solvent, indicating an ionic mechanism. Studies employing substrates containing substituted cyclopropyl rings demonstrated pronounced regioselectivity during nucleophilic ring opening with alcohols, with preferential cleavage of the bond between the two substituted carbon atoms. This selectivity is consistent with partial positive-charge stabilization in the transition state. The corresponding enyne ether products were isolated in 98–31% isolated yields, in most cases as a single regio- and E/Z stereoisomer (5 h at 45 °C, 5 mol% [FeCp2][BF4] catalyst load, six equivalents alcohol nucleophile). The ferrocenium-catalyzed cyclopropyl ring opening establishes a convenient method for accessing enyne motifs, which are important structural units in organic synthesis and medicinal chemistry.