Mechanistic Insight into Lewis Acid-Catalyzed Cycloaddition of Bicyclo[1.1.0]butanes with Ketene: Bicyclo[1.1.0]butanes Serving as an Electrophile

Abstract

Lewis acid-catalyzed cycloaddition between bicyclo[1.1.0]butanes (BCBs) and unsaturated substrates has recently been demonstrated to be a powerful strategy for synthesizing bicyclo[2.1.1]hexanes. However, their reaction mechanisms remain elusive. This computational work explored the recently developed TMSOTf-catalyzed cycloaddition of BCB ketone to ketene and determined the rate-determining step as the activation of BCB ketone. Contrary to the previous proposal of BCB enolate as the active species, this work instead identified the catalytically active species to be a partially Lewis acid-activated BCB cation, which shows a greater electrophilicity and larger orbital interactions with ketene compared to those of the pristine BCB. The most favorable reaction pathway uniquely utilizes this activated BCB species as an electrophile to react with ketene as a nucleophile, while the previously proposed enolate is relatively inactive. Moreover, the in situ-generated TfO anion is revealed to be non-innocent, and its coordination mode and orientation could affect the reaction kinetics.

Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

“…Interestingly, Zhang and coworkers conducted a computational investigation into this reaction mechanism and suggested that a Lewis acidactivated BCB ketone acts as an electrophile for a ketene nucleophile (right panel of the proposed mechanism). [51] Regardless of the exact mechanism of cycloaddition, Studer and coworkers demonstrated a broad scope of ketenes and BCB ketones including alkyl BCB ketones 158 and 159. However, BCB esters and amides only provided trace product, presumably due to a less electrophilic BCB to either TMSOTf activation or the ketene nucleophiles.…”

B(C6F5)3-Catalyzed Formal (n + 3) (n = 5 and 6) Cycloaddition of Bicyclo[1.1.0]butanes to Medium Bicyclo[n.1.1]alkanes

“…Subsequent nucleophilic addition of imidazolidine/hexahydropyrimidine 2 / 3 to the carbocation center of intermediate II forms ammonium species III . Importantly, it is obviously different from the pioneering precedents by Leitch and co-workers, Studer and co-workers, and Glorius and co-workers that triggered the reaction with nucleophilic attack from the anion moiety of intermediate II (path b in Scheme B) . Subsequent aminal ring opening affords zwitterionic iminium species IV , followed by intramolecular cyclization to afford the target product 4 / 5 with the release of the B(C 6 F 5 ) 3 catalyst.…”