Access to allyl-gem-difluorides via allylation and Cope rearrangement

Abstract

Fluorinated molecules play crucial roles in medicinal and materials chemistry, as the presence of fluorine profoundly alters molecular electronics and reactivity. Among them, allyl gem-difluorides have attracted growing attention as versatile synthetic intermediates, but their selective construction remains challenging. Here, we disclose an efficient strategy for synthesizing allyl gem-difluorides bearing (E)-vinyl boronic esters through a LiOtBu-mediated deborylative allylation/Cope rearrangement sequence of 3-boryl-1,1-difluoro allylboronic ester with allyl bromides. Four competing pathways (α-S_N2, α-S_N2′, γ-S_N2, and γ-S_N2′) were identified: α-addition generates intermediates that undergo Cope rearrangement, while γ-addition directly delivers the same products. Mechanistic studies, supported by control experiments as well as NBO and FMO analyses, demonstrate a synergistic effect between the 1,1-difluoro group and the boronic ester that lowers the activation barrier of the rearrangement. This transformation displays broad substrate scope and provides versatile building blocks for the construction of allyl gem-difluorides.