Rapid (≤25 °C) cycloisomerization of anhydride-tethered triynes to benzynes – origin of a remarkable anhydride linker-induced rate enhancement†

Abstract

The hexadehydro-Diels–Alder (HDDA) reaction is a cycloisomerization between a conjugated diyne and a tethered diynophile that generates ortho-benzyne derivatives. Considerable fundamental understanding of aryne reactivity has resulted from this body of research. The multi-yne cycloisomerization substrate is typically pre-formed and the (rate-limiting) closure of this diyne/diynophile pair to produce the isomeric benzyne generally requires thermal input, often requiring reaction temperatures of >100 °C and times of 16–48 h to achieve near-full conversion. We report here that diynoic acids can be dimerized and that the resulting substrate, having a 3-atom anhydride linker (i.e., OCOCO), then undergoes HDDA cyclization within minutes at or below room temperature. This allows for the novel in situ assembly and cyclization of HDDA benzyne precursors in an operationally simple protocol. Experimental kinetic data along with DFT computations are used to identify the source of this surprisingly huge rate acceleration afforded by the anhydride linker: >10⁷ faster than the analogous multi-yne having, instead, a CH₂OCH₂ ether linker.