Synthesis of push–pull-activated ynol ethers and their evaluation in the bioorthogonal hydroamination reaction

Abstract

A new class of push–pull-activated alkynes featuring di- and trifluorinated ynol ethers was synthesized. The difluorinated ynol ether exhibited an optimal balance of stability and reactivity, displaying a substantially improved half-life in the presence of aqueous thiols over the previously reported 1-haloalkyne analogs while reacting just as fast in the hydroamination reaction with N,N-diethylhydroxylamine. The trifluorinated ynol ether reacted significantly faster, exhibiting a second order rate constant of 0.56 M⁻¹ s⁻¹ in methanol, but it proved too unstable toward thiols. These fluorinated ynol ethers further demonstrate the importance of the hyperconjugation–rehybridization effect in activating alkynes and demonstrate how substituent effects can both activate and stabilize alkynes for bioorthogonal reactivity.