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

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.

Automated summary

A new class of push-pull-activated alkynes featuring di- and trifluorinated ynol ethers was synthesized. The difluorinated ynol ether displayed an optimal balance of stability and reactivity, while the trifluorinated ynol ether was highly reactive but unstable towards thiols. These fluorinated ynol ethers highlight the importance of the hyperconjugation-rehybridization effect and substituent effects in activating and stabilizing alkynes for bioorthogonal reactivity.