We desribe the bioorthogonal reaction between N,N-dialkylhydroxylamines and activated alkynes. We found that both strained and push-pull-activated linear alkynes are able to undergo rapid hydroamination by hydroxylamines. These reactions feature a highly regioselective transformation between small, easily functionalizable reaction components with second-order rate constants reaching 84 M–1 s–1. The reaction with strained alkynes is orthogonal to the inverse-electron demand Diels–Alder reactions between tetrazine and strained alkenes, and its components exhibit exquisite stability and chemoselectivity in cell lysate. We explored the use of rehybridization effects in activating linear alkynes, and we showed that electronic effects, when competing stereoelectronic and inductive factors are properly balanced, sufficiently activate a linear alkyne in this reaction. This retro-Cope elimination reaction introduces a new member to the bioorthogonal reaction compendium outside the prolific class of cycloaddition reactions.

Bioorthogonal hydroamination of strained and push-pull-activated linear alkynes

ACS Spring 2022

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