Bioorthogonal Hydroamination of Push–Pull‐Activated Linear Alkynes

• Published in: Angewandte Chemie Vol. 133; no. 31; pp. 17084 - 17089
• Main Authors: Kang, Dahye, Cheung, Sheldon T., Kim, Justin
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 26-07-2021
• Subjects: Alkynes; bioorthogonal; Chemistry; Cycloaddition; enamine N-oxide; hydroamination; Hydroxylamine; Nucleophiles; rehybridization effect; retro-Cope elimination
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202104863

A bioorthogonal reaction between N,N‐dialkylhydroxylamines and push–pull‐activated halogenated alkynes is described. We explore the use of rehybridization effects in activating alkynes, and we show that electronic effects, when competing stereoelectronic and inductive factors are properly balanced, sufficiently activate a linear alkyne in the uncatalyzed conjugative retro‐Cope elimination reaction while adequately protecting it against cellular nucleophiles. This design preserves the low steric profile of an alkyne and pairs it with a comparably unobtrusive hydroxylamine. The kinetics are on par with those of the fastest strain‐promoted azide‐alkyne cycloaddition reactions, the products regioselectively formed, the components sufficiently stable and easily installed, and the reaction suitable for cellular labeling.
A rapid and regioselective click reaction between N,N‐dialkylhydroxylamines and linear alkynes is described. This bioorthogonal reaction between two small components is enabled by the rehybridization effect of terminally halogenated alkynes and the careful balancing of alkyne π‐electron density through a push–pull mechanism.