Green and rapid acid-catalyzed ynamide skeletal rearrangement and stereospecific functionalization with anisole derivatives

Environmentally friendly acid-catalyzed ynamide N-Csp bond cleavage, skeletal rearrangement and chemo-, regio- and stereospecific functionalization with nucleophiles are of great interest in synthetic chemistry. However, such transformations present remarkable regio- and stereospecific challenges due to the biased carbon-carbon (& alpha; and & beta;) triple bonds in ynamides. Herein, we developed a greener and faster acid-catalyzed ynamide N-Csp bond fission, skeletal rearrangement and stereospecific functionalization with nucleophilic anisole derivatives to produce thermodynamically unstable challenging cis-alkene tethered indole scaffolds in a very short reaction time (5-10 min). The key features of this transformation are its transition-metal-free nature, broad scope, ease of handling, simple setup, mild reaction conditions, atom/step/time economy, and the gram-scale experiment. Most importantly, 13C-isotope labeling experiments in mechanistic studies confirmed the alkyne-carbon position in the rearrangement process. The green chemistry metrics evaluation and EcoScale score (75 on a scale of 0-100) indicate that our transformation is safer, environmentally friendly, and economically feasible. Environmentally friendly acid-catalyzed 2-alkynyl-ynamides (N-Csp) bond cleavage, alkyne migration and stereospecific functionalization with anisole derivatives for the synthesis of challenging indole scaffolds in 5-10 minutes.

Automated summary

Environmentally friendly acid-catalyzed ynamide N-Csp bond cleavage, alkyne migration, and stereospecific functionalization with anisole derivatives for the synthesis of challenging cis-alkene tethered indole scaffolds in a very short reaction time (5-10 min).