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

• Published in: Green chemistry : an international journal and green chemistry resource : GC 2023-10, Vol.25 (2), p.8124-8133
• Main Authors: Mutra, Mohana Reddy, Chandana, T. L, Wang, Yun-Jou, Wang, Jeh-Jeng
• Format: Article
• Language: English
• Subjects: Alkynes; Anisole; Carbon; Green chemistry; Nucleophiles; Transformations; Transition metals
• ISSN: 1463-9262; 1463-9270
• DOI: 10.1039/d3gc02460a

Environmentally friendly acid-catalyzed ynamide N-C sp 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 (α and β) triple bonds in ynamides. Herein, we developed a greener and faster acid-catalyzed ynamide N-C sp 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, 13 C-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.