DOI: 10.1021/acs.orglett.6c02421 ISSN: 1523-7060
Brønsted Acid-Catalyzed [3 + 2] Cycloaddition of Indoles with Azabicyclobutanes: Access to Indole-Fused 1-Azabicyclo[2.1.1]hexanes
Debasis Aich, Arpan Naskar, Subrata Hazra, Suchandrima Banerjee, Boudhayan Bandyopadhyay, Santanu PandaAbstract
1-Azabicyclo[2.1.1]hexanes are valuable nitrogen-rich scaffolds with growing importance in medicinal chemistry. We report a Brønsted acid-catalyzed formal cycloaddition of N-substituted indoles with azabicyclobutane (ABB) ketones, providing a mild, transition-metal-free, and highly stereoselective route to aza-bicyclohexanes. Using pTSA·H2O in HFIP, the reaction proceeds at room temperature in up to 93% yield and 99:1 d.r. Mechanistic studies suggest cooperative activation by pTSA and HFIP via hydrogen-bond-assisted proton transfer. The synthesized scaffolds also exhibited promising antimicrobial activity.