Palladium Catalyzed Aza-Wakcer/Povarov Reaction of Aryl Amines and 1,6-Dienes: Synthesis of Hexahydro-Cyclopenta[b]quinoline Framework

Abstract Palladium catalyzed tandem reaction represents a one-pot synthetic approach to efficiently synthesize complex functionalized molecules while reducing synthetic steps, aligning with the principles of green chemistry. However, achieving a direct cascade of the aza-Wacker and Povarov reactions in one-pot synthesis presents a challenge due to substrate compatibility issues between the two reactions. In this work, we describe an aza-Wacker/Povarov reaction employing a highly electrophilic palladium catalyst, which effectively converts anilines and 1,6-dienes into hexahydro-cyclopenta[b]quinolines. The optimized conditions yield up to 79%, with a diastereoselectivity > 20:1. Substrate range testing revealed compatibility with various sensitive functional groups, and successful late-stage modifications were performed on several natural products and drug molecules, demonstrating the versatility and practicality of the method. Additionally, a preliminary investigation into the reaction mechanism suggests an aza-Wacker process followed by a Povarov process.