Cyclization Cascades via N‑Amidyl Radicals toward Highly Functionalized Heterocyclic Scaffolds

• Published in: Journal of the American Chemical Society 2015-01, Vol.137 (2), p.964-973
• Main Authors: Fuentes, Noelia, Kong, Wangqing, Fernández-Sánchez, Luis, Merino, Estíbaliz, Nevado, Cristina
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja5115858

The addition of a variety of radicals to the double bond of N-(arylsulfonyl)­acrylamides can trigger cyclization/​aryl migration/​desulfonylation cascades via amidyl radical intermediates 2. Herein, we demonstrate the synthetic utility of these intermediates in subsequent C–C and C–X bond-forming events to rapidly build up molecular complexity. First, we describe a regio­selective one-pot synthesis of CF3-, SCF3-, Ph2(O)­P-, and N3-containing indolo­[2,1-a]­isoquinolin-6­(5H)-ones from N-[(2-ethynyl)­arylsulfonyl]­acrylamides through a multi-step radical reaction cascade. The process involves the one-pot formation of four new bonds (one C–X, two C–C, and one C–N), a formal 1,4-aryl migration, and desulfonylation of the starting material. Second, we present a one-pot synthesis of 3,3-disubstituted-2-dihydro­pyridinones from N-(arylsulfonyl)­acrylamides and 1,3-dicarbonyl compounds. In this case, a silver-catalyzed radical cascade process involving the sequential formation of two new C–C bonds and one C–N bond, a formal 1,4-aryl migration, and desulfonylation of the starting material explains the regio­selective formation of densely functionalized heterocycles in a straightforward manner. Control experiments have unraveled the key intermediates as well as the sequence of individual steps involved in these transformations.