Tandem Radical Cyclization of N-Arylacrylamides: An Emerging Platform for the Construction of 3,3-Disubstituted Oxindoles

Abstract

3,3-Disubstituted oxindoles are an important family of biologically active heterocycles, and numerous synthetic methodologies have been developed for their synthesis over past decades. Recently, the tandem radical cyclization of N-arylacrylamides has provided a new powerful approach to access various diversely functionalized 3,3-disubstituted oxindoles. This review will highlight recent advances in this field as well as applications in natural product synthesis in terms of different types of radical source. Particular emphases have also been placed on working models. 1 Introduction 2 Tandem Radical Addition/Cyclization Reaction of N-Arylacrylamides with Carbon Radicals 2.1 Aryl Radicals 2.2 Alkyl Radicals 2.3 Fluorine-Containing Carbon Radicals 2.4 Acyl Radicals 3 Tandem Radical Addition/Cyclization Reaction of N-Arylacrylamides with Heteroatom Radicals 3.1 Phosphonyl Radicals 3.2 Sulfur Radicals 3.3 Nitrogen Radicals 4 Conclusion and Perspective Key words N-arylacrylamides, heterocycles, oxindoles, radical cyclizations, tandem reactions Jia-Rong Chen was born in 1980. He received his B.Sc. in Chemistry at Central China Agricultural University in 2003 and finished his Ph.D. studies in 2009 under the direction of Prof. Wen-Jing Xiao in Central China Normal University. From 2011 to 2012, Dr. Chen worked as a Humboldt postdoctoral fellow with Prof. Carsten Bolm at the RWTH Aachen University. Then, he returned to Central China Normal University, where he is now an associate professor. His current research interests include the development of new catalysts for asymmetric catalysis and cycloaddition reactions. Xiao-Ye Yu was born in 1989 in ShanXi, P. R. of China. She received her B.S. from Taiyuan Normal University in 2009. She then began her M.Sc. studies in the group of Prof. Wen-Jing Xiao at Central China Normal University, working on asymmetric catalysis and heterocycle synthesis. Wen-Jing Xiao was born in 1965. He received his B.Sc. in chemistry from Central China Normal University (CCNU) in 1984 and then his M.Sc. under the supervision of Professor Wen-Fang Huang in 1990 at the same university. In 2000, he received his Ph.D. under the direction of Professor Howard Alper in University of Ottawa, Canada. Following postdoctoral studies with Professor David W. C. MacMillan (2001-2002) at Caltech, USA, in 2003, Dr. Xiao became a full professor in the College of Chemistry at CCNU, China. His current research interests include the development of new synthetic methodologies and the synthesis of biologically active compounds.

Mechanistic investigation on radical-induced construction of oxindoles: radical versus electrophilic cyclization

“…[1][2][3][4] Due to the advantage of atom and step economy, this strategy has been focused by synthetic chemists and was comprehensively applied in total synthesis. [5][6][7][8][9] In recent years, thanks to tandem radical cyclization strategy, the easily accessible N-arylacrylamides have been widely used for the synthesis of 3,3-disubstituted oxindole skeletons [10][11][12][13] which commonly exist in numerous natural compounds. [14][15][16] It is easy to put a variety of functional groups on the C3-position of oxindoles with different radical substrates.…”

Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst

“…This mechanistic variation, which avoids the use of a stoichiometric H atom donor, was successfully implemented to enable the preparation of functionalized (hetero)aromatic products. The sequential radical addition/cyclization of aromatic acrylamides 6 31 , promoted by catalyst 1c, provided a range of differently substituted oxindoles 7 (Fig. 3c).…”

Copper‐Catalyzed Regioselective Oxidative Cycloamidation of α‐[(β‐Dimethylamino)propenoyl]‐Alkylamides: Synthetic Route to Substituted Pyrrolidine‐2,4‐diones

“…When transition metal is copper, intermediate F can be generated via another pathway, namely, the ring‐opening reaction of C ocurrs to give a chelated Cu II species I , followed by an oxidative cyclization to form a metallacycle J , and the reductive elimination of J leads to intermediate F ,. During this process, the oxidation of the released Cu I by PIFA or iodanyl radical B to Cu II brings reaction to the next catalytic cycle,, and hence the copper‐involved redox cycle further facilitates the oxidative cycloamidation of 1 to 3 .…”