Visible-Light-Induced Cascade Radical Ring-Closure and Pyridylation for the Synthesis of Tetrahydrofurans

Significance 

Generally, biologically active compounds comprise tetrahydrofurans that are normally used as precursors in the formation of other compounds such as polymers. Recently, great efforts have been devoted towards development of Pd-catalyzed alkene carboxylation reactions to enable assess of various substituted tetrahydrofurans. For example, this has led to the realization of Pd-catalyzed carboetherification reactions of tertiary hydroxyl groups with acyclic internal alkenes.

Regardless of the significant improvements, there are several drawbacks concerning the synthesis of substituted tetrahydrofurans attributed to the hinderance of the reaction sites resulting in the production of by-products. Specifically, arylpalladium complexes formed from disubstituted alkenes during the synthesis have remained a major challenge. Therefore, the compatibility of Pd (0) catalytic systems with several functional groups especially in harsh conditions should be enhanced.

In a recently published literature, researchers proposed that inclusion of radical pathways could address the aforementioned problems considering that the highly reactive nature of the alkoxy radicals which makes them acts as good platforms in various investigations regarding chemical transformations. Alternatively, visible-light photoredox catalysts have been recently identified as promising candidates for the generation of alkoxy radicals under mild conditions. This has been demonstrated in several published papers. Despite the exemplary efforts and great potential, the transition-metal-free alkoxy racial cyclization and heteroarylation strategy have not been fully explored. Therefore, inspired by the photocatalyzed radical reactions, the authors have predicted the possibility of developing bond-forming reactions based on the alkoxy radical-triggered cyclization and pyridyl moiety installation in one step.

To this note, researchers at Korea Advanced Institute of Science and Technology (KAIST): Dr. Yechan Kim, Kangjae Lee (PhD candidate), Dr. Gangadhar Rao, Inwon Kim (PhD candidate), and led by Professor Sungwoo Hong developed a visible-light-induced cascade alkoxy radical cyclization and pyridylation by using N-alkenyloxypyridinium salts under metal-free and mild conditions. Fundamentally, the strategy was based on photoredox tandem radical process entailing: sequential fragmentation of the N-alkenyloxypyridinium salts, radical cyclization process and the pyridylation process. Furthermore, the alkoxy radical was generated through a single electron transfer process. This process further triggered intramolecular alkoxy radical cyclization thus enabling the substrate addition and installation of the pyridyl group. The research work is currently published in the research journal, Green Chemistry.

The authors observed that the employed cyclization and pyridylation approach exhibited broader substrate scope, good functional group tolerance and exemplary good compatibility especially at mild conditions thus offering suitable tools for effective evaluation of pyridine-tethered tetrahydrofuran products. This was attributed to the easy accessibility and efficiency of the N-alkenyloxypyridinium salts especially when used as bench-stable precursors of alkoxy radical during photocatalysis process. Additionally, it was worth noting that radical cascade cyclization enabled the synthesis of the pyridine-tethered bicyclic ring that could not be realized previously.

In summary, Professor Sungwoo Hong and his research group at KAIST successfully demonstrated an effective approach for the synthesis of tetrahydrofurans under metal-free and mild conditions. From the obtained results, the approach can be extended to the late-stage functionalization of complex molecules which would, in turn, advance various applications including the construction of chemical libraries.

Visible-Light-Induced Cascade Radical Ring-Closure and Pyridylation for the Synthesis of Tetrahydrofurans - Advances in Engineering

About the author

Sungwoo Hong is a Professor at the Department of Chemistry at Korea Advanced Institute of Science and Technology (KAIST, Korea) and an Associate Director of the Center for Catalytic Hydrocarbon Functionalizations at the Institute for Basic Science (IBS). He graduated from Seoul National University (Korea), where he gained his BS and MS degrees. He then went on to Pennsylvania State University (USA) for his PhD program. After he had finished his postdoctoral course at Harvard University (USA, 2006), under the supervision of Prof. E. J. Corey, he joined GlaxoSmithKline (GSK, USA) as a Principal Scientist. In 2009, he started independent work at KAIST. His research interests are in the field of development of new reactions and synthesis, medicinal chemistry and bioorganic chemistry.

About the author

Yechan Kim received his BS degree in chemistry in 2013 and received Ph.D in 2018 from Korea Advanced Institute of Science and Technology (KAIST). Currently, he works for Samsung Electronics. His research interests was C–H activation via transition metal and photoredox catalysis.

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About the author

Kangjae Lee earned his BS in chemistry at Korea Advanced Institute of Science and Technology (KAIST) in 2017. He is currently in an integrated Master’s & PhD program under the supervision of Prof. Sungwoo Hong. His research interests focus on photocatalytic C–H bond functionalization.

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About the author

Gangadhar Rao Mathi attended VIT University (India) for his Master’s in organic chemistry after completing undergraduate studies from Andhra University (India) in 2009. After graduation, he worked as a research associate in Syngene international limited (BIOCON). In 2014, he went on to University of Science and Technology (Korea) for his PhD (KRICT, Korea). Starting in 2018, he joined as a post-doctoral fellow in the group of Prof. Sungwoo Hong at CCHF, IBS. His current research focuses on development of novel methods for catalytic hydrocarbon functionalizations.

About the author

Inwon Kim received his B.S. degree in Chemistry at Sungkyunkwan University (SKKU), South Korea, in 2016. He is currently a Ph.D. candidate under the guidance of Prof. Sungwoo Hong in the Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST). His research interests are on the development, synthetic applications, and mechanistic understanding of the site-selective C–H functionalization.

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Reference

Kim, Y., Lee, K., Mathi, G., Kim, I., & Hong, S. (2019). Visible-light-induced cascade radical ring-closure and pyridylation for the synthesis of tetrahydrofurans. Green Chemistry, 21(8), 2082-2087.

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