Electrosynthesis of Five-membered Heterocycles through Ionic and Radical Annulations

Mallick, Samrat (2025) Electrosynthesis of Five-membered Heterocycles through Ionic and Radical Annulations. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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Abstract

This thesis entitled as “Electrosynthesis of Five-membered Heterocycles through Ionic and Radical Annulations” illustrates development of innovative and unique synthetic routes for the creation of various cherished five membered hetercocyclic scaffolds through electrochemical annulations. The contents of this thesis are described in 6 chapters, reflecting the conclusions drawn from the experimental investigations, carried out over the whole course of my research tenure. Due to their diverse chemical properties and biological activities, five-membered heterocycles hold immense significance in various scientific and industrial domains for which unwavering devotion was shown by the synthetic community to construct them through development of green and sustainable protocols. In this premise, electro-organic synthesis has emerged as a cutting-edge alternative to fabricate complex molecular architectures. This technique excels in the construction of a diverse array of C-C and C-Het bonds through incorporating electrons as redox elements and thereby excluding the essential requirement of external redox reagents to facilitate the overall process. Moreover, additional flexibility in regulating the reaction parameters (e.g. applied potential or electricity) is capable of providing superior selectivity and efficiency in the production of the desired frameworks by eliminating competing reaction pathways. Herein, adapting this electrochemical approach different five membered aromatic (imidazole, carbazoles) and alicyclic (oxazolines, isoxazolines, imidazolnes) heterocycles are manufactured. The first chapter, Chapter 1 describes the fundamental aspects of electro organic synthesis, highlighting instrumentations and different modes of electrolysis and their influence in the generation of reactive transient species. Furthermore, a brief description regarding the synthesis of numerous five membered heterocycles through electrolysis is also provided. Chapter 2 unveils an electrochemical oxidative chalcogenation protocol demonstrating the fabrication of chalcogenated oxazolines and isoxazolines from the corresponding β,γ- unsaturated amides and oximes via olefin activation. Control experiments and mechanistic investigations suggested both radical and ionic cyclization process during the course of reaction. In Chapter 3, the appropriate control over the N-H acidity (tuned via the judicious selection of N-protecting groups) in conjunction with this alkene activation technique allowed for the production of indole moieties with diverse substitution patterns. Following this, in Chapter 4 a formal [3+2] cyloaddition strategy between α-Amino Carbonyls and Tosylmethyl Isocyanide (TosMIC) is depicted, permitting the fabrication of 1,5-disubstituted imidazole derivatives. Mechanistic studies revealed the generation of reactive imine intermediate by anodic oxidation followed by cycloaddition and aromatization constructing C−C and C−N bonds in a consecutive manner. Chapter 5 describes the synthesis of 4,5-dihydro-1Himidazole derivatives and is divided into two sections. In the first section (Chapter 5A), an electrochemical heterocoupling between two N-aryl glycinate derivatives is demonstrated which provided highly diastereoselective 4,5-dihydro-1H-imidazole carboxylates through an acid mediated epimerization sequence. A follow up cascade annulation strategy was successfully adopted in Chapter 5B fabricating bicyclic [3,3,0] scaffolds through appropriate substrate modification. Finally, in Chapter 6 a switchable regioselective C(sp³)-H/C(sp²)-H arylation was detected by fine-tuning the pH of the reaction medium. Under strong acidic condition, C(sp²)-H arylation was performed leading to highly substituted carbazole manifolds whereas, basic condition is necessary to execute C(sp³)-H employing the identical precursors. Each chapter includes comprehensive experimental protocols as well as characterization of synthesized compounds. The relevant references are also cited at the end of each chapter.

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