Developing sustainable strategies for the construction of heterocycles and cyano-functionalization

This thesis presents the development of novel synthetic methods for the preparation of various nitrogen-containing heterocycles and polyheterocycles, utilizing greener and more sustainable methodologies. It also explores new electrochemical cyanation protocols that employ safer cyanide sources and/or milder reaction conditions. The Introduction emphasizes the significance of heterocyclic compounds in everyday chemistry, briefly discussing their applications in pharmaceuticals and industry. Chapter 1 introduces the isoindolinone core and its biological properties. The importance of cascade procedures in the synthesis of isoindolinone derivatives is also highlighted, with a particular focus on electrochemical methods. The chapter first details an electro-induced cascade reaction for synthesizing 3-N-aryl substituted isoindolinones using catalytic amounts of current and supporting electrolyte. The method was then extended to synthesize isoindolinone-containing polyheterocycles exploiting the second reactivity of suitable electrophilic moieties at the ortho-position of the reagents. Finally, the chapter concludes by describing a one-pot cascade protocol for preparing a C-10-substituted batracylin analog using Cs₂CO₃, as the solely catalyst. A preliminary photophysical characterization of the attained analog is also reported. Chapter 2 discusses the importance of nitrile group in organic chemistry, outlining the limitations of traditional cyanation protocols and the consequent need for safer cyanide sources and greener methods. Two novel electrochemical cyanation reactions are described: the cyanation of chalcones and imines through the catalytic electrochemical activation of acetone cyanohydrin, as cyanating agent; the exploration of the 5-aminotetrazole as a novel and safer CN surrogate, capable of generating both electrophilic and nucleophilic cyanide for the cyanation of a large range of substrates. This latter method was also optimized in flow-electrochemical systems. Chapter 3 explores the advantages of combining of the Pictet-Spengler and Ugi four component reactions for the first synthesis of 4-imidazolidinone-tetrahydro-β carboline hybrids by means of TMSOTf as an effective mediator.