Photoinduced Strategies for the Functionalisation of Strained Systems and Distal C(sp³)−H Bonds

Vinjamuri, Srinivasu (2026) Photoinduced Strategies for the Functionalisation of Strained Systems and Distal C(sp³)−H Bonds. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Srinivasu Vinjamuri (21RS007)) 21RS007.pdf - Submitted Version Restricted to Repository staff only Download (17MB)

Abstract

Visible-light photoredox catalysis has transformed modern synthetic chemistry by enabling the activation of small molecules and the generation of radical intermediates under mild, energy-efficient, and environmentally benign conditions. Motivated by the need for sustainable catalytic systems and versatile radical-based transformations, this thesis explores photo-induced strategies for constructing complex molecular architectures, with a particular focus on strained carbocyclic frameworks and remote C(³)–H functionalisation. The first part of the thesis investigates the reactivity of highly strained systems, bicyclo[1.1.0]butanes, [1.1.1]propellane, and azabicyclo[1.1.0]butanes, towards photochemically generated radical species. Arenes and Heteroarenes, the most ubiquitous structural moieties in marketed small-molecule drugs, are frequently associated with poor ‘drug-like’ properties, including metabolic instability and poor aqueous solubility. To overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp³)-rich bioisosteric scaffolds relative to arenes. We utilized highly strained bicyclic and tricyclic systems, such as bicyclo [1.1.0]butane, Aza-Bicyclo [1.1.0]butane, and [1.1.1]propellane, to access such saturated motifs. This thesis led to the development of several strain-release-driven methodologies, including the synthesis of heteroarylated spirocyclobutyl oxindoles, metal-free four-component strategies to 1,3-functionalised bicyclopentanes, divergent EDA-complex-mediated routes to α-amino bicyclopentyl iodides and methylene cyclobutanols, and photocatalytic access to densely substituted azetidine–BCP scaffolds bearing multiple contiguous quaternary centers. Together, these approaches significantly advance the synthetic toolkit for accessing medicinally relevant bicyclic and polycyclic motifs. The latter chapters focus on developing remote C(sp³)–H functionalisation strategies mediated by radical translocation via 1,5-hydrogen atom transfer (1,5-HAT). New photocatalytic protocols are presented for cross-dehydrogenative C(sp²)–C(sp³) coupling of heteroarenes with secondary amines, double 1,5-HAT cascades enabling distal C(sp³)–H activation for the synthesis of 2-pyrrolidinones, and a catalyst-free EDA-driven platform achieving 1,n-difunctionalisation (n > 6) of unactivated alkenes through multiple successive HAT events. These methodologies offer broad substrate scope, high chemoselectivity, and excellent compatibility with complex, drug-like molecules. Overall, this thesis establishes a unified framework for harnessing visible-light-driven radical processes to functionalise strained architectures and remote C(sp³)–H bonds. The strategies developed herein expand the boundaries of photoredox reactivity and provide broadly applicable tools for the synthesis and late-stage modification of diverse biologically and pharmaceutically relevant molecules.

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