Transition Metal and Photoredox Catalyzed Routes to C−H Activation and Trifluoromethylthiolation

Garai, Sumit (2024) Transition Metal and Photoredox Catalyzed Routes to C−H Activation and Trifluoromethylthiolation. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Sumit Garai (18RS029)) 18RS029.pdf - Submitted Version Restricted to Repository staff only Download (10MB)

Abstract

Transition metal-catalyzed C−H activation is a transformative approach in organic synthesis, offering improved atom and step economy while reducing waste. Transition metal catalysts enable direct functionalization of organic molecules by selectively cleaving inert C−H bonds. Catalysts like ruthenium, palladium, and iridium coordinate with substrates, initiating key steps like oxidative addition and reductive elimination. This methodology, guided by ligand design and directing groups, allows for precise control over regio- and stereoselectivity. In recent years, our group has dedicated efforts to functionalizing aromatic and aliphatic compounds by C−H activation, employing directing groups to guide these transformations. Initially, our research group directed its efforts towards the cyanomethylation reaction, aiming to activate both C(sp²)−H and C(sp³)−H bonds. This focus stemmed from the widespread presence of the nitrile group in biologically active compounds. Over 30 pharmaceuticals containing cyano groups are prescribed for various medical conditions, while more than 20 nitrile-containing pharmaceuticals are undergoing clinical development. Also, the cyano group can be transformed into pharmaceutically important functional groups like amine, amide, carboxylic acid, tetrazole, etc. Considering this context, we have devised an efficient and adaptable method for directly cyanomethylating unactivated arenes and amino acid derivatives. This technique employs inexpensive chloroacetonitrile (ClCH2CN) as the cyanomethylating agent, with activation of the inert C(sp²)−H and C(sp³)−H bonds facilitated by a palladium catalyst in conjunction with 8-aminoquinoline serving as a directing group. Likewise, incorporating a fluorinated moiety (like −CF₃, −SCF₃, −CH₂CF₃, −CHF₂) in organic compounds significantly changes physicochemical properties, including metabolic stability, lipophilicity, and membrane permeability. Due to the scarcity of naturally occurring organofluorine compounds, there is a need for the development of a new methodology to introduce fluorinated moieties. To fulfill this demand, we have developed a straightforward approach to introduce the trifluoroethyl moiety into the useful amino and carboxylic acid derivatives by activating the inert β−C(sp³)-H bonds with the help of a palladium catalyst. This method ensures high chemo and regioselectivity and enables the straightforward synthesis of a diverse array of important γ-trifluoromethyl amino acid and carboxylic acid derivatives. In contemporary times, photoredox catalysis is one of the fastest-growing interests in the organic chemistry research arena for synthesizing complex structures. This approach accesses reaction pathways that are inaccessible by traditional methods and operates under mild conditions, reducing by-products and enhancing atom efficiency. Embracing the photoredox strategy, we have extended our focus to synthesizing diverse biologically active molecules, particularly incorporating the fluorinated moiety. Employing cyclopropyl ketones and AgSCF₃ as a thifluorothiomethyl source, we have developed novel catalytic methods to synthesize biologically active SCF3-substituted dihydrofurans and unsymmetrical 1,4-diones using a photocatalytic approach. The thesis entitled “Transition Metal and Photoredox Catalyzed Routes to C−H Activation and Trifluoromethylthiolation” is structured into five chapters, each focusing on distinct aspects of synthesizing pharmaceutically active cores. It delves into utilizing both classical transition metal catalysis and contemporary photoredox catalysis. The chapters cover the introduction and importance of each developed methodology, optimization, scope, mechanism, and characterization, providing a comprehensive understanding of these catalytic approaches in pharmaceutical core synthesis.

Actions (login required)

View Item