Photocatalytic Reductive Coupling of Iminiums: New Umpolung Strategy for Tertiary Amine Synthesis

This project falls within the EPSRC Synthetic Organic Chemistry research area.
The biologically-relevant a-functionalised amine functionality is ubiquitous within the structures of numerous natural products, pharmaceutical agents and agrochemicals. As a result, the development of a novel and efficient methodology that would allow for rapid access to these structures through carbon-carbon bond formation is highly relevant for academic and industrial applications. A commonplace access point for amine functionalisation has been nucleophilic addition into the inherently electrophilic iminium functional group using organometallic reagents. However, developing a new synthetic strategy that would reverse the natural polarity of iminium ions provides an opportunity to diversify the range of accessible chemical transformations and tertiary amine scaffolds. Hence, we propose an unprecedented strategy that entails the combination an iridium-catalysed tertiary amide reduction with a subsequent photocatalytic, reductive coupling step in one pot. Due to their inherent stability, tertiary amides hold potential as powerful starting points for a-functionalised amine construction. Vaska's catalyst (IrCl(CO)(PPh3)2), in tandem with the TMDS (1,1,3,3-tetramethyldisiloxane) reductant, initially reduces the amide to give a hemiaminal intermediate, which eliminates to form the iminium species in situ. Under photocatalytic, single electron reductive conditions, this intermediate is transformed into a nucleophilic a-amino radical, which can couple with an appropriate electrophilic reagent resulting in the formation of the a-functionalised tertiary amine product. The goal of this project is to obtain the fully optimised reaction conditions, using a N-methyl anilide derivative as a model substrate, and expand the substrate scope by combining a range of tertiary amides with alkene coupling partners (i.e. Michael acceptors, styrene derivatives, etc.). Furthermore, it is proposed to employ density functional theory (DFT) calculations in order to fine-tune the photocatalyst selection for synthetically challenging substrates. In the later stages of this project, we aim to use computational chemistry to elucidate the mechanism of this transformation. In addition to developing a novel synthetic method, this project will also focus on applying the photocatalytic, reductive strategy to the synthesis and derivatisation of biologically relevant compounds. For example, by adapting this intermolecular system to an intramolecular variant, we aim to obtain di-substituted N-heterocycles from tertiary amides. Moreover, we plan to utilise the highly chemoselective nature of this method for late stage functionalisation of natural products and pharmaceutical agents, such as Vassopresin, by selectively introducing derivatisation via the tertiary amide motif. Overall, we hope to develop and efficient and widely applicable strategy that would be of considerable interest for the medicinal chemistry field and the pharmaceutical industry.