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

Lead Research Organisation: University of Oxford


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.


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Kaldas SJ (2018) Modular Synthesis of ß-Amino Boronate Peptidomimetics. in The Journal of organic chemistry

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Leitch JA (2020) Dearomative Photocatalytic Construction of Bridged 1,3-Diazepanes. in Angewandte Chemie (International ed. in English)

Description Industrial Fellowship
Amount £80,000 (GBP)
Organisation Royal Commission for the Exhibition of 1851 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 10/2022
Description Postgraduate Scholarship-Doctoral Program
Amount $63,000 (CAD)
Funding ID PGSD3 532666-2019 
Organisation Natural Sciences and Engineering Research Council of Canada (NSERC) 
Sector Public
Country Canada
Start 06/2019 
End 07/2022
Description Interview for RxNet 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I did an interview with the online new site called RxNet, which is primarily targeted towards scientists in industry and academia alike, for discussions on recent findings in chemistry and biochemistry that are relevant for pharmaceutical discovery and development. The primary objective of this interview was to discuss my current progress and investigational efforts as an early-stage researcher and the potential long-term applications that it could find in industry.
Year(s) Of Engagement Activity 2020
Description Spectroscopy in a Suitcase School Visit (Oxford) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact As part of the Royal Society of Chemistry educational initiative, I acted as an ambassador for a Spectroscopy in a Suitcase educational workshop at a local school in Oxfordshire. The purpose of this activity is to provide a free, hands-on experience of fundamental spectroscopic principles to students aged 16-19, that complements and enhances the teaching material that is presented in the classroom. Not only did students get to directly engage with their course material, they also get an opportunity to learn about the applications of spectroscopic techniques in research and industry, as well as opportunities in chemistry-related careers.
Year(s) Of Engagement Activity 2019