Umpolung Amine Synthesis: Photocatalytic Generation of Nucleophilic Alpha-Amino Radicals

Amines are ubiquitous motifs in organic chemistry, with applications extending into pharmaceuticals, agrochemicals, natural products and fine chemical research. For this reason, amine formation has been at the forefront of synthetic method development for decades, and has remained a key focal point in the establishment of contemporary methods. A significant proportion of these methods rely on the reductive chemistry of imines to afford complex amine architectures, with much well-established chemistry relying on the addition of various nucleophilic species to the electrophilic imine. For example, Grignard reagents are commonly added to imines to afford alpha-branched amines, and reductive amination (the addition of hydride) is a common technique to obtain simpler amines. This commonplace use of imines is largely due to the ease with which they may be synthesised from the corresponding anilines or alkyl amines and aldehydes or ketones. However, these techniques are inherently limited to the addition of nucleophilic species, and thus, many modern methods seek to use imines in an umpolung (reverse polarity) fashion.

One such method, which has come to be of significant interest to the Dixon group in the past few years, is the generation of inherently-nucleophilic alpha-amino radical species. Such species have been shown to engage in radical-radical couplings, as well as in Giese-type additions to unsaturated olefins.

The single electron reduction of imines to form alpha-amino radicals was first reported in a samarium-iodide-induced aza-pinacol coupling reported by Imamoto in 1990, and subsequent work proceeded to validate the alpha-amino radical as a viable reactive intermediate. However, the development of a catalytic method of single electron imine reduction was to come with the advancement of reductive photocatalytic methods. In this sense, the use of visible-light-activated photocatalysts allows for a controlled enhancement of the reactivity of imines, allowing them to participate in reactions that would otherwise be infeasible. Reports by the Dixon group, as well as Chen, demonstrated the feasibility of the reductive coupling of alpha-amino radical species with electrophiles in 2017, and it is upon this work that this project is based.

Falling within the EPSRC Synthetic Organic Chemistry research area, the proposed project looks to develop methods of preparing amine-based architectures with increased structural complexity, by means of a photocatalytic approach. In the preliminary work undertaken, this has involved trapping alpha-amino radical species with intramolecular Michael acceptors, affording carbocyclic amine products. The project looks to expand this work to form structures that are of interest to pharmaceutical, agrochemical, and natural product chemistry alike.