Lighting the path to simplified chemical reactions

In drug discovery, synthesising new molecules involves multiple steps, with a chemical compound being transformed though a series of individual chemical reactions to create the desired molecule.

As drug molecules often contain nitrogen, one of the most important chemical reactions is the formation of carbon-nitrogen (C-N) bonds. There are many methods to achieve this reaction, however they often involve an indirect, step-wise process.

A new publication in Nature Chemistry from researchers at Manchester University and AstraZeneca describes a new method which uses visible light (blue LEDs) photocatalysis to simplify this important chemical reaction and directly generate specific C-N bonds in a molecule, in a single ‘one-pot’ reaction.
 

In synthetic chemistry the formation of C-N bonds is a very common reaction, but it can still be a challenge. Although there are a lot of great methods currently available, we hope our new simple process offers a useful alternative for researchers, one that is broadly applicable to a range of chemistry disciplines.

James Douglas Associate Principal Scientist, Pharmaceutical Sciences, AstraZeneca

In the formation of C-N bonds, aromatic amines – organic compounds that often form parts of therapeutic small molecules – are made up of an ‘aromatic’ ring of carbon attached to a nitrogen-containing ‘amine’ group. These molecules are typically assembled through a series of reactions starting with the hazardous nitration of the aromatic ring, followed by a stepwise transformation to the required amine. Due to the importance of this reaction to the pharmaceutical industry, numerous alternative strategies have been implemented. Whilst these approaches, such as the Buchwald-Hartwig reaction, have been revolutionary, they often require multiple steps.

In collaboration with scientists at Manchester University, James Douglas, Associate Principal Scientist, Pharmaceutical Sciences, AstraZeneca, published details of how blue light can be used allow direct reactions of arenes and alkyl amines, forming C-N bonds without the need for multiple reaction steps. This streamlined photochemical process is performed in one pot, thereby offering an improved, cost-effective strategy for drug molecule design which would previously have made significant demands on time and resource.

The possibility to create C-N bonds in a single step reaction has, to date, been elusive by any approach. The methodology we developed addresses this challenge and we hope it will become a viable alternative to classical methods

Daniele Leonori Reader in Organic Chemistry, University of Manchester

By simplifying this widely-used reaction, it offers increased capacity for exploring chemical space and rapidly generating large numbers of potential therapeutic molecules. Additional studies also demonstrated the scalability of the reaction, with successful use at multi-gram scale, making this reaction translatable from discovery to later stage drug development.

The impact of this research is far-reaching, not only for AstraZeneca and drug discovery, but in a much broader range of applications across academia and the chemical industry.