Elusive reactive intermediate tamed for use in synthesis
Researchers at the University of Oxford, in collaboration with scientists at the pharmaceutical company MSD, and Manchester University, have developed a method that allows the generation and use of an elusive reactive intermediate that is crucial in synthetic chemistry. The new method is published in Nature Catalysis.
Triplet excited state intermediates generated from imines are notoriously challenging to use in synthesis. The intermediates have traditionally been regarded as too unstable to be used productively, and work-arounds, usually involving the use of specially engineered substrates are required. The new work, led by Prof Michael Willis in the Oxford's Department of Chemistry, established that imines substituted with a specific group – a sulfamoyl fluoride unit – can be generated and used efficiently in a synthesis. The researchers used the key intermediates to develop a ring-forming process known as an aza Paternò-Büchi reaction. These reactions combine imines with alkenes under photochemical conditions to make 4-membered ring amine products, known as azetidines.
Azetidines are attractive units for use in medicinal chemistry, but these rings are difficult to make using conventional chemistry, because their small size makes them highly strained and unstable. The new route developed by the Willis group allows a broad range of azetidines to be prepared, as it combines two simple starting materials – alkenes and imines – in the ring-forming process, and is mediated by visible light and a simple organic photocatalyst. In addition to controlling the reactivity of the imine intermediates, the sulfamoyl fluoride unit provides a versatile reactive handle for further functionalization of the products. For example, the researchers showed that the azetidines could be incorporated into amino acids, used in cross-coupling reactions, or reacted with amines to form sulfamide products.
The team also used computational modelling alongside laboratory experiments to understand why their approach worked so well. They found that the sulfamoyl fluoride group raises the energy barrier for decomposition, preventing the imine from falling apart before it can react. At the same time, it controls the way the alkene approaches the imine, ensuring regioselective and efficient ring formation.
In summary, this work provides chemists with a powerful, general method to make azetidines from simple, readily available starting materials under mild conditions using visible light. By solving a long-standing problem in synthetic chemistry – how to generate and use imine derived triplets – it opens the door to wider use of these intermediates to develop further synthetic transformations.
Read the full paper in Nature Catalysis.
