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Better use of C-H bonds

Researchers have developed novel production methods that take advantage of carbon-hydrogen (C-H) bonds abundant in nature to synthesise highly valuable compounds.

Industrial Technologies

Chemical synthesis has a tremendous impact on society by providing highly valuable compounds as new materials, drugs, sensors or sources of energy. Producing these molecules efficiently and sustainably is a constantly evolving field of study. The last decade has seen development of a new reactivity concept, taking advantage of the ubiquitous C-H bond. Changing the function of this bond allows for more economical and faster methods to produce organic compounds for industry. The EU-funded HINDAMINE (Pd(II)-catalyzed direct Csp3-H functionalization of amines: A new platform for the synthesis of privileged molecules) initiative set out to develop new methods to functionalise types of C-H bonds that usually do not react easily. This has important applications for synthesis of compounds with a wide range of uses, from drug discovery to advanced materials. HINDAMINE created a blueprint for palladium-catalysed C-H bond functionalisation of amines without the presence of any directing group. The researchers wanted to develop a way to use previously unreactive molecules as synthetic intermediates in chemical synthesis. Central to the design was a simple ketone that bound the palladium catalyst to connect the acetate ligand and the free N-H. The researchers found that amino-alcohol derivatives displaying aryl, protected hydroxyl and amino motifs all worked well in the C-H carbonylation process. HINDAMINE observed that palladium had to ‘choose’ between a four- and five-membered ring reaction and that the reaction proceeded through a larger ring pathway. To show that this reaction was broadly applicable, the researchers tried to simplify a traditionally challenging carbon-carbon reaction process. The team first assessed the reaction of hindered amines with trifluoroethyl acrylate in the presence of palladium acetate and silver acetate. The researchers observed the formation of the corresponding pyrrolidine that formed from the C-H alkenylation reaction, followed by intramolecular aza-Michael addition. These results demonstrate that manipulating the properties of aliphatic amines can lead to a broad strategy for C-H functionalisation of amino alcohols and ketones. This report opens the door to the application of this new strategy to other prevalent amine-containing structural motifs prevalent in nature.

Keywords

C-H bond, chemical synthesis, HINDAMINE, amines, palladium-catalysed, ketones

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