The preparation of three-dimensional molecules from simple and readily available aromatic compounds combined with the efficient introduction of essential functional groups represents an attractive approach to synthetically useful piperidines.The Donohoe group has recently reported a novel iridium-catalysed reductive hydroxymethylation of pyridines. In addition to the formation of two C–H bonds, a new C–C bond is introduced in a single transformation. Activation of the substrates is crucial and can be achieved through the quaternisation of the nitrogen and the presence of an electron-withdrawing group (EWG) at the 4-position of the pyridine. The EWG on the <i>C</i>-4 position presents a substantial limitation to the pyridine scope, hence we have developed a strategy to lift these limitations. The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium catalysed dearomative functionalisation of a range of electronically more diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. Paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. The synthetic utility of the method was illustrated with a synthesis of (±)-paroxetine.

Single point activation of pyridines enables reductive hydroxymethylation

ACS Spring 2022

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