Although asymmetric hydrogenation (AH) has been applied successfully to a wide range of substrates, the development of catalysts for the AH of substituted pyridines is still in its early stages. Such substrates are particularly challenging due to their high resonance stabilisation energy and strong ability to deactivate the catalyst via coordination to the metal. During the last 10 years, several successful methods have been disclosed for the homogeneous AH of 2-substituted pyridines, and more recently of di- and tri-substituted pyridines. In most of these contributions, a quaternisation of the pyridine nitrogen atom is used to lower the resonance energy of the ring and prevent substrate coordination to the catalyst. Unfortunately, the translation of these methods to 3-substituted pyridines is not straightforward. Although there is no general agreement on the mechanism of the AH of N-heteroarenes, the current data led us to speculate that the poor enantiomeric excesses obtained with 3-substituted pyridines in comparison to their 2-substituted analogues were due to a non-enantioselective enaminium-iminium isomerization of a partially hydrogenated intermediate (Scheme 1a). Based on this hypothesis, we surmised that the addition of a base in the AH of N-benzylated pyridines could retard the tautomerisation by scavenging HBr produced during the reaction. As a consequence, the formation and subsequent hydrogenation of a racemic iminium salt would be prevented (Scheme 1a). This analysis was borne out in practice as asymmetric hydrogenation of a range of N-benzyl 3-substituted pyridinium salts using a catalyst made in situ from Rh(COD)2OTf and one of the Josiphos ligands led to formation of the 3-substituted piperidines in remarkably enhanced ee if the hydrogenation was carried out in the presence of a base such as Et3N (Scheme 1b).

Why is asymmetric hydrogenation of 3-substituted pyridinium salts so problematic?

253rd National Meeting (2017)

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