A Highly Efficient N‐Mesityl Thiazolylidene for the Aliphatic Stetter Reaction: Stereoelectronic Quantification for Comparison of N‐Heterocyclic Carbene Organocatalysts

The NHC‐catalysed intermolecular Stetter reaction provides direct access to 1,4‐diketones, however current NHC catalysts for this specific transformation remain underdeveloped, significantly limiting the use of this reaction in target‐oriented synthesis. Here we report a novel N‐mesityl thiazolium NHC as a high‐performing catalyst for this reaction, enabling high yields and short reaction times for a range of sterically non‐trivial aliphatic aldehydes reacting with enone substrates. Quantification of the properties of novel and known NHC organocatalysts revealed that both steric and electronic properties play an important role in the success of the new N‐mesityl thiazolium NHC for this reaction. These developments will facilitate wider application of the Stetter reaction as a key carbon‐carbon bond forming reaction for coupling of complex fragments under mild conditions. An N‐mesityl thiazolylidene N‐heterocyclic carbene (NHC) catalyst delivers significantly improved outcomes in the synthetically‐challenging intermolecular aliphatic Stetter reaction, affording 1,4‐diketones in high yields and short reaction times without acyloin formation. Stereoelectronic quantification methods optimised for NHCs as organocatalysts gave insights into the observed reactivity, and provide a foundation for ongoing NHC development.