The Robinson annulation reaction is a well-known cascade process, initiated by an intermolecular Michael addition, which is then succeeded by an intramolecular aldol condensation. Recently we became interested in developing an organocatalytic system for a particular variant of an asymmetric Robinson annulation, which involves a simple ketone, serving as a nucleophile at both steps of the annulation.<br/>While, in general, organocatalytic asymmetric Robinson annulation sequences have been successfully promoted by both acid and base catalysts, to the best of our knowledge, an enantioselective version of the particular annulation variant, involving a ketone and a non-enolizable enone, has never been reported.<br/>In our line of work we chose to use chalcones and acetone as substrates for the Robinson annulation reaction (e.g. Scheme 1). In the case of this model reaction, by screening various amine catalysts by several analytical methods (including a fluorogenic assay), we found that pyrrolidine was practically the only suitable catalyst. Furthermore, an addition of acidic additives, such as phenols or carboxylic acids, in substoichiometric amounts to the catalytic system demonstrated great improvement in the reaction yield. Moreover, in a series of trails with chiral pyrrolidine-derived catalysts we were able to obtain a reaction with a moderate to excellent yield (depending on the reactivity of the chalcone) and, for the first time, a significant enantioselectively.

Improvement of organocatalytic Robinson annulation by acid additives

254th National Meeting (2017)

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