Organocatalytic approach to vinylic nucleophilic substitution at electrophilic alkenes

Abstract

Nucleophilic catalysis is a powerful and well-developed tool for activating and manipulating carbon-centered electrophiles. However, its application to substitution at sp²-carbon atoms has been explored mainly in acylation reactions, and, to a limited extent, in nucleophilic aromatic substitution, with studies limited to a handful of molecular moieties. Herein, we report that dimethylaminopyridine efficiently promotes the nucleophilic substitution reactions of β-chlorinated Michael acceptors with various O-, N-, S- and C-nucleophiles with diverse electronic and steric properties. The reactions proceed via the formation of vinylpyridinium electrophilic species, which can either be generated in situ under catalytic conditions or, more beneficially, isolated and used further in a separate synthetic step. The reactions performed include the preparation of relevant pharmaceutical precursors and cascade processes. Furthermore, quantum chemical calculation methods quantified an approximately 10⁶-fold rate increase in the key substitution step of a catalytic reaction compared to a non-catalyzed reaction and established the impact of intermolecular noncovalent interactions on the reaction course.