Copper-Mediated Vicarious Nucleophilic Substitution

Abstract: This thesis suggests and examines a novel approach for copper-mediated cross-couplings. We call this mechanistic approach copper-mediated vicarious nucleophilic substitution. Our hypothesis is that copper-promoted cross-couplings proceed via an intermediate s-adduct, a Meisenheimer adduct. This hypothesis is valid for cross-couplings between 1,3-dinitrobenzene and halogenated carbanions in the presence of copper tert-butoxide and pyridine. The hypothesis is also shown to be valid for cross-couplings between 1,3-dinitrobenzene or 1,3,5-trinitrobenzene and electron-rich iodoarenes, which is exemplified by the productive cross-coupling between iodophenols and dinitro- or trinitrobenzene. The reaction is generally applicable to iodinated methylene compounds, such as iodomethyl phenyl sulfone, iodoacetic esters and iodoacetonitrile. The bromo analogues are less efficient if an extra electron-withdrawing group is not present, while bromomalonic esters couple in good yields. The mechanism for these couplings is similar to that of ordinary vicarious nucleophilic substitution. The copper-mediation give a very high selectivity for substitution at C-2 of the dinitroarene.

This thesis also presents an extension of the Castro coupling. With 2-iodophenols and ethyl propiolate as starting materials this extension gives isocoumestans (tetracyclic compounds) in a one-pot synthesis rather than the expected 2-substituted benzofurans. Cupriated benzofurans are suggested to be intermediates in this reaction. The scope and limitations of this extension are examined.