Pushing it to the Limit, Advancements in Negishi Couplings

Abstract

Palladium catalyzed cross-couplings have revolutionized the field of organic synthesis. Using this family of reactions, many different bonds can be formed in a selective manner, include C-C, C-N, C-S and C-O bonds. One reaction included in this family is Negishi cross-coupling, which uses an organozinc reagent as the nucleophilic coupling partner. One aspect of these reactions that has gone largely overlooked is their dependence on inorganic salt additives. In this work, the beneficial, and sometimes harmful, effects of salt additives are investigated. This work realized two new roles for salt additives on Negishi-coupling, the prevention of product inhibition and catalyst deactivation. Throughout these studies, the choice of catalyst is shown to have significant impacts on the yield and selectivity of Negishi coupling reactions. In particular, the use of a chlorine functionalized N-heterocyclic carbene (NHC) ligand is shown to be a critical choice that must be carefully considered. In alkyl-alkyl couplings, this modification was shown to erode the selectivity under certain circumstances. This thesis comes around full circle in the final chapter where insights from mechanistic studies are applied to a commercially relevant cross-coupling. A variety of unnatural amino acids were synthesized using a Negishi coupling as the critical, diversification step. A chlorine functionalized catalyst and salt additive were critical for these couplings, highlighting the importance of studying mechanistic intricacies.