Part I: Backbone modification of n-heterocyclic carbenes: new ligands and applications to catalysis Part II: Large scale synthesis of NHC precursor 2,6-di(3-pentyl)aniline

The first part of this research is focused on the development and application of backbone-modified N-heterocyclic carbene (NHC) ligands in palladium-catalyzed cross-coupling. Various backbone substituted imidazole-2-ylidine NHCs and their corresponding Pd-PEPPSI complexes were synthesized and S.A.R. studies were performed in a series of challenging cross-coupling reactions to determine the effect of backbone substitution on catalyst activity. Pd-PEPPSI-IPentCl, featuring chlorines on the backbone of our IPent NHC, was identified as one of the most active and selective catalysts yet reported in the literature in the secondary alkyl Negishi coupling, an important method for the installation of secondary alkyl groups onto aromatic systems. Mechanistic studies, supported by DFT calculations and IR spectroscopic analyses, indicate that the effect imparted by the backbone substituents is primarily steric in origin.

Further optimizing the architecture of the trans-ligated pyridine culminated in the development of Pd-PEPPSI-IPentCl-picoline, which we have shown to be a superior catalyst for the unprecedented room temperature Buchwald-Hartwig amination of aryl halides with electronically deactivated anilines using a mild carbonate base. These conditions are milder than any yet reported in the literature for the cross-coupling of anilines and represent a significant advance in the field.

The second part of this research deals with the development of a method for the large-scale preparation of 2,6-di(3-pentyl)aniline, a precursor to the IPent family of novel, highly active NHC ligands. Our newly developed synthetic route features a Pd-catalyzed cross-coupling of 3-lithio-2-pentene, derived from 3-pentanone, to readily available 2,6-dibromoaniline. This new sequence represents a significant improvement in overall process efficiency in the form of a lower step count, higher product yield, and increased reproducibility relative to earlier syntheses. Since its inception, this method has been applied successfully towards the synthesis of nearly 0. 7 kg of 2,6-di(3-pentyl)aniline and has the potential for larger scale implementation.