Ni-catalyzed sustainable and scalable approaches to nitrogenated compounds

Abstract: This proposal describes the development of sustainable methodologies using Earth-abundant Ni-based catalysts to synthesize nitrogen-containing molecules. The proposed projects target improving the synthesis of amines, amides, and nitriles by overcome pervasive challenges in the field, like the limited scalability of current state-of- the-art photocatalytic methods and the need for toxic reagents for nitrile synthesis. These functional groups are both commonly relied upon as readily manipulated synthetic intermediates and are also ever-present in biologically active molecules, commercial drugs, and polymers. The first project describes the design of Ni catalysts to mediate C−N bond-forming reactions. The objective is to enable reaction mechanisms similar to those observed under light irradiation with Ir cocatalysts, but while bypassing the limitations of those systems. Specifically, we aim to enable processes that do not require Ir or light to proceed. This is because photochemical reactions are difficult to perform at industrially relevant scales and avoiding the use of Ir will reduce the reaction cost. If successful, the new systems will enable the coupling of amines and amides at ambient temperatures. This contrasts with other non-photochemical approaches that require high temperatures and strong bases to promote these reactions. It is expected that the milder conditions will allow for a wider functional group tolerance and thus increase the scope of molecules that will be directly accessible by these methodologies. The second project describes the use of aryl nitriles as cyanide sources. Aryl nitriles are ideal CN precursors because, unlike most cyanide sources, they are non-toxic. Consequently, the development of synthetic methods relying upon them would be highly advantageous. In this context, preliminary data is presented for two different transformations: (i) the carbocyanation of alkenes and (ii) the addition of electrophiles and cyanides to cyclopropyl ketones to yield open-chain ketones. Both these transformations facilitate the introduction of two different groups in a single step. As a result, these protocols enable direct access to a broad range of nitrile- containing products in an efficient and sustainable manner.