CAS: Iron-Catalyzed Three-Component Coupling Methods via Iron Azametallacyclobutene Complexes

With the support of the Chemical Synthesis Program in the Division of Chemistry, Jamie Neely of Saint Louis University is studying iron-catalyzed processes that join together three distinct chemical building blocks to generate products that are of value to medicine, agriculture, and materials science. The choice of iron complexes as the catalysts for these methods is rooted in their ability to interact with the three coupling partners in a controlled fashion, each at a specific stage of the reaction pathway.

The catalysts of interest have the added benefit of being based on the most abundant transition metal in the Earth’s crust, as well as one of the least expensive and least toxic, accentuating the sustainability and potential practical utility of the processes under development. The broader impacts of the funded project will extend to providing evidence that the distinct behavior of Earth-abundant metals can complement the reactivity of the rare precious metals that are more commonly deployed in current transition metal-catalyzed technology.

Students participating in the funded research will gain a comprehensive education encompassing all aspects of transition metal catalysis, providing them with the capacity to become knowledgeable and insightful contributors to the scientific community. The activities supported by the award include outreach efforts directed toward establishing an undergraduate summer research program for students from minority groups underrepresented in science, technology, engineering, and mathematics (STEM) from the Saint Louis area.

The funded research is focused on the development of iron-catalyzed three-component coupling reactions of nitrene precursors (e.g., azides), alkynes, and nitrile or isonitrile substrates for the synthesis of value-added, nitrogen-containing compounds. The methods under investigation capitalize on [2+2] cycloaddition reactivity of sterically congested iron imide complexes that is highly sensitive to the nature of the alkyne substrate, allowing for the incorporation of unsymmetrical alkynes with high regioselectivity.

Reactions of nitrile coupling partners will provide a general and modular route to imidazoles, a pervasive structural motif in biologically active compounds, with further application to the preparation of diversely substituted N-heterocyclic carbenes. Early efforts in imidazole formation will focus on translating the stoichiometric behavior observed in preliminary studies to catalytic reactivity, with later work aimed at optimizing reaction conditions and exploring the scope of the process with respect to each of the three substrates.

Iron-catalyzed coupling using isonitriles will be explored to access imidoyl ketenimine products that have broad utility as synthetic intermediates. Initial stoichiometric studies will target conditions that favor three-component coupling over a competing process identified in preliminary experiments. These observations will inform later efforts to render the reaction catalytic in iron.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.