RUI: Development of Bench-stable N-Quaternized Ketene N,O-Acetals as Multifunctional Reagents for Organic Synthesis

About This Grant

With the support of the Chemical Synthesis (SYN) Program in the Division of Chemistry, Professor Max Majireck of Hamilton College is studying the development of a new class of compounds that enable the production of essential materials of modern society, such as medicinal drugs and agrochemicals. A key aspect of this research is based on a discovery by the Majireck laboratory that a class of molecules called N-quaternized ketene N,O-acetals, which were previously regarded as too unstable to isolate, can be stabilized in a manner that allows them to be used in a broad range of important chemical reactions. For example, a goal of the funded project will be to use these compounds in the design and manufacture of nitrogen-containing products, a common feature found in pharmaceutical compounds like antibiotics and anticancer agents. The broader impacts of this project will provide research opportunities in organic chemistry to undergraduate students at Hamilton College, as well as the design of research-based organic chemistry laboratory courses. Collectively, these efforts will train and recruit students to pursue careers in STEM, thereby strengthening the U.S. scientific workforce. This project aims to advance the chemistry of newly available bench-stable N-quaternized ketene N,O-acetals by establishing them as a versatile class of reagents for organic synthesis. Historically considered too unstable for practical use, these species have recently become synthetically accessible through methods developed in the P.I.'s laboratory, enabling the extensive exploration of their unique reactivity and stability. The proposed research will expand their utility in key transformations such as catalyst-free nucleophilic aromatic substitutions and ketenium ion-based electrophilic aromatic substitutions and cycloadditions, facilitating the synthesis of pharmaceutically relevant scaffolds including indole-linked pyridines and other drug-like heterocyclic compounds. These methodologies offer distinct advantages over traditional protocols by eliminating the need for elevated temperatures, excess reagents, and precious metal catalysts, thereby providing efficient and cost-effective routes to bioactive molecules with immediate relevance to drug discovery and medicinal chemistry. 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.