Intermediary Arene Dearomatization as an Approach for meta-Selective Functionalization of Arenols and Heteroarenols

About This Grant

With the support of the Chemical Synthesis program in the Division of Chemistry, Professors Angus Lamar and Gordon Purser of the University of Tulsa are investigating new methods for the modification of arenols and heteroarenols, which are compounds commonly found in medicines, agricultural products, and advanced materials. The predictable decoration of an aromatic framework is a cornerstone of chemical synthesis, and significant effort has been devoted toward the expansion of a synthetic toolkit to allow for installation of molecular complexity. Despite the intense synthetic focus, access to certain substitution patterns of polysubstituted aromatics is largely restricted by intrinsic substituent effects. Due to this inherent activity, 1,2- and 1,4-substituent patterns dominate marketed drugs and chemical catalogs. The planned studies will provide direct architectural access to rarely observed polysubstituted bicyclic frameworks with 1,3-substituent patterns which will open the chemical landscape for the rapid construction of potentially bioactive frameworks that have thus far gone unexplored. During the funding period, the planned studies will provide Ph.D. students and undergraduate researchers with the opportunity to develop laboratory skills in chemical synthesis and computational chemistry, which will prepare them for careers in pharmaceutical, agrochemical, and materials industries. In addition, the researchers involved in this project will participate in STEM-related outreach activities at a local public school in the Tulsa area. The goal of the project is to provide new, operationally simple organic reactions to directly install functionality into privileged scaffolds relevant to medicinal chemistry. As a result of this work, our fundamental understanding of regioselective methods for installation of functionality involving (hetero)arenols will be advanced. The methods that will be investigated center around an approach to partially dearomatize an arenol to produce an intermediate that can be functionalized in a subsequent step by a nucleophile in a conjugate addition reaction. The resulting product from the two-step, one-pot reaction is substituted meta to the initial -OH group of the arenol and has also retained a halogen from the dearomatization step, which can then be used as a chemical handle for further reactions to produce densely functionalized products with rare substitution patterns. In addition to synthetic investigations, a computational study will be conducted to understand the reaction mechanism of the two-step, one-pot approach. 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.