Biaryls are one of the most pervasive structural motifs in biologically active molecules, and they can be found within the scaffolds of numerous highly prescribed drugs in the United States (e.g., Lipitor(r), Gleevec(r), Crestor(r), Celebrex(r)). An emerging strategy for the synthesis of biaryls involves palladium-catalyzed oxidative cross-coupling through two arene C-H activations to form an aryl-aryl bond;this strategy has attracted attention because arene prefunctionalization is unnecessary. Because palladium-catalyzed oxidative arene cross-coupling is a relatively nascent field, the mechanisms of these processes remain poorly understood;additionally, there exist ongoing challenges to the development of efficient processes, due to the relative inertness of C-H bonds. The proposed research entails systematic mechanistic studies of a recently reported palladium-catalyzed aerobic oxidative indole arylation. This method demonstrates that neutral ligands, which are uncommon in palladium-catalyzed oxidative arene couplings, have a positive influence on regiocontrol (selective C-H activation) and general reactivity; additionally, they enable the use of O2 as the sole, atom-economical, oxidant. Our mechanistic approach will include elucidation of the catalytic cycles for two regioselective (C2- ad C3-) indole arylations, via the synthesis and testing of potential key catalytic intermediates, coupled with kinetics and spectroscopic studies in order to determine the rate law, rae-determining step, and catalytic resting state. Additionally, the role of palladium and the neutral ligand in the event of each elementary step will be examined through a combination of experimental efforts and computational kinetic modeling. Insights gained will enable the logical design of more efficient palladium/neutral ligand systems for this process, and, more broadly, this study will prompt and direct efforts to develop new palladium-catalyzed aerobic oxidative arene coupling reactions that take advantage of neutral ligands as a tool for improving reactivity.

Public Health Relevance

Our society's demand for medicinal drugs on multi-ton scales testifies to the significance of medications in maintaining sound health, by helping to prevent, treat and cure diseases. While there exist a myriad of different drugs, many of them contain common architectural themes when examined on a molecular level. This proposal aims to study a new chemical process that enables access to a prevalent molecular architecture in drugs; upon more necessary research and improvement, this process will essentially be devoid of toxic waste byproducts.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04-W (20))
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Lees, Robert G
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University of Wisconsin Madison
Schools of Arts and Sciences
United States
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Zultanski, Susan L; Zhao, Jingyi; Stahl, Shannon S (2016) Practical Synthesis of Amides via Copper/ABNO-Catalyzed Aerobic Oxidative Coupling of Alcohols and Amines. J Am Chem Soc 138:6416-9
Zultanski, Susan L; Stahl, Shannon S (2015) Palladium-Catalyzed Aerobic Acetoxylation of Benzene using NOx-Based Redox Mediators. J Organomet Chem 52:97-102