The majority of pharmaceutical drugs that are essential for human health consist of nitrogen containing compounds. A particularly attractive approach to these targets is the modification of cheap and readily available amines by means of C-H bond functionalization. However, methods that accomplish this task efficiently are scarce and severely lacking in scope. Moreover, the currently known approaches typically require the use of expensive transition metal catalysts and/or oxidants. This proposal is focused on the design and development of efficient and practical methods for amine functionalization. The main goal is the ?- and ?-functionalization of amines through conceptually new and underdeveloped methods of substrate activation. A major focus is on redox-neutral approaches to C-H bond functionalization that do not require expensive oxidants or precious metal catalysts. The central theme of our proposed work is to couple an oxidative C-H bond functionalization with a productive reduction event that contributes to the formation of products by allowing for the generation of additional C-C, or C-X bonds. Our proposed reactions proceed via iminium ion, azomethine ylide and enamine intermediates that can be accessed under relatively mild conditions. In addition to targeting the rapid preparation of biologically active compounds such as epiquinamide, harmicine and quinazolinone alkaloids, our efforts will center on the development of particularly powerful reactions that rapidly generate new polycylic amines. A priority is the generation of novel structural frameworks that are absent from current drug discovery screening libraries.

Public Health Relevance

As most pharmaceutical drugs contain nitrogen, the ability to prepare these materials in the most rapid way possible is of the utmost importance. The broad availability of drugs is directly dependent on the existence of cost-efficient methods that can reliably build complex molecular structures. The objective of this proposal is the development of powerful new methods and strategies for amine C-H bond functionalization that will facilitate rapid access to valuable building blocks for the synthesis of biologically active compounds and pharmaceuticals.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Rutgers University
Schools of Arts and Sciences
New Brunswick
United States
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Zhu, Zhengbo; Chandak, Hemant S; Seidel, Daniel (2018) Redox-Annulations of Cyclic Amines with 2-(2-Oxoethyl)malonates. Org Lett 20:4090-4093
Chen, Weijie; Ma, Longle; Paul, Anirudra et al. (2018) Direct ?-C-H bond functionalization of unprotected cyclic amines. Nat Chem 10:165-169
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