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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101389-02
Application #
8549270
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2012-09-21
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$271,698
Indirect Cost
$88,348
Name
Rutgers University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Ma, Longle; Paul, Anirudra; Breugst, Martin et al. (2016) Redox-Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α- and β-C-H Functionalization. Chemistry 22:18179-18189
Chen, Weijie; Seidel, Daniel (2016) Redox-Annulation of Cyclic Amines and β-Ketoaldehydes. Org Lett 18:1024-7
Kang, YoungKu; Seidel, Daniel (2016) Decarboxylative Annulation of α-Amino Acids with γ-Nitroaldehydes. Org Lett 18:4277-9
Zhu, Zhengbo; Seidel, Daniel (2016) An Ugi Reaction Incorporating a Redox-Neutral Amine C-H Functionalization Step. Org Lett 18:631-3
Platonova, Alena Yu; Seidel, Daniel (2015) The Rügheimer-Burrows reaction revisited: Facile preparation of 4-alkylisoquinolines and 3,5-dialkylpyridines from (partially) saturated amines. Tetrahedron Lett 56:3147-3150
Seidel, Daniel (2015) The azomethine ylide route to amine C-H functionalization: redox-versions of classic reactions and a pathway to new transformations. Acc Chem Res 48:317-28
Ma, Longle; Seidel, Daniel (2015) Intramolecular Redox-Mannich Reactions: Facile Access to the Tetrahydroprotoberberine Core. Chemistry 21:12908-13
Kang, YoungKu; Chen, Weijie; Breugst, Martin et al. (2015) Asymmetric Redox-Annulation of Cyclic Amines. J Org Chem 80:9628-40
Kang, YoungKu; Richers, Matthew T; Sawicki, Conrad H et al. (2015) C-H functionalization of cyclic amines: redox-annulations with α,β-unsaturated carbonyl compounds. Chem Commun (Camb) 51:10648-51
Chen, Weijie; Seidel, Daniel (2014) The redox-Mannich reaction. Org Lett 16:3158-61

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