This research program aims to develop catalytic synthetic methods that form amines, ethers and sulfides and to obtain precise mechanistic information for the design of new catalysts and for deducing relationships between emerging catalytic processes that form C-N, C-O and C-S bonds and related catalytic processes that form C-C or C-H bonds. The proposed research focuses on several synthetic methods that have become widely utilized and that have inspired other groups to develop related chemistry. Each of the specific aims of this proposal focuses on developing a firm mechanistic platform from which we will build new catalysts and reaction processes. One portion of the proposed research will focus on the development of a new generation of palladium catalysts for the coupling of amines with aryl halides using data on the factors that control catalyst initiation, the rates of individual steps of the catalytic cycle, and equilibria that control selectivity. A second portion of the proposal will establish a mechanistic understanding of copper-catalyzed couplings of aryl halides with nitrogen and oxygen nucleophiles and the use of this information as inspiration to develop catalysts for the formation of aryl carbon-heteroatom bonds using other metals. A third portion of the proposed research will focus on a recently discovered type of rhodium catalyst that promises to significantly increase the scope of alkene hydroaminations. These studies will use recent structural data to understand the mechanism of this process and to design new catalysts. A fourth portion of the research will focus on enantioselective methods to prepare allylic amines and ethers. Again, recent structural data will be used to understand the mechanism of the reaction and to design catalysts that react with classes of reagents that have not been encompassed by this process previously. Thus, the proposed research will significantly advance reactions with organometallic catalysts to form the carbon-heteroatom bonds in pharmaceutically important materials, while demonstrating approaches to use mechanistic data in the design and development of new organometallic catalysts that increase the efficiency, diversity and capability of organic synthesis.

Public Health Relevance

Some of the catalysts that have resulted from this project dramatically improve methods to prepare pharmaceutical intermediates and new catalysts that will result from the proposed research promise to be equally important for the synthesis of these and other biologically active materials. Thus, successful development of the proposed research will significantly increase the accessibility of compounds that improve human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Hagan, Ann A
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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Hartwig, John F; Larsen, Matthew A (2016) Undirected, Homogeneous C-H Bond Functionalization: Challenges and Opportunities. ACS Cent Sci 2:281-92
Karimov, Rashad R; Sharma, Ankit; Hartwig, John F (2016) Late Stage Azidation of Complex Molecules. ACS Cent Sci 2:715-724
Peacock, D Matthew; Roos, Casey B; Hartwig, John F (2016) Palladium-Catalyzed Cross Coupling of Secondary and Tertiary Alkyl Bromides with a Nitrogen Nucleophile. ACS Cent Sci 2:647-652
Lee, Taegyo; Hartwig, John F (2016) Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C-H Bonds. Angew Chem Int Ed Engl 55:8723-7
Lee, Taegyo; Wilson, Tyler W; Berg, Robert et al. (2015) Rhodium-catalyzed enantioselective silylation of arene C-H bonds: desymmetrization of diarylmethanols. J Am Chem Soc 137:6742-5
Sharma, Ankit; Hartwig, John F (2015) Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization. Nature 517:600-4
Brusoe, Andrew T; Hartwig, John F (2015) Palladium-Catalyzed Arylation of Fluoroalkylamines. J Am Chem Soc 137:8460-8
Madrahimov, Sherzod T; Li, Qian; Sharma, Ankit et al. (2015) Origins of Regioselectivity in Iridium Catalyzed Allylic Substitution. J Am Chem Soc 137:14968-81
Green, Rebecca A; Hartwig, John F (2015) Nickel-catalyzed amination of aryl chlorides with ammonia or ammonium salts. Angew Chem Int Ed Engl 54:3768-72
Fier, Patrick S; Hartwig, John F (2014) Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution. J Am Chem Soc 136:10139-47

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