This research program encompasses palladium-catalyzed amination and etherification of aryl halides and palladium-catalyzed hydroamination of olefins. Studies during the previous grant period led to some of the most active catalysts for the palladium-catalyzed amination and etherification, including three different catalysts sold or used commercially. In unpublished work, we have isolated the true amido and alkoxo intermediates in reactions with the most active catalysts and have gained initial results that suggest a solution to the amination and etherification of heteroaromatic substrates, which typically poison or retard the activity of the most active palladium catalysts for aryl amination. We have also found palladium catalysts for the hydroamination of dienes and vinylarenes with both aromatic and aliphatic amines and have found conditions for highly enantioselective hydroamination of dienes. We have uncovered the mechanism for palladium-catalyzed hydroamination and have isolated the intermediate that reacts with amine to form the hydroamination product. Most recently, we discovered the first hydroamination of olefins catalyzed by ruthenium complexes, and the scope of the proposed research will expand to include these new catalysts for hydroamination. This application requests renewed support for studies of recently developed catalysts for each of these reactions. We will investigate the mechanisms of catalytic amination and etherification of aryl chlorides and tosylates. These investigations will include studies to reveal the chemistry of new three-coordinate amido and alkoxo complexes and studies to unravel the complex kinetic behavior that results from a dependence of the reaction rate on the concentration of base and halogen. In addition, we will investigate reactions with ligands based on a chelating structure with hindered dialkylphosphino substituents that will increase the scope of the couplings and should increase the lifetimes of the catalysts. The structure of this ligand generates palladium complexes that undergo fast oxidative addition but resist displacement by amines or basic heterocycles. In addition, we will investigate the scope and mechanism of the hydroamination reactions we have discovered. We will investigate the effects of varying ligand structure on the rates and selectivities of the palladium-catalyzed hydroamination of vinylarenes and will delineate the basic steps of the ruthenium-catalyzed reactions. With recently identified palladium catalysts that display higher activities than those of the original systems, we will investigate the functional group tolerance of the reactions catalyzed by these complexes. In addition, we will strive to develop conditions to add other nitrogen substrates to vinylarenes and to add amines to more substituted vinylarenes and simple alkenes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Jiang, Xingyu; Hartwig, John F (2017) Iridium-Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates. Angew Chem Int Ed Engl 56:8887-8891
Hartwig, John F (2017) Catalyst-Controlled Site-Selective Bond Activation. Acc Chem Res 50:549-555
Jiang, Xingyu; Beiger, Jason J; Hartwig, John F (2017) Stereodivergent Allylic Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and Lewis Base Catalysis. J Am Chem Soc 139:87-90
Ge, Shaozhong; Green, Rebecca A; Hartwig, John F (2017) Correction to ""Controlling First-Row Catalysts: Amination of Aryl and Heteroaryl Chlorides and Bromides with Primary Aliphatic Amines Catalyzed by a BINAP-Ligated Single-Component Ni(0) Complex"". J Am Chem Soc 139:3300
Hill, Christopher K; Hartwig, John F (2017) Site-selective oxidation, amination and epimerization reactions of complex polyols enabled by transfer hydrogenation. Nat Chem 9:1213-1221
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
Hartwig, John F; Larsen, Matthew A (2016) Undirected, Homogeneous C-H Bond Functionalization: Challenges and Opportunities. ACS Cent Sci 2:281-92
Strom, Alexandra E; Balcells, David; Hartwig, John F (2016) Synthetic and Computational Studies on the Rhodium-Catalyzed Hydroamination of Aminoalkenes. ACS Catal 6:5651-5665
Karimov, Rashad R; Sharma, Ankit; Hartwig, John F (2016) Late Stage Azidation of Complex Molecules. ACS Cent Sci 2:715-724
Lee, Taegyo; Hartwig, John F (2016) Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C-H Bonds. Angew Chem Int Ed Engl 55:8723-7

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