In three years at Yale Prof. Hartwig's group has developed a class of transition metal-catalyzed reactions that is fundamentally distinct from other metal-mediated processes. This proposal presents studies to extend the scope of this catalytic chemistry and to apply it to current synthetic problems. The reactions they have developed are palladium.catalyzed aminations of aryl halides. These reactions produce N-alkyl and N-aryl anilines by intermolecular amination or nitrogen-containing heterocycles from intramolecular amination in high yields and with high turnover numbers. Their published work has provided a thorough mechanistic understanding of palladium-catalyzed aminations. As a result of these studies, they have recently produced new reaction procedures, amide reagents, and palladium catalysts that significantly improve upon published methods. The research described in this proposal stems from these recent synthetic advances and includes the following specific aims. The general strategy for their proposed research is to develop the scope and essential mechanistic features of our recently developed systems for aryl halide amination including reactions with primary amines, heteroaromatics, aryl halides and aryl sulfonates. Concurrently, they will seek metal complexes that will catalyze the formation of aryl ethers from aryl halides and alkoxides. These methodological studies constitute the majority of this proposed work. Once the scope of these synthetic methods are developed to the stage of understanding the general strengths and limitations of the published and newly developed methods, however, they will use these reactions to construct isosteric analogs of isodityrosine-containing materials, to adapt these methods for their use in solid-phase reactions, and to evaluate their use in producing solid-supported libraries, including those of isodityrosine natural product analogs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29GM055382-03S1
Application #
6017494
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Jiang, Xingyu; Boehm, Philip; Hartwig, John F (2018) Stereodivergent Allylation of Azaaryl Acetamides and Acetates by Synergistic Iridium and Copper Catalysis. J Am Chem Soc 140:1239-1242
Hartwig, John F (2017) Catalyst-Controlled Site-Selective Bond Activation. Acc Chem Res 50:549-555
Litman, Zachary C; Sharma, Ankit; Hartwig, John F (2017) Oxidation of Hindered Allylic C-H Bonds with Applications to the Functionalization of Complex Molecules. ACS Catal 7:1998-2001
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
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
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
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
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

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