Several efficient, transition metal-catalyzed routes to amines and ethers are presented in this proposal. Many amines and ethers are biologically active, and most of the best-selling drugs contain this type of functionality. During the past funding period, we uncovered several transition metal-catalyzed routes to amines and ethers. We developed palladium-catalyzed C-N and C-O coupling of aryl halides and we recently uncovered new metal-catalyzed hydroaminations. The amination of aryl halides and accompanying mechanistic information has already affected dramatically how drug discovery and process groups prepare arylamines. Our hydroaminations should influence the way they prepare alkylamines. In the next funding period, we will gain an understanding of how our new, most active catalysts work and we will determine the extent to which these catalysts improve the scope of C-N bond formation. In addition, we will seek an understanding of the mechanism of related C-O bond forming cross-couplings that use recently discovered catalysts. We will also outline rules that govern the scope and rates for palladium- catalyzed aromatic aminations with medicinally important heterocyclic substrates. In addition to aromatic C-N and C-O bond-forming processes, we will investigate our new hydroaminations of dienes and vinylarenes. Diene hydroaminations produce allylic amines, which are common synthetic intermediates. Vinylarene hydroaminations produce phenethylamines, which are part of drugs such as Sertraline. We will define the scope of these new processes, will investigate enantioselective hydroaminations and will obtain a detailed understanding of how the reactions occur. This information should enable us to design efficient hydroamination catalysts with broad substrate scope and to use mild reaction conditions for highly enantioselective hydroaminations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055382-09
Application #
6700756
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1996-12-01
Project End
2005-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
9
Fiscal Year
2004
Total Cost
$296,632
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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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