My group recently discovered a new class of C-C bond-forming reaction: the direct alpha-arylation of ketones catalyzed by palladium complexes. We have now extended this reaction to include the alpha-arylation of carboxylic acid derivatives such as amides and malonates, while finding remarkable catalysts that provide alpha-arylation of ketones at room temperature using aryl bromides and at only 70 C using aryl chlorides. Under NIH support my group would 1) study new alkylphosphine ligands for the catalytic process based on our hypothesis that sterically hindered, chelating alkyl phosphines accelerate reaction rates, 2) expand the scope of this new process to other types of carbonyl compounds, alkyl cyanides, and nitroalkanes and 3) develop a detailed, quantitative mechanistic understanding of the reactions comprising the catalytic cycle. More specifically, we will prepare alkylphosphine ligands containing large and small substituents at phosphorus and with backbones that provide large and small bite angles. These ligands will be used to further improve yields, rates, and substrate scope, while uncovering the features of our current ligands that provide such fast rates. These ligands will also be used in studies toward extending the scope of electrophiles to vinyl and heteroaromatic halides and sulfonates, and to nucleophilic partners such as the anions of alpha-diketones, alpha-siloxy ketones, alpha, beta-unsaturated ketones, beta-dicarbonyl compounds, esters, nitriles, nitroalkanes, and azlactones. A detailed mechanistic description of the catalytic chemistry based on firm quantitative data is an important goal of the proposed research. In general, we will conduct a careful study to determine how ligands steric and electronic properties affect each step of the catalytic cycle, including oxidative addition of aryl halide that is likely to be the rate determining step of the reaction, formation of an arylpalladium enolate complex from the resulting arylpalladium halide complex, and C-C bond-forming reductive elimination that is the crucial coupling step in the catalytic cycle. We have conducted the first direct observation of this type of reductive elimination. Beta-Hydrogen elimination from the palladium enolate complexes, which competes with reductive elimination, will be investigated to determine how this process can be prevented. Finally, we will begin a detailed mechanistic study of the initial asymmetric version of the ketone arylation process in conjunction with Buchwald's synthetic effort as a means for our two groups to create improved enantioselective catalysts.

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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Chen, Ming; Hartwig, John F (2016) Iridium-Catalyzed Regio- and Enantioselective Allylic Substitution of Trisubstituted Allylic Electrophiles. Angew Chem Int Ed Engl 55:11651-5
Arlow, Sophie I; Hartwig, John F (2016) Synthesis of Aryldifluoroamides by Copper-Catalyzed Cross-Coupling. Angew Chem Int Ed Engl 55:4567-72
Hartwig, John F (2016) Evolution of C-H Bond Functionalization from Methane to Methodology. J Am Chem Soc 138:2-24
Chen, Ming; Hartwig, John F (2015) Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides. J Am Chem Soc 137:13972-9
Chen, Wenyong; Chen, Ming; Hartwig, John F (2014) Diastereo- and enantioselective iridium-catalyzed allylation of cyclic ketone enolates: synergetic effect of ligands and barium enolates. J Am Chem Soc 136:15825-8
Ge, Shaozhong; Green, Rebecca A; Hartwig, John F (2014) 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 136:1617-27
Green, Rebecca A; Hartwig, John F (2014) Palladium-catalyzed amination of aryl chlorides and bromides with ammonium salts. Org Lett 16:4388-91
Chen, Wenyong; Hartwig, John F (2014) Cation control of diastereoselectivity in iridium-catalyzed allylic substitutions. Formation of enantioenriched tertiary alcohols and thioethers by allylation of 5H-oxazol-4-ones and 5H-thiazol-4-ones. J Am Chem Soc 136:377-82
Ge, Shaozhong; Cha?adaj, Wojciech; Hartwig, John F (2014) Pd-catalyzed ?-arylation of ?,?-difluoroketones with aryl bromides and chlorides. A route to difluoromethylarenes. J Am Chem Soc 136:4149-52
Chen, Ming; Hartwig, John F (2014) Iridium-catalyzed regio- and enantioselective allylic substitution of silyl dienolates derived from dioxinones. Angew Chem Int Ed Engl 53:12172-6

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