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)
Program Officer
Lees, Robert G
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University of California Berkeley
Schools of Arts and Sciences
United States
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Giri, Ramesh; Brusoe, Andrew; Troshin, Konstantin et al. (2018) Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates. J Am Chem Soc 140:793-806
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
He, Zhi-Tao; Hartwig, John F (2018) Enantioselective ?-functionalizations of ketones via allylic substitution of silyl enol ethers. Nat Chem :
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
Hartwig, John F (2017) Catalyst-Controlled Site-Selective Bond Activation. Acc Chem Res 50:549-555
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

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