This research program aims to develojs catalytic synthetic methods that formamines, ethers and sulfides and to obtain precise mechanistic intormation for the design of new catalysts and for deducing relationships between emerging catalytic processes that form G-N, C-Q and G-S bonds and relatedcatalytic processes that form C-C or C-H bonds. The proposed research focuses on several synthetic methods that have become widely utiMzed and that have inspired other groups to developirelated chemistry. Each ofthe 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 ofthe catalytic cycle, and equilibria that controf selectivity. A second portion pfthe proposal will establish a mechanistic understandirig: of copper-catalyzed couplings of aryt Halides With nitrogen and oxygen nucleophiles and the use ofthis information as inspiration to develop catalysts forthe formation of aryl carbon-heteroagom 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 inci-easeitheiscope of alkene hydroaminations. These studies will us^ reeenl : structural data to understand the mechanisni ofthis process and to design new catalysts. A fourth portiiahof the research will focus on enantioselective methods to prepare allylic amines and ethers. Again, recent :; structural data will be used to understahd the mechanism ofthe reaction and to design catalysts that reaibt;; with classes of reagents that have not been encornpassed by this process previously. Thus,.the proposed: research will significantly advance reactions with prgianometallic catalysts to form the carbon-heteroatorri bonds in pharmaceutieally important materials, While;demonstrating approaches to use mechanistic data in the design and development of new organometallic catalysts that increase the efficiency, diversity and ^ ? caoabilitv of organic synthesis. - . . .. - ? :-"""""""":.;? '..;;

Public Health Relevance

; Some ofthe catalysts that have resultedi from this project dramatically improve methods to prepare pharmaceutical intermediates and riew: catalysts that will result from the proposed researchrpromise to be equally important for the synthesis of theseand other biologically active materials. Thus, successfut ,; development of the proposed research vyiM sighificantly 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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Special Emphasis Panel (NSS)
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 :
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

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