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. .. ''?? "- - ??'? : - ?;:? ' '

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM055382-21
Application #
8510816
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lees, Robert G
Project Start
1999-02-01
Project End
2019-01-31
Budget Start
2014-03-01
Budget End
2015-01-31
Support Year
21
Fiscal Year
2014
Total Cost
$470,179
Indirect Cost
$142,179
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Hartwig, John F; Larsen, Matthew A (2016) Undirected, Homogeneous C-H Bond Functionalization: Challenges and Opportunities. ACS Cent Sci 2:281-92
Karimov, Rashad R; Sharma, Ankit; Hartwig, John F (2016) Late Stage Azidation of Complex Molecules. ACS Cent Sci 2:715-724
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
Lee, Taegyo; Hartwig, John F (2016) Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C-H Bonds. Angew Chem Int Ed Engl 55:8723-7
Lee, Taegyo; Wilson, Tyler W; Berg, Robert et al. (2015) Rhodium-catalyzed enantioselective silylation of arene C-H bonds: desymmetrization of diarylmethanols. J Am Chem Soc 137:6742-5
Sharma, Ankit; Hartwig, John F (2015) Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization. Nature 517:600-4
Brusoe, Andrew T; Hartwig, John F (2015) Palladium-Catalyzed Arylation of Fluoroalkylamines. J Am Chem Soc 137:8460-8
Madrahimov, Sherzod T; Li, Qian; Sharma, Ankit et al. (2015) Origins of Regioselectivity in Iridium Catalyzed Allylic Substitution. J Am Chem Soc 137:14968-81
Green, Rebecca A; Hartwig, John F (2015) Nickel-catalyzed amination of aryl chlorides with ammonia or ammonium salts. Angew Chem Int Ed Engl 54:3768-72
Fier, Patrick S; Hartwig, John F (2014) Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution. J Am Chem Soc 136:10139-47

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