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)
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Lees, Robert G
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University of California Berkeley
Schools of Arts and Sciences
United States
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Tran, Ba L; Li, Bijie; Driess, Matthias et al. (2014) Copper-catalyzed intermolecular amidation and imidation of unactivated alkanes. J Am Chem Soc 136:2555-63
Tran, Ba L; Driess, Matthias; Hartwig, John F (2014) Copper-catalyzed oxidative dehydrogenative carboxylation of unactivated alkanes to allylic esters via alkenes. J Am Chem Soc 136:17292-301
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
Green, Rebecca A; Hartwig, John F (2014) Palladium-catalyzed amination of aryl chlorides and bromides with ammonium salts. Org Lett 16:4388-91
Sharma, Ankit; Hartwig, John F (2013) Enantioselective functionalization of allylic C-H bonds following a strategy of functionalization and diversification. J Am Chem Soc 135:17983-9
Strom, Alexandra E; Hartwig, John F (2013) One-pot anti-Markovnikov hydroamination of unactivated alkenes by hydrozirconation and amination. J Org Chem 78:8909-14
Fier, Patrick S; Hartwig, John F (2013) Selective C-H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342:956-60
Klinkenberg, Jessica L; Hartwig, John F (2011) Catalytic organometallic reactions of ammonia. Angew Chem Int Ed Engl 50:86-95
Liu, Zhijian; Yamamichi, Hideaki; Madrahimov, Sherzod T et al. (2011) Rhodium phosphine-?-arene intermediates in the hydroamination of alkenes. J Am Chem Soc 133:2772-82
Hartwig, John F; Stanley, Levi M (2010) Mechanistically driven development of iridium catalysts for asymmetric allylic substitution. Acc Chem Res 43:1461-75

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