One of the major challenges facing synthetic chemists is the design of novel and efficient methods for the functionalization of simple organic substrates. When a synthetic sequence can be rendered shorter, it enables the production of a greater variety of molecules by medicinal chemists in a more rapid timeframe. The net effect is that the drug discovery process becomes both cheaper and faster. This proposal describes a method for the enantioselective, direct beta-arylation of simple carbonyl compounds using ruthenium(ll) catalysts and readily available aryl halides. The proposed reaction has the potential to replace traditional synthetic approaches to this class of compounds which typically involve multi-step sequences that require the use of stoichiometric oxidants as well as organometallic reagents. The proposed transformation proceeds via initial activation of a beta sp3 C-H bond in a carbonyl compound by a ruthenium(ll) catalyst to form a metallacycle intermediate. Subsequent oxidative addition of an aryl halide followed by C-C bond-forming reductive elimination would then yield the arylated product. It is anticipated that the use of ruthenium(ll) as a catalyst will allow for the inclusion of ancillary ligands on the metal center which can control the chemo-, regio- and stereoselectivity of the transformation. The study would begin by investigating the stoichiometric activation of methyl C-H bonds by Ru(ll) pincer complexes, and subsequently examining the reaction of the isolated metallacycles with aryl halides. Conditions that render the overall process catalytic would then be identified and the scope of the reaction surveyed. By careful modification of the ligands, the more challenging functionalization of methylene C-H bonds would be investigated. Following preliminary mechanistic studies, an enantioselective version of the proposed reaction would then be developed by employing chiral pincer ligands.

Public Health Relevance

The development of novel chemical transformations that proceed with high efficiency is essential to streamlining the process of drug discovery, which in turn is critical for improving public health. This application proposes a new method for the synthesis of an important class of organic molecules, which would be significantly more efficient than existing methods and would lead to shorter synthetic sequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32GM087901-03
Application #
8117098
Study Section
Special Emphasis Panel (ZRG1-F04A-L (20))
Program Officer
Gerratana, Barbara
Project Start
2009-08-16
Project End
2012-08-15
Budget Start
2011-08-16
Budget End
2012-08-15
Support Year
3
Fiscal Year
2011
Total Cost
$51,326
Indirect Cost
Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Simmons, Eric M; Hartwig, John F (2012) On the interpretation of deuterium kinetic isotope effects in C-H bond functionalizations by transition-metal complexes. Angew Chem Int Ed Engl 51:3066-72
Simmons, Eric M; Hartwig, John F (2012) Catalytic functionalization of unactivated primary C-H bonds directed by an alcohol. Nature 483:70-3
Simmons, Eric M; Hartwig, John F (2010) Iridium-catalyzed arene ortho-silylation by formal hydroxyl-directed C-H activation. J Am Chem Soc 132:17092-5