Elucidation of Active Iron Species and Mechanism in Simple Iron Salt and Iron-N-Heterocyclic Carbene Catalyzed C-C Cross-Couplings

University Of Rochester, Rochester NY

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Abstract

The selective formation of C-C bonds is of fundamental importance in the synthesis of pharmaceuticals, natural products and bio-active molecules for both health related research and clinical use. Iron-catalyzed C-C cross-coupling has emerged as a highly promising alternative to traditional precious metal catalysis, offering reduced cost, low toxicity and novel reactivities. Despite many recent achievements in the development of effective iron-catalyzed C-C cross-couplings, these methods only begin to address the potential of iron-based catalysts, and numerous challenges and areas for significant improvement remain. Examples include the current requirements for large amounts of toxic NMP co-solvent in many ferric salt catalyzed cross-couplings, the lack of broadly applicable methods for stereoselective cross-coupling with iron, and the need to broaden the scope of the nucleophiles and electrophiles that can be cross-coupled (including for alkyl-alkyl cross-coupling reactions). Motivation for the proposed research derives from the hypothesis that a detailed understanding of active catalyst structure and mechanism can provide the basis for improvements in current catalytic systems, as well as the inspiration for the development of new catalysts and methodologies that will greatly expand the scope and utility of iron in C-C cross-coupling. The objective of my proposed project is to utilize a novel experimental approach combining inorganic spectroscopies, density functional theory and synthesis combined with kinetic studies to develop molecular-level insight into active catalyst structure. This will shed light on the mechanisms involved in current leading edge iron-catalyzed C-C cross-coupling reactions involving simple ferric salt catalysts and combinations of simple ferric salts and NHC ligand additives. Building upon previous studies by the Neidig group on the isolation and characterization of FeMe4-, I will investigate the reduced iron species formed in reactions of simple ferric salts and methyl and ethyl Grignards in order to identify the active iron species and mechanisms underlying cross-coupling catalysis. Additional studies will extend this work to the effects of NMP and the presence of ?-hydrogens (i.e. in EtMgBr) on the in-situ formed iron species and mechanism in cross-couplings with simple ferric salts. In the area of iron-NHC catalyzed C-C cross- couplings, I will evaluate the active catalyst species, mechanisms of catalysis and the effects of NHC structure on reactivity in aryl-aryl and aryl-alkyl cross-coupling with iron-NHCs. Studies will include the spectroscopic identification of the in-situ formed iron species, their structural characterization and detailed evaluation of their reactions with electrophiles. The expected outcome of the proposed work is a detailed understanding of active iron catalyst structures and reaction mechanisms in leading edge iron cross- coupling systems that will facilitate and inspire the development of novel reaction methodologies based upon this fundamental insight.