Transition-Metal Catalyzed Carbon−Hydrogen Bond Functionalization Using Directing Groups



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Chapter 1: 1-Aminopyridinium ylides are efficient directing groups for palladium-catalyzed β-arylation and alkylation of sp3 C–H bonds in carboxylic acid derivatives. The efficiency of these directing groups depends on the substitution at the pyridine moiety. The unsubstituted pyridine-derived ylides allow functionalization of primary C–H bonds, while methylene groups are unreactive in the absence of external ligands. 4-Pyrrolidinopyridine-containing ylides are capable of C–H functionalization in acyclic methylene groups in the absence of external ligands, thus rivaling the efficiency of the aminoquinoline directing group. Preliminary mechanistic studies have been performed. A cyclopalladated intermediate has been isolated and characterized by X-ray crystallography, and its reactivity was studied. Chapter 2: The N-Aminopyridinium ylide-directing group was employed for copper-promoted chalcogenation of sp2 C–H bonds with aryl and alkyl disulfides as well as diphenyl diselenide. Reactions proceed in hexafluoroisopropanol (HFIP) solvent at elevated temperatures and are promoted by copper(II) acetate. Chapter 3: The preliminary results of ligand-accelerated arylation of primary sp3 C–H bonds at room temperature were reported and moderate yields of arylation products were obtained (up to 75%). In addition, these ligands also enable enantioselective arylation of secondary sp3 C–H bonds at ambient temperature, inducing up to 45% ee. Chapter 4: A method of palladium-catalyzed ring formation via twofold sp3 C–H functionalization was investigated. The reactions were carried out under silver-free conditions using dibromide electrophiles as coupling partners.



directing group, C-H activation, C-H functionalization, C-H bond, transition metal, catalyst


Portions of this document appear in: Le, K. K. A.; Nguyen, H.; Daugulis, O. 1-Aminopyridinium Ylides as Monodentate Directing Groups for sp3 C–H Bond Functionalization. J. Am. Chem. Soc. 2019, 84, 14728−14735. DOI: 10.1021/jacs.9b06643; and in: Nguyen, H.; Daugulis, O. N-Aminopyridinium Ylide-Directed, Copper-Promoted Chalcogenation of Arene C–H Bonds. J. Org. Chem. 2020, 85, 13069–13079. DOI: 10.1021/acs.joc.0c01757