Cobalt-catalyzed directed ortho-C-H alkylation of arenes via radical processes
Date of Issue2019
School of Physical and Mathematical Sciences
Alkylated arenes are important structural moieties that are prevalent in many natural products, pharmaceuticals and functional materials. Therefore, significant efforts from the synthetic community have been devoted to the synthesis of these structural motifs. In this context, transition metal-catalyzed, directing group-assisted arene C–H alkylation represents an attractive means for the introduction of alkyl groups to arenes because of the atom- and step-economical nature of the process as well as the predictable regioselectivity. In particular, C–H alkylation using alkyl halides as the alkylating agents has been extensively developed over the last decade, using precious transition metal catalysts as well as earth-abundant first-row transition metal catalysts. The latter catalysts have received significant attention not only for their cost-effectiveness but also for their distinct mode of activation of alkyl halides, that is, single electron transfer to generate alkyl radicals. Given the above background, this thesis research has focused on the development of cobalt-catalyzed directed ortho-C–H alkylation reactions of arenes with novel alkylating agents, capitalizing on the radical nature of the cobalt catalysis. Chapter 1 describes a brief review of the transition metal-catalyzed alkylation of arenes, with a particular focus on aryl-alkyl cross-coupling and directed arene C–H alkylation reactions using first-row transition metals including cobalt. The single electron transfer from an arylmetal species to an alkyl halide, which is commonly involved in these reactions, has provided inspiration for this thesis work. Specifically, reaction systems comprised of cobalt–N-heterocyclic carbene (NHC) catalysts and Grignard reagents, which have proved successful in a series of cross-coupling and C–H functionalization reactions, allowed the design of the whole project. Chapter 2 describes a C(sp2)–H/C(sp3)–H coupling reaction between aryl imines and 2-bromobenzyl-protected secondary amines promoted by the combination of a cobalt–NHC catalyst and a Grignard reagent. Featuring a merger of directed C–H activation and 1,5-hydrogen atom transfer, the reaction allows for ortho-α-aminoalkylation of the aryl imine at a mild temperature. Chapter 3 describes a tandem radical cyclization/C–C coupling between tethered bromo-alkenes and aryl N–H imines initiated by imine-directed C–H activation. Fine-tuning of the NHC ligand allowed the reaction to proceed smoothly, allowing for the introduction of a pyrrolidinylmethyl group to the ortho position of the imine. Chapter 4 describes ortho-methylation of arenes using methyl tosylate as a readily available and convenient methylation agent. Using CD3OTs instead of MeOTs, the reaction also allows facile incorporation of a CD3 group into arenes. Lastly, Chapter 5 is a concluding chapter that summarizes the whole thesis research.