Development of N-heterocyclic carbene ligands for transition-metal-catalysis

Functionalization reactions of π-systems enable highly efficient and selective C-C, C–O and C–N bond formation to construct some of the most fundamental functional motifs in synthetic chemistry. Specifically, hydration reactions of alkynes result in the formation of carbonyl compounds directly from broadly available alkyne feedstocks. This transformation was initially performed using mercury salts, however, concerns about toxicity spurred the development of alternative catalysts with the emergence of gold(I)-N-heterocyclic carbene complexes (N-heterocyclic carbene = NHC) as the most active catalysts developed to date. Based on mechanistic studies, the active species is a cationic [NHC–Au+] obtained by counterion abstraction from well-defined [NHC–Au–Cl] complexes. In this catalysis paradigm, N-heterocyclic carbene ligands provide strong Au(I)–NHC bond, preventing catalyst decomposition and increasing the stability and lifetime of the active Au(I) species. In a related avenue, the intramolecular cyclization of N-propargylic amides has emerged as a powerful strategy to construct medicinally-relevant oxazoline frameworks. This transformation proceeds via cationic gold(I)-mediated electrophilic activation of alkynes, followed by intramolecular nucleophilic attack by the amide moiety. The steric and electronic tunability of the carbene ligands play a decisive role in controlling the reaction pathway, suppressing side reactions, and enhancing both reactivity and selectivity.Furthermore, the development of bulky-yet-flexible NHC ligands has proven particularly effective in transition-metal catalysis, where the exceedingly large N-aryl wingtips provide highly effective steric protection around the metal center, while their conformational flexibility permits to accommodate key elementary steps of diverse catalytic cycles. In the last decade, sterically-demanding N-heterocyclic carbenes have evolved into exceptionally powerful ligands in homogeneous catalysis, enabling a broad spectrum of valuable synthetic transformations.With the above considerations in mind, the first part of this thesis describes the activation and functionalization of C–C, C–O and C–N bonds via sterically-demanding and conformationally-flexible Au(I)–N-heterocyclic carbene complexes. This part describes the development and application of biaryl imidazo[1,5-a]pyridine-2-ylidenes in cationic Au(I) catalyzed hydration of alkynes and cyclization of propargylic amides.The second part of this thesis describes the development of highly sterically demanding N-heterocyclic carbene ligands, focusing on their design, synthesis, and structural characterization. This part includes the development of highly hindered IPr**(4-Bp) ligands with biphenyl wingtip that extends beyond the metal coordination sphere and are characterized by the highest buried volume described to date. The third part of the thesis describes the development of ImQunArDipp, sterically-demanding-yet-flexible N-heterocyclic carbenes by exploiting imidazo[1,5-a]quinolin-1-ylidene architecture. In these ligands, the N2 wingtip mimics the steric properties of the classical imidazol-2-ylidene scaffold, while the C8 wingtip provides expanded flexibility, while extending well-beyond the metal coordination sphere. The fourth part of this thesis describes the development of cationic Au(I) complexes of quinone-annulated N-heterocyclic carbenes. These quinoline-based carbenes feature a significant enhancement of π-acceptor properties as well as additional steric demand around the metal center as a result of steric interaction of N-aryl wingtips with the carbonyl groups. These properties are critical for their high activity in a selection of processes, such as alkyne and nitrile hydration, alkyne hydroamination, alkyne hydroarylation, alkyne hydrophenoxylation, and alkyne cyclization reactions forming C–C, C–N, and C–O bonds, representing model reactions of π-activation of alkynes that are broadly applicable in organic synthesis.