Highly functionalized azole scaffolds are common target molecules in drug discovery, however, mild and efficient diversifying routes towards such building blocks are underdeveloped. Typical synthetic strategies consist of multi-step, de-novo syntheses of the azole core or metal catalyzed late-stage functionalization protocols employing harsh reaction conditions while showing often a high substrate dependence. This talk will present a novel strategy of a mild, silyl triflate mediated C-H aminoalkylation of azole scaffolds via a three-component coupling approach. The unique reactivity allows access to a diverse platform of highly functionalized azole scaffolds, including oxazoles, benzoxazoles, thiazoles, imidazoles, and benzimidazoles while tolerating functional groups such as alkynes, amides, ketones, and other heterocycles. Density functional theory (DFT) is applied to investigate the reaction mechanism, which identified an azole deprotonation equilibrium as key step of the reaction, determining the reactivity of the given azole substrate. The elucidation of the reaction mechanism highlights the unique role of the Lewis acid R3SiOTf, acidifying the C-2 position of the azole substrate resulting in a reactive N-silylated intermediate. Overall, this talk will present a promising strategy of a mild, silyl triflate mediated C-H functionalization of azole scaffolds, developed via high throughput experimentation (HTE) and its translation towards new C-C bond formations by applying different electrophile sources.

Direct C-H functionalization of azoles via silyl triflate activation

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.