This talk describes the development of a mild, highly functional group tolerant and metal-free C-H aminoalkylation of azoles via high throughput experimentation (HTE). A base screen provides insight into the effect of exogenous bases on the reactivity, identifying iPr2NEt as a key component of the reaction mixture. The novel method allows C-H functionalization of a wide range of azoles, including oxazoles, benzoxazoles, thiazoles, imidazoles, and benzimidazoles, in the presence of functional groups such as alkynes, amides, ketones, and other heterocycles. This demonstrates the suitability of the reaction conditions for employment in relatively complex molecular settings. Furthermore, the robustness of the protocol is demonstrated by adapting the protocol to a standard parallel medicinal chemistry workflow, thus showcasing its ability to synthesize a range diversified products in the same process. DFT analysis of the proposed mechanism allows the identification of an important azole deprotonation equilibrium that determines reactivity of the employed substrates. Based on these data, we postulate that the role of the Lewis acid R3SiOTf is to acidify the azole substrate by formation of a N-silylated intermediate. Overall, this talk outlines a novel strategy to diversify azoles by silyl triflate mediated C-H functionalization under milder conditions than those typically employed with transition metal catalysts or metalation strategies.

Mild C-H aminoalkylation of azoles via silyl-triflate mediated three component coupling

ACS Spring Meeting 2021

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