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Lewis acid mediated, mild C-H aminoalkylation of azoles via three component coupling.

ABSTRACT: This manuscript reports the development of a mild, highly functional group tolerant and metal-free C-H aminoalkylation of azoles via a three-component coupling approach. This method enables the C-H functionalization of diverse azole substrates, such as oxazoles, benzoxazoles, thiazoles, benzothiazoles, imidazoles, and benzimidazoles. DFT calculations identify a key deprotonation equilibrium in the mechanism of the reaction. Using DFT as a predictive tool, the C-H aminoalkylation of initially unreactive substrates (imidazoles/benzimidazoles) can be enabled through an in situ protecting/activating group strategy. The DFT-supported mechanistic pathway proposes key interactions between the azole substrate and the Lewis acid/base pair TBSOTf/EtNⁱPr₂ that lead to azole activation by deprotonation, followed by C-C bond formation between a carbene intermediate and an iminium electrophile. Two diverse approaches are demonstrated to explore the amine substrate scope: (i) a DFT-guided predictive analysis of amine components that relates reactivity to distortion of the iminium intermediates in the computed transition state structures; and (ii) a parallel medicinal chemistry workflow enabling synthesis and isolation of several diversified products at the same time. Overall, the presented work enables a metal-free approach to azole C-H functionalization via Lewis acid mediated azole C-H deprotonation, demonstrating the potential of a readily available, Si-based Lewis acid to mediate new C-C bond formations.

SUBMITTER: Emmert MH

PROVIDER: S-EPMC8179430 | biostudies-literature |

REPOSITORIES: biostudies-literature

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