Issue 11, 2021

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.

Graphical abstract: Lewis acid mediated, mild C–H aminoalkylation of azoles via three component coupling

Supplementary files

Article information

Article type
Edge Article
Submitted
16 dec 2020
Accepted
02 feb 2021
First published
05 feb 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 3890-3897

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

M. H. Emmert, C. Q. He, A. A. Shah and S. Felten, Chem. Sci., 2021, 12, 3890 DOI: 10.1039/D0SC06868C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements