The catalytic enantioselective preparation of densely functionalized amines is a fundamental synthetic challenge. To address this challenge, we report for the first time that the Winstein rearrangement can be enlisted as the racemization pathway in a dynamic kinetic resolution of allylic azides. Alkene functionalization by Sharpless dihydroxylation affords tertiary azides in excellent enantioselectivity (up to 99:1 er). This approach establishes the chirality of the tertiary azide, obviates the need to directly forge either a congested C-N or C-C bond at the new nitrogenous stereocenter, and establishes additional functionality. Several examples demonstrate further elaboration of this functionality.
The spontaneous rearrangement of allylic azides is thought to be a sigmatropic reaction. Presented herein is a detailed investigation into the rearrangement of several allylic azides. A combination of experiments including equilibrium studies, kinetic analysis, density functional theory calculations, and selective N-isotopic labeling are included. We conclude that the Winstein rearrangement occurs by the assumed sigmatropic pathway under most conditions. However, racemization was observed for some cyclic allylic azides. A kinetic analysis of this process is provided, which supports a previously undescribed ionic pathway.
Allylic azides are underutilized in organic synthesis when compared to other organic azides or other allylic functionality. This is likely because allylic azides rearrange at room temperature, resulting in a potentially complex mixture of azides. This rearrangement has been termed the Winstein rearrangement. Understanding the mechanism and basic principles governing the allylic azide equilibrium may aid in developing applications for these molecules based on either alkene or azide functionalization. Presented herein is a compilation of the key observations regarding the nature of the allylic azide rearrangement. Mechanistic considerations are explicitly addressed with key examples from the literature.
An enantioselective copper-catalyzed azide− alkyne cycloaddition (E-CuAAC) is reported by kinetic resolution. Chiral triazoles were isolated in high yield with limiting alkyne (up to 97:3 enantiomeric ratio (er)). A range of substrates were tolerated (>30 examples), and the reaction was scaled to >1 g. The er of a triazole product could be enhanced by recrystallization and the recovered scalemic azide could be racemized and recycled. Recycling the azide allows efficient use of the undesired azide enantiomer.
Triazoles are privileged heterocycles for a variety of applications. The synthesis of 1H-triazoles can be accomplished by the Banert cascade from propargylic azides. Depending on the substrate and conditions, the Banert cascade can proceed by either a sigmatropic or prototropic mechanism. This report describes the first detailed kinetic analysis of the Banert cascade proceeding by both pathways including substituent effects and KIE. The analysis identified the inflection point in the divergent pathways, allowing future work to predict which Banert products are accessible.
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