Direct alpha-Amination of Amides and Lactams Enabled by the (3+2) Vinyl Azide-Enolate Cycloaddition Manifold

27 May 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Direct alpha-amination of carbonyl compounds remains an important yet synthetically challenging transformation. Here we report a solution for direct alpha-amination of amides and lactams, identified through fundamental exploration of (3+2) vinyl azide-enolate cycloaddition chemistry. Initial cycloadducts undergo rearrangement via 1,2-N-migration to afford imine intermediates that are readily converted to the target alpha-amino amides or lactams. The sequence requires no pre-functionalisation, can be performed on a range of substrates, including compound classes unsuccessful using reported methods, and delivers primary or secondary alpha-amines. This work highlights the diversity and synthetic potential of the rapidly expanding (3+2) azide-enolate cycloaddition manifold.

Keywords

alpha-Amination
Cycloaddition
Vinyl azides
Nitrogen migration
Reaction mechanisms

Supplementary materials

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Description
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Supporting Information
Description
Experimental procedures, additional reaction optimisation data, unsuccessful substrates, NMR spectra and computational information.
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