Scaffold Hopping of α,β-Unsaturated Ketones via Divergent Alkyl Amine Insertion

Huiguang Yu，Lili Xu，Luyao Li，Chang Min*

JACS 2025

https://pubs.acs.org/doi/10.1021/jacs.5c06690

Abstract

α,β-Unsaturated carbonyl compounds are pivotal intermediates in organic synthesis, widely utilized in nucleophilic addition reactions for constructing C–C and C–heteroatom bonds. Primary amines are essential building blocks in drug discovery, and their reactions with α,β-unsaturated carbonyl compounds yield key intermediates for pharmaceuticals, natural products, and bioactive molecules. Traditional methods often emphasize 1,2- or 1,4-additions, targeting peripheral modifications. Meanwhile, skeletal nitrogen-insertion reactions are primarily effective with electron-rich alkenes or saturated ketone sites, while the direct editing of α,β-unsaturated ketones is typically limited to problematic Schmidt reactions. In this study, we realize a divergent skeletal editing strategy for α,β-unsaturated ketones via 2,3- and 3,4-amine insertion. This approach facilitates the selective incorporation of alkyl amines between C–C bonds within the same substrate. Our reagent-controlled protocol enables tunable insertion sites through regioselective aziridine intermediate formation and targeted C–C bond cleavage, producing most amine insertion products in a one-pot process. Importantly, this strategy provides differential and complementary regioselectivity to traditional Schmidt reactions, allowing selective synthesis of various pyridyl isomers from a single substrate, including complex natural products and drug candidates.