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

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.