Leveraging the Domino Skeletal Expansion of Thia-/Selenazolidinones via Nitrogen-Atom Transfer in Hexafluoroisopropanol: Room Temperature Access to Six-Membered S/Se,N-Heterocycles

Herein, a highly regioselective domino skeletal-expansion process that transforms 2-aminothiazolidinone into six-membered S,N-heterocycle is developed with the aid of TMS-azide in hexafluoroisopropanol (HFIP) at ambient temperature. Functioning of the C2 tertiary amine as latent reactive group on thiazolidinone moiety was the key to this development, which allowed relay substitution with azide and imparted subsequent ring-expansion under metal/acid free-conditions. The reaction also underscored an intermolecular nitrogen-atom transfer process from TMS-azide leading to final products, where any intermediary azidothiazolidinone was absent. The strategy was extendable to analogous synthesis of Se,N-heterocycles, and furthermore, late-stage drug-modification and follow-up transformations were also performed. Density functional theory calculations and control experiments provided important mechanistic insights and highlighted potential roles of HFIP in the transformation.

Automated summary

A highly regioselective domino skeletal-expansion process has been developed to transform 2-aminothiazolidinone into six-membered S,N-heterocycle, utilizing TMS-azide in HFIP at ambient temperature. The C2 tertiary amine functioned as a latent reactive group, allowing relay substitution with azide and subsequent ring-expansion under metal/acid free-conditions. The strategy showed potential for synthesis of Se,N-heterocycles and late-stage drug-modification.