Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor–Acceptor Cyclopropanes and Anilines/Benzylamines

Abstract

We developed a straightforward synthetic route to pharmacologically important 1,5-substituted pyrrolidin-2-ones from donor–acceptor cyclopropanes bearing an ester group as one of the acceptor substituents. This method includes a Lewis acid-catalyzed opening of the donor–acceptor cyclopropane with primary amines (anilines, benzylamines, etc.) to γ-amino esters, followed by in situ lactamization and dealkoxycarbonylation. The reaction has a broad scope of applicability; a variety of substituted anilines, benzylamines, and other primary amines as well as a wide range of donor–acceptor cyclopropanes bearing (hetero)aromatic or alkenyl donor groups and various acceptor substituents can be involved in this transformation. In this process, donor–acceptor cyclopropanes react as 1,4-C,C-dielectrophiles, and amines react as 1,1-dinucleophiles. The resulting di- and trisubstituted pyrrolidin-2-ones can be also used in subsequent chemistry to obtain various nitrogen-containing polycyclic compounds of interest to medicinal chemistry and pharmacology, such as benz[g]indolizidine derivatives.

Keywords

• donor–acceptor cyclopropanes
• primary amines
• pyrrolidin-2-ones
• benz[<i>g</i>]indolizidines