Multigram Synthesis of 4,4-disubstituted-3-oxopyrrolidones – efficient starting material for diverse 3 functionalized pyrrolidones

The practical rapid development of chemical leads for drug discovery is strongly dependent on scalable procedures for building block synthesis. N-heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them. 4,4-disubstituted-3-oxopyrrolidones synthesis was an essential milestone in the diversity-oriented production of 3-aminopyrrolidones, 3-hydroxypyrrolidones and 3,3’-difluoropyrrolidines. Those can be functionalized with conformationally flexible spirocyclic substituents. We developed the multigram procedure for 4,4-disubstituted-3-oxopyrrolidones from commercially accessible and cost-saving reagents via the short three-step procedure. Also, here we are reporting the robust conversion procedure of 3-oxopyrrolidones to 3-aminopyrrolidones, 3,3’-difluoropyrrolidones and 3-hydroxypyrrolidones, involving a minimal amount of steps. We demonstrate the scope and limitations and further perspectives for such synthetic approaches.