Synthesis of 3-Borylated Pyrrolidines by 1,3-Dipolar Cycloaddition of Alkenyl Boronates and Azomethine Ylide.

A scalable and efficient process for the preparation of 3-borylated pyrrolidines by 1,3-dipolar cycloaddition of N-benzyl azomethine ylide generated in situ has been developed. The optimized method included the use of LiF in DMSO at 110 °C and was suitable for α-mono-, α,ß-di-, and α,ß,ß-trialkyl-, ß,ß-(hetera)cycloalkylidene-, CO2 Et-, as well as most ß-(het)aryl-substituted alkenyl boropinacolates. The 1,3-dipolar reaction proceeded on a multigram scale providing 3-borylated pyrrolidines with diverse substitution patterns (including fused and spirocyclic ones) in a diastereoselective manner. The Pd(OH)2 -mediated N-debenzylation of pyrrolidine hydrochlorides was successfully performed to give the corresponding bifunctional building blocks on an up to 130 g scale, thus providing a substantial expansion of the synthetic and medicinal chemist's toolbox. Other reactions included the preparation of trifluoroborates, Zweifel-Aggarwal sp3 -sp2 coupling, and oxidative deborylation as an example of C-heteroatom bond formation.

Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-Cycloaddition.

A general approach to bicyclic fused pyrrolidines via [3 + 2]-cycloaddition between nonstabilized azomethyne ylide and endocyclic electron-deficient alkenes was elaborated. "Push-pull" alkenes and CF3-alkenes did not react with the azomethyne ylide under the previously reported conditions, and we developed a superior protocol (LiF, 140 °C, no solvent). Among obtained products were medchem-relevant bicyclic sulfones, monofluoro-, difluoro-, and trifluoromethyl-substituted pyrrolidines. This approach not only allowed preparation of novel molecules but also significantly simplified synthesis of the existing ones (e.g., sofinicline).