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).

Citation

Vladimir I Savych, Vladimir L Mykhalchuk, Pavlo V Melnychuk, Andrii O Isakov, Taras Savchuk, Vadim M Timoshenko, Sergiy A Siry, Sergiy O Pavlenko, Dmytro V Kovalenko, Oleksandr V Hryshchuk, Vitalii A Reznik, Bohdan A Chalyk, Vladimir S Yarmolchuk, Eduard B Rusanov, Pavel K Mykhailiuk. Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-Cycloaddition. The Journal of organic chemistry. 2021 Oct 01;86(19):13289-13309

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PMID: 34428062

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