Incorporation of gem-Difluorocycloalkyl Substituents into Heterocycles via the Levin’s “Nitrogen Deletion” Strategy




cycloalkanes, fluorine, Levin’s anomeric amide, “Nitrogen deletion”, reductive amination


A series of compounds containing heterocyclic cores and gem-difluorocycloalkyl substituents was obtained under conditions of the parallel synthesis (i.e., simultaneous performance of reaction procedures, treatment of the reaction mixture, and product isolation for a number of similar transformations) using the reductive amination – the “Nitrogen deletion” reaction sequence. The synthesis of the target compounds commenced from heteroaromatic aldehydes and the corresponding gem-difluorocycloalkyl or (gem-difluorocycloalkyl)methyl amines and included the NaBH3CN-mediated reductive amination and “Nitrogen deletion” upon the action of Levin’s anomeric amide. It has been shown that the method can be used to obtain compounds with the aforementioned structural fragments separated by one or two methylene units. The developed protocol allowed for the preparation of a 12-member compound library (67 % synthetic efficiency). Therefore, this novel synthetic methodology is suitable for decorating heterocyclic cores with sp3-enriched substituents that are attractive for medicinal chemistry.

Supporting Agency

  • The work was supported by Enamine Ltd., the Ministry of Education and Science of Ukraine (grants No. 0121U100387 (21BF037-01M) and 0122U001962 (22BF037-02)), and National Academy of Sciences of Ukraine (grant No. 0119U102718).


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How to Cite

Holovach, S. M.; Melnykov, K. P.; Poluektova, M. S.; Rozhenko, O. B.; Grygorenko, O. O. Incorporation of Gem-Difluorocycloalkyl Substituents into Heterocycles via the Levin’s “Nitrogen Deletion” Strategy. J. Org. Pharm. Chem. 2023, 21, 11-16.



Original Researches