Synthesis and Physicochemical Characteristics of 6,6-Difluorobicyclo[3.2.0]heptane Derivatives

Bohdan L. Moroz; Serhii M. Holovach; Kostiantyn P. Melnykov; Dmytro S. Lesyk; Andriy A. Filatov; Oleksandr O. Grygorenko

doi:10.24959/ophcj.24.314176

Authors

Bohdan L. Moroz Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd., Ukraine https://orcid.org/0009-0002-8989-0451
Serhii M. Holovach Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Enamine Ltd., Ukraine https://orcid.org/0009-0004-2214-1880
Kostiantyn P. Melnykov Enamine Ltd.; Taras Shevchenko National University of Kyiv, Ukraine https://orcid.org/0009-0003-6522-681X
Dmytro S. Lesyk Enamine Ltd.; Taras Shevchenko National University of Kyiv, Ukraine https://orcid.org/0009-0001-3391-5165
Andriy A. Filatov Enamine Ltd.; Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0002-1921-213X
Oleksandr O. Grygorenko Enamine Ltd.; Taras Shevchenko National University of Kyiv, Ukraine https://orcid.org/0000-0002-6036-5859

DOI:

https://doi.org/10.24959/ophcj.24.314176

Keywords:

fluorine, bicyclic compounds, acidity, lipophilicity, building blocks

Abstract

The gram-scale synthesis of 6,6-difluorobicyclo[3.2.0]heptane-derived building blocks (i.e., primary amine and carboxylic acid) was performed via the deoxofluorination of the corresponding bicyclic keto ester with diethylaminosulfur trifluride (DAST). Physicochemical properties of the compounds obtained (i.e., pK_a) or their model benzamide / anilide derivatives (i.e., LogP) were determined experimentally and compared to those of monocyclic and non-fluorinated bicyclic counterparts. It was found that gem-difluorination expectedly decreased the pK_a values by 0.3 - 0.5 units, whereas the LogP values were decreased by 0.54 - 0.55 units. Meanwhile, the bicyclic system itself had a negligible impact on the compounds’ acidity and lipophilicity compared to the monocyclic counterparts.

Supporting Agency

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

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