trans -1,2-Disubstituted Cyclopropanes with CH ₂ -Extended Functional Groups: Synthesis and Physicochemical Properties
6 affiliations
- 1Enamine Ltd., Winston Churchill Street 78, Kyїv, Ukraine, 02094
- 2V. P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 1, Kyїv, Ukraine, 02066
- 3Enamine Scientific Research Institute, Winston Churchill Street 67, Kyїv, Ukraine, 02094
- 4Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyїv, Ukraine, 01601
- 5Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Akademik Kukhar Street 5, Kyїv, Ukraine, 02066
- 6Bienta/Enamine Ltd., Winston Churchill Street 78, Kyїv, Ukraine, 02094
Abstract
An efficient multigram synthesis of trans -1,2-disubstituted cyclopropane derivatives bearing two functional groups (including fluoroalkyl substituents), with one or both of them attached to the ring through a CH 2 spacer, was developed. The strategy was based on a Michael-initiated ring closure reaction (MIRC), followed by functional group transformations to provide a series of over 70 structurally diverse building blocks, including free carboxylic acids, amines, and other synthetically relevant derivatives, on up to 370 g scale. The methodology also enabled the preparation of fluorinated derivatives bearing CH 2 CF 3 , CH 2 CHF 2 , and CH 2 CH 2 F substituents. The combined effect of fluorination and the CH 2 spacer on key physicochemical properties was investigated through acidity/basicity (p K a ) and lipophilicity (Log P ) measurements. It was found that insertion of the spacer between the fluoroalkyl group and the cyclopropane ring increased pKa by 0.5–0.7 units for the carboxylic acids and by 1.1–1.5 units for the protonated amines, whereas its contribution to lipophilicity was lower than expected from additivity. Enumeration of a virtual library based on the proposed building blocks allowed us to demonstrate their potential for lead-oriented synthesis in drug discovery.
Related
- Modular synthesis of 3,3-diarylpropylamines via the photo- and copper-catalyzed 1,3-aminoarylation of cyclopropanes
- Gamma-irradiation applied to the synthesis of selenium nanoparticles and its influence on physicochemical properties
- Hydrothermal Zn–Fe Mixed Oxide Nanocatalysts: Influence of Synthesis Conditions on Physicochemical Properties, Acidity, and Catalytic Activity in the Biginelli Reaction
- Synthesis, Physicochemical Characterization, and Density Functional Theory Investigation of ZIL2 (3-(1,3-diethyl-1H-imidazol-3-ium-4-yl) propanoate)
- Synthesis of colloidal silver-polyphenols nanocomplexes - physicochemical properties, DFT calculation, modeling of adsorption and antibacterial activity
BibTeX
@misc{redka2026trans,
title = {{trans -1,2-Disubstituted Cyclopropanes with CH ₂ -Extended Functional Groups: Synthesis and Physicochemical Properties}},
author = {Mykhailo Redka and Oleksandr S. Liashuk and Dmytro Durylin and Andrii Hotynchan and Dmytro Lesyk and Petro Borysko and Oleksandr O. Grygorenko},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15011038/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011038/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - trans -1,2-Disubstituted Cyclopropanes with CH ₂ -Extended Functional Groups: Synthesis and Physicochemical Properties
AU - Mykhailo Redka
AU - Oleksandr S. Liashuk
AU - Dmytro Durylin
AU - Andrii Hotynchan
AU - Dmytro Lesyk
AU - Petro Borysko
AU - Oleksandr O. Grygorenko
PY - 2026
DA - 2026/10/26
PB - ChemRxiv
DO - 10.26434/chemrxiv.15011038/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011038/v1
AB - An efficient multigram synthesis of trans -1,2-disubstituted cyclopropane derivatives bearing two functional groups (including fluoroalkyl substituents), with one or both of them attached to the ring through a CH 2 spacer, was developed. The strategy was based on a Michael-initiated ring closure reaction (MIRC), followed by functional group transformations to provide a series of over 70 structurally diverse building blocks, including free carboxylic acids, amines, and other synthetically relevant derivatives, on up to 370 g scale. The methodology also enabled the preparation of fluorinated derivatives bearing CH 2 CF 3 , CH 2 CHF 2 , and CH 2 CH 2 F substituents. The combined effect of fluorination and the CH 2 spacer on key physicochemical properties was investigated through acidity/basicity (p K a ) and lipophilicity (Log P ) measurements. It was found that insertion of the spacer between the fluoroalkyl group and the cyclopropane ring increased pKa by 0.5–0.7 units for the carboxylic acids and by 1.1–1.5 units for the protonated amines, whereas its contribution to lipophilicity was lower than expected from additivity. Enumeration of a virtual library based on the proposed building blocks allowed us to demonstrate their potential for lead-oriented synthesis in drug discovery.
ER -