2‐ and 3‐Fluorocyclobutane Building Blocks for Organic and Medicinal Chemistry

• Published in: European journal of organic chemistry Vol. 27; no. 32
• Main Authors: Malashchuk, Andrii, Demchuk, Oleksandr P., Razhyk, Bohdan V., Holumbievskyi, Vitalii O., Kudryk, Oleksandr V., Chernykh, Anton V., Hryshchuk, Oleksandr V., Sosunovych, Bohdan S., Volochnyuk, Dmytro M., Vashchenko, Bohdan V., Grygorenko, Oleksandr O.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 26-08-2024
• Subjects: acidity; Alcohols; Amines; Bromides; building blocks; Chemical synthesis; Cyclobutane; Fluorination; Fluorine; Functional groups; lipophilicity; Orientation effects; Position measurement; Stereoisomerism; Thiols
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202400493

Multigram synthesis of 3‐fluorinated cyclobutane building blocks has been disclosed. The proposed synthetic schemes were based on nucleophilic fluorination and eventually led to 3‐fluorocyclocutanecarboxylic acid as a key target compound and intermediate. Further functional group transformations provided monofluorinated cyclobutane‐derived alcohols, amines, bromides, thiols, sulfonyl chlorides, etc. Furthermore, the synthesis of diastereopure cis‐ and trans‐isomeric 2‐ and 3‐fluorocyclobutanecarboxylic acids and amines was also performed. In both cases, diastereomer separation was used to obtain pure stereoisomers. The effect of the fluorine position and relative spatial orientation on the physicochemical properties of the corresponding monoflurinated derivatives was studied by measurements of pKa and logP values.
Multigram synthesis of 2‐ and 3‐monofluorinated cyclobutane building blocks was disclosed. In both cases, fluorocyclobutanecarboxylic acids were the key intermediates used to obtain all other derivatives, e. g., amines, alcohols, bromides, thiols, sulfonyl chlorides, etc. For both target chemotypes, diastereopure cis‐ and trans‐isomers of the corresponding carboxylic acids and amines were obtained through diastereomer separation. Characterization of 2‐ and 3‐fluorocyclobutyl substituents by pKa and LogP measurements for the model derivatives was also performed.