3‐Fluoroalkyl (CF3, CHF2, CH2F) Cyclobutane‐Derived Building Blocks for Medicinal Chemistry: Synthesis and Physicochemical Properties

• Published in: European journal of organic chemistry Vol. 26; no. 24
• Main Authors: Demchuk, Oleksandr P., Bobovskyi, Bohdan V., Vashchenko, Bohdan V., Hryshchuk, Oleksandr V., Skreminskyi, Artem, Chernykh, Anton V., Moskvina, Viktoriia S., Hordiyenko, Olga V., Volochnyuk, Dmitriy M., Grygorenko, Oleksandr O.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 21-06-2023
• Subjects: Amines; amines carboxylic acids; building blocks; Carboxylic acids; Chemical synthesis; Cyclobutane; Fluorination; fluorine; Substitutes; Substrates
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202300292

Synthesis and physicochemical characterization of all possible cis‐ and trans‐1,3‐disubstituted cyclobutane‐derived amines and carboxylic acids bearing mono‐, di‐ and trifluoromethyl groups at the C‐3 position is disclosed. Tetramethylammonium fluoride (TMAF)‐ or morpholinosulfur trifluoride (Morph‐DAST)‐mediated nucleophilic fluorination of appropriate cis‐ and trans‐diastereomeric substrates was used as the key step for the preparation of CH2F‐ and CHF2‐substituted derivatives. To obtain the corresponding cis‐ and trans‐isomeric CF3‐substituted derivatives, resolution of known 3‐(trifluoromethyl)cyclobutanecarboxylic acid (obtained as a mixture of diastereomers) was applied. The proposed procedures were suitable for the preparation of corresponding fluoroalkyl‐substituted cyclobutane‐derived amines and carboxylic acids on up to 50 g scale. All 12 building blocks obtained were characterized by measuring dissociation constants (pKa) and lipophilicities (LogP, for model derivatives) to evaluate the effect of the fluoroalkyl substituents on their physicochemical properties relevant to further drug discovery applications.
Scalable and efficient approaches towards the synthesis of cis‐ and trans‐1,3‐disubstituted mono‐, di‐ and trifluoromethylcyclobutane building blocks are disclosed. Effects of the fluoroalkyl substituents and other structural features on their physicochemical properties (pKa, LogP, and aqueous solubility) are evaluated.