Fluoroalkyl‐Containing 1, 2‐Disubstituted Cyclobutanes: Advanced Building Blocks for Medicinal Chemistry. Issue 1 (9th December 2020)

• Record Type: Journal Article
• Authors: Demchuk, Oleksandr P.; Hryshchuk, Oleksandr V.; Vashchenko, Bohdan V.; Trofymchuk, Serhii A.; Melnykov, Kostiantyn P.; Skreminskiy, Artem; Volochnyuk, Dmitriy M.; Grygorenko, Oleksandr O.
• Is Part Of: European journal of organic chemistry. Issue 1(2021)
• Page Start: 87
• Page End: 95
• Publication Date: 2020-12-09
• Subjects: Amines -- Building blocks -- Carboxylic acids -- Cyclobutane -- Fluorine; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.202001345
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract: Synthesis of previously unavailable 1, 2‐disubstituted cyclobutane building blocks bearing mono‐, di‐ and trifluoromethyl groups are disclosed. The key steps included deoxofluorination or TMAF‐mediated nucleophilic substitution in the appropriate bifunctional cyclobutanes; for the CF3 ‐substituted derivatives, alternative methods based on cyano‐ or azidotrifluoromethylation of cyclobutene using the Togni reagent II were also proposed. All methods provided trans diastereomers of the target primary amines and carboxylic acids (6 representatives) and were suitable for their multigram preparation. Furthermore, dissociation constants (p K a ) and lipophilicity (log P ) values were measured to evaluate the effect of the fluoroalkyl substituents on acidity/basicity and lipophilicity of the building blocks obtained. Abstract : Scalable and efficient approaches towards the synthesis of 1, 2‐disubstituted mono‐, di‐, and trifluoromethylcyclobutane building blocks are reported. Physico‐chemical properties (i. e. p Ka and Log P ) of the title building blocks or derivatives thereof are measured and compared with those for the non‐fluorinated counterparts.